Mallinckrodt Inc.

Manufacturer Details

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Mallinckrodt Inc. Drugs

Morphine Sulfate

Morphine Sulfate

2.1    Initial Dosing

Morphine sulfate extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with morphine sulfate extended-release tablets [see Warnings and Precautions (5.2)].

Morphine sulfate extended-release tablets must be taken whole. Crushing, chewing, or dissolving morphine sulfate extended-release tablets will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)].

Use of Morphine Sulfate Extended-Release Tablets as the First Opioid Analgesic

Initiate treatment with morphine sulfate extended-release tablets with 15 mg tablets orally every 8 or 12 hours.

Use of Morphine Sulfate Extended-Release Tablets in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is morphine sulfate extended-release tablets 15 mg orally every 12 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Oral Morphine to Morphine Sulfate Extended-Release Tablets

Patients receiving other oral morphine formulations may be converted to morphine sulfate extended-release tablets by administering one-half of the patient's 24-hour requirement as morphine sulfate extended-release tablets on an every-12-hour schedule or by administering one-third of the patient's daily requirement as morphine sulfate extended-release tablets on an every-8-hour schedule.

Conversion from Other Opioids to Morphine Sulfate Extended-Release Tablets

There are no established conversion ratios for conversion from other opioids to morphine sulfate extended-release tablets defined by clinical trials. Discontinue all other around-the-clock opioid drugs when morphine sulfate extended-release tablets therapy is initiated and initiate dosing using morphine sulfate extended-release tablets 15 mg orally every 8 to 12 hours.

It is safer to underestimate a patient’s 24-hour oral morphine requirements and provide rescue medication (e.g., immediate-release morphine) than to overestimate the 24-hour oral morphine requirements and manage an adverse reaction. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products.

Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Morphine Sulfate Extended-Release Tablets

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to morphine sulfate extended-release tablets, consider the following general points:

Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient.

Other parenteral or oral non-morphine opioids to oral morphine sulfate: Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine.

Conversion from Methadone to Morphine Sulfate Extended-Release Tablets

Close monitoring is of particular importance when converting methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2    Titration and Maintenance of Therapy

Individually titrate morphine sulfate extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dose increase of morphine sulfate extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate extended-release tablets dose. Because steady-state plasma concentrations are approximated in 1 day, morphine sulfate extended-release tablets dosage adjustments may be done every 1 to 2 days.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3    Discontinuation of Morphine Sulfate Extended-Release Tablets

When the patient no longer requires therapy with morphine sulfate extended-release tablets, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue morphine sulfate extended-release tablets.

2.4    Administration of Morphine Sulfate Extended-Release Tablets

Morphine sulfate extended-release tablets must be taken whole. Crushing, chewing, or dissolving morphine sulfate extended-release tablets will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)].
Ultra-technekow V4

Ultra-technekow V4

Sodium Pertechnetate Tc 99m is administered by intravenous injection. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose.

For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder.

The suggested dose ranges employed for various diagnostic indications in the average ADULT PATIENT (70 kg) are as follows:

Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi)Thyroid gland imaging: 37 to 370 MBq (1 to 10 mCi)Salivary gland imaging: 37 to 185 MBq (1 to 5 mCi)Nasolacrimal drainage system: Maximum dose of 3.7 MBq (100 µCi)

The recommended dosages in PEDIATRIC PATIENTS are:

Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi)Thyroid gland imaging: 2.22 to 2.96 MBq (60 to 80 µCi) per kg body weight

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If the solution is discolored, discontinue use of the generator immediately. The solution to be administered as the patient dose should be clear, colorless, and contain no particulate matter.

Radiation Dosimetry

The estimated absorbed radiation doses to an average ADULT and PEDIATRIC patient from an intravenous injection of various doses of Sodium Pertechnetate Tc 99m distributed uniformly in the total body are shown in Tables 5 and 6.

Table 5. Absorbed Radiation Doses from Intravenous Injection

Organ

Absorbed Radiation Dose (mGy) for a 1110 MBq (30mCi) dose

Adrenals

4.1

Urinary Bladder Wall

20

Bone Surfaces

6.2

Brain

2.2

Breasts

2

Gallbladder Wall

8.3

Stomach Wall

29

Small Intestine

18

ULI Wall

63

LLI Wall

23

Heart Wall

3.5

Kidneys

6

Liver

4.7

Lungs

2.9

Muscle

3.6

Ovaries

11

Pancreas

6.3

Red Marrow

4.1

Skin

2

Spleen

4.8

Testes

3.1

Thymus

2.7

Thyroid

24

Uterus

9

Remaining Tissues

3.9

Effective Dose (mSv)

14

To obtain radiation absorbed dose in rads (30 mCi dose) from the above table, divide individual organ values by a factor of 10 (does not apply for effective dose).

Table 6. Pediatric Absorbed Radiation Doses (mGy) from Intravenous Injection

Age

15 years

10 years

5 years

1 year

Administered activity in MBq (mCi)

1110 (30)

740 (20)

555 (15)

370 (10)

Organ

Adrenals

5.3

5.4

6.2

7.1

Urinary Bladder Wall

26

22

18

22

Bone Surfaces

7.6

7.5

8.1

10

Brain

2.8

3.1

3.7

4.5

Breasts

2.6

2.6

3.2

4.1

Gallbladder Wall

11

12

13

13

Stomach Wall

38

36

43

59

Small Intestine

22

23

26

30

ULI Wall

81

89

110

140

LLI Wall

31

33

40

48

Heart Wall

4.5

4.6

5.2

6.4

Kidneys

7.2

6.9

7.8

8.5

Liver

6

6.7

8

9.1

Lungs

3.8

3.8

4.4

5.3

Muscle

4.5

4.5

5

6

Ovaries

14

13

14

17

Pancreas

8.1

8.2

8.9

10

Red Marrow

5.1

5

5.2

6

Skin

2.5

2.6

3.2

3.8

Spleen

6

6

6.7

7.8

Testes

4.1

4.3

4.9

6

Thymus

3.6

3.5

4.2

5.3

Thyroid

40

41

67

81

Uterus

11

11

12

14

Remaining Tissues

4.8

4.8

5.4

6.4

Effective Dose (mSv)

19

19

23

29

To obtain radiation absorbed dose in rads (30 mCi dose) from the above table, divide individual organ values by a factor of 10 (does not apply for effective dose).

The estimated absorbed radiation doses to an ADULT patient from the nasolacrimal imaging procedure using a maximum dose of 3.7 megabecquerels (100 microcuries) of Sodium Pertechnetate Tc 99m are shown in Table 7.

Table 7. Absorbed Radiation Doses from Dacryoscintigraphy

Tissue

3.7 MBq (100 µCi)Dose of Sodium Pertechnetate Tc 99m

mGy

rad

Eye Lens:

If lacrimal fluid turnover is 16%/min

0.140

0.014

If lacrimal fluidturnover is 100%/min

0.022

0.002

If drainagesystem is blocked

4.020

0.402

Total Body*

0.011

0.001

Ovaries*

0.030

0.003

Testes*

0.009

0.001

Thyroid*

0.130

0.013

*Assuming no blockage of draining system.

In pediatric patients, an average 30 minute exposure to 37 MBq (1 mCi) of Tc-99m pertechnetate following instillation for direct cystography, will result in the following estimated radiation doses:

Table 8. Absorbed Radiation Doses from Cystography (PEDIATRIC)

Age

Bladder wall dose, mGy (rad)

Gonadal dose, mGy (rad)

1 year

3.6 (0.36)

0.15 (0.015)

5 years

2.0 (0.2)

0.095 (0.0095)

10 years

1.3 (0.13)

0.066 (0.0066)

15 years

0.92 (0.092)

0.046 (0.0046)
Neutrospec

Neutrospec

Adults

To prepare NeutroSpecTM the reaction vial containing fanolesomab is reconstituted with sodium pertechnetate Tc 99m Injection, USP solution prior to use. (See INSTRUCTIONS FOR PREPARATION).

Fanolesomab is not intended for direct administration to the patient without reconstitution and labeling with sodium pertechnetate Tc 99m Injection, USP. NeutroSpecTM [Technetium (99m Tc) fanolesomab] is intended for a single intravenous (IV) administration through an intravenous access that has been demonstrated to be patent, e.g., butterfly, running IV line, or equivalent injection system to assure that no dose infiltration occurs. Following administration, flush the injection line with an appropriate volume of saline to assure administration of the total dose.

For imaging, 75 to 125 mcg of fanolesomab is labeled with 10 to 20 mCi (370 to 740 MBq) and administered as a single dose of NeutroSpecTM.

Planar imaging should be performed using a large field of view camera fitted with a low-energy, parallel-hole, high-resolution collimator. The camera should be positioned so that the lower edge of the liver is at the upper end of the field of view at the midline of the patient.

Dynamic image acquisition over the lower abdomen should begin at the time of injection and consist of 10 sequential four-minute images. Following dynamic image acquisition, the patient should ambulate for approximately 10 to 15 minutes and void. Static planar images should then be collected, including supine anterior, posterior, 10–25 degree RAO and LAO views of the lower abdomen, followed by a standing anterior image of the lower abdomen. After the camera has been positioned (as described above), it is recommended that a total of one million counts be collected for the anterior supine image. All remaining images should be collected for the same duration of time required for the anterior supine image.

Children (Five years and older)

NeutroSpecTM is administered in a single dose of 0.21 mCi/kg to a maximum of 20 mCi. Recommended imaging times and procedures are the same as for adults.

Dose adjustment has not been established in patients with renal insufficiency, in geriatric patients or in pediatric patients under five years of age.

Image Interpretation

The biodistribution of the NeutroSpecTM radiopharmaceutical is imaged in the blood pool, reticuloendothelial system (liver, spleen, bone marrow), and urinary excretion organs (kidneys and urinary tract). Imaging of the uterus has been noted, consistent with blood pool activity of NeutroSpecTM.

In the 200-patient clinical trial (see CLINICAL STUDIES), based on the average of the three blinded reader interpretations, 75% of the 59 true positive cases of appendicitis were identified (range 66-81%).

Among those with a blinded diagnosis of appendicitis, 76% displayed uptake of radiotracer activity in the appendix within 30 minutes following injection and 98% did so by 60 minutes following injection.

In the trial the acquisition of image collection was performed for a 90 minute period. The image finding of a persistent or intensifying uptake in the right lower quadrant (appendix zone) that is seen before the completion of the entire imaging sequence may be considered a positive study, and imaging may be terminated at this time. In the case of a negative image finding at 30 and 60 minutes, collection to 90 minutes is recommended prior to termination of the study.

A diagnostic abnormality is characterized by the presence of an irregular, asymmetric uptake of radiotracer localized in the right lower quadrant of the abdomen. The abnormal localization of radiotracer remains constant or increases in intensity in follow up imaging.
Neutrogena Skinclearing...

Neutrogena Skinclearing

The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride capsules in 520 adults, and 91 children and adolescents with OCD. During initial titration, clomipramine hydrochloride capsules should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.

Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change (see CLINICAL PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.

Initial Treatment/Dose Adjustment (Adults)

Treatment with clomipramine hydrochloride capsules should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, clomipramine hydrochloride capsules should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Initial Treatment/Dose Adjustment (Children and Adolescents)

As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS, Pediatric Use). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Maintenance/Continuation Treatment (Adults, Children, and Adolescents)

While there are no systematic studies that answer the question of how long to continue clomipramine hydrochloride capsules, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine hydrochloride capsules after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with clomipramine hydrochloride capsules. Conversely, at least 14 days should be allowed after stopping clomipramine hydrochloride capsules before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Clomipramine Hydrochloride Capsules With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start clomipramine hydrochloride capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving clomipramine hydrochloride capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, clomipramine hydrochloride capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with clomipramine hydrochloride capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with clomipramine hydrochloride capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Optiray

Optiray

General

As with all radiopaque contrast agents, only the lowest dose necessary to obtain adequate visualization should be used. A lower dose may reduce the possibility of an adverse reaction. Most procedures do not require use of either the maximum volume or the highest concentration of Optiray. The combination of volume and concentration of Optiray to be used should be carefully individualized accounting for factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. Other factors such as anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed should be considered.

It is desirable that intravascularly administered iodinated contrast agents be at or close to body temperature when injected.

If during administration a reaction occurs, the injection should be stopped until the reaction has subsided.

Patients should be well hydrated prior to and following Optiray (ioversol injection) administration.
Fentanyl Citrate

Fentanyl Citrate

Healthcare professionals who prescribe oral transmucosal fentanyl citrate on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of oral transmucosal fentanyl citrate [see Warnings and Precautions (5.10)].

As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

2.1 Initial Dose

Individually titrate oral transmucosal fentanyl citrate to a dose that provides adequate analgesia and minimizes side effects. The initial dose of oral transmucosal fentanyl citrate to treat episodes of breakthrough cancer pain is always 200 mcg. The oral transmucosal fentanyl citrate unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg oral transmucosal fentanyl citrate units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose.

2.2 Dose Titration

From this initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia using a single oral transmucosal fentanyl citrate dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of oral transmucosal fentanyl citrate over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted.

In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the oral transmucosal fentanyl citrate unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of oral transmucosal fentanyl citrate for any breakthrough pain episode.

Patients must wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. To reduce the risk of overdosing during titration, patients should have only one strength of oral transmucosal fentanyl citrate available at any one time.

2.3 Maintenance Dosing

Once titrated to an effective dose, patients should generally use ONLY ONE oral transmucosal fentanyl citrate unit of the appropriate strength per breakthrough pain episode.

On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the oral transmucosal fentanyl citrate unit, patient may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. Once a successful dose has been found (i.e., an average episode is treated with a single unit), patients should limit consumption to four or fewer units per day.

Dosage adjustment of oral transmucosal fentanyl citrate may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

Generally, the oral transmucosal fentanyl citrate dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated.

2.4 Administration of Oral Transmucosal Fentanyl Citrate

Open the blister package with scissors immediately prior to product use. The patient should place the oral transmucosal fentanyl citrate unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The oral transmucosal fentanyl citrate unit should be sucked, not chewed. A unit dose of oral transmucosal fentanyl citrate, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology (12.3)].

The oral transmucosal fentanyl citrate unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in oral transmucosal fentanyl citrate clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses.

2.5 Discontinuation of Oral Transmucosal Fentanyl Citrate

For patients requiring discontinuation of opioids, a gradual downward titration is recommended because it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.
Fludarabine Phosphate

Fludarabine Phosphate

ROXICODONE® is intended for the management of moderate to severe pain in patients who require treatment with an oral opioid analgesic. The dose should be individually adjusted according to severity of pain, patient response and patient size. If the pain increases in severity, if analgesia is not adequate, or if tolerance occurs, a gradual increase in dosage may be required.

Patients who have not been receiving opioid analgesics should be started on ROXICODONE® in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. The dose should be titrated based upon the individual patient’s response to their initial dose of ROXICODONE®. Patients with chronic pain should have their dosage given on an around-the-clock basis to prevent the reoccurrence of pain rather than treating the pain after it has occurred. This dose can then be adjusted to an acceptable level of analgesia taking into account side effects experienced by the patient.

For control of severe chronic pain, ROXICODONE® should be administered on a regularly scheduled basis, every 4 to 6 hours, at the lowest dosage level that will achieve adequate analgesia.

As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. Although it is not possible to list every condition that is important to the selection of the initial dose of ROXICODONE®, attention should be given to: 1) the daily dose, potency, and characteristics of a pure agonist or mixed agonist/antagonist the patient has been taking previously, 2) the reliability of the relative potency estimate to calculate the dose of oxycodone needed, 3) the degree of opioid tolerance, 4) the general condition and medical status of the patient, and 5) the balance between pain control and adverse experiences.

Conversion From Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs:

When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of ROXICODONE® in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose ROXICODONE® should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia.

Patients Currently on Opioid Therapy:

If a patient has been receiving opioid-containing medications prior to taking ROXICODONE®, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone.

In converting patients from other opioids to ROXICODONE® close observation and adjustment of dosage based upon the patient’s response to ROXICODONE® is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of ROXICODONE® may be necessary, especially in patients who have disease states that are changing rapidly.

Maintenance of Therapy:

Continual re-evaluation of the patient receiving ROXICODONE® is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain.

During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), the continued need for the use of opioid analgesics should be re-assessed as appropriate.

Cessation of Therapy:

When a patient no longer requires therapy with ROXICODONE® or other opioid analgesics for the treatment of their pain, it is important that therapy be gradually discontinued over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see DRUG ABUSE AND DEPENDENCE section for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. It is not known at what dose of ROXICODONE® that treatment may be discontinued without risk of the opioid abstinence syndrome.
Indium In 111 Chloride ...

Indium In 111 Chloride Solution

Radiation Dosimetry

Please refer to the package insert for ProstaScint or Zevalin for this information on the final drug product.
Technescan Hdp

Technescan Hdp

General Instructions

The recommended adult dose of Technetium Tc 99m-labeled TechneScan HDP is 555 MBq (15 mCi) with a range of 370 to 740 MBq (10 to 20 mCi). The recommended pediatric dose is 7.4 MBq (0.20 mCi)/kg with a range of 7.4 to 13 MBq (0.20 to 0.35 mCi)/kg. The recommended minimum total pediatric dose is 37 MBq (1.0 mCi). The maximum total dose injected into a pediatric or adult patient is 740 MBq (20.0 mCi). The maximum dose of oxidronate sodium should not exceed 2 mg.

Unit dose preparation instructions should be followed for pediatric patients. The radioactivity of each dose should be measured by a suitable radiation calibration system just prior to administration. The dose should be given intravenously by slow injection. For optimal results imaging should be performed 1 to 4 hours post-injection.
Benazepril Hydrochlorid...

Benazepril Hydrochloride

XARTEMIS XR is not interchangeable with other oxycodone/acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration.

2.1       Initial Dosage

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with XARTEMIS XR [see Warnings and Precautions (5.2)].

Use of XARTEMIS XR as the First Opioid Analgesic The recommended dose of XARTEMIS XR is 2 tablets every 12 hours administered with or without food. The second dose of 2 tablets may be administered as early as 8 hours after the initial dose if patients require analgesia at that time. Subsequent doses are to be administered 2 tablets every 12 hours.

XARTEMIS XR is given orally. XARTEMIS XR tablets should be swallowed whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in mouth [see Patient Counseling Information (17)]. Do not break, chew, crush, cut, dissolve or split the tablets. Breaking, chewing, crushing, cutting, dissolving or splitting XARTEMIS XR tablets will result in uncontrolled delivery of oxycodone and can lead to overdose or death [see Warnings and Precautions (5.1)].

The total daily dose of acetaminophen from all drug products should not exceed 4000 milligrams.

2.2       Hepatic Impairment

In patients with hepatic impairment start with one tablet and adjust dosage as needed. Monitor closely for respiratory depression [see Clinical Pharmacology (12.3)].

2.3       Renal Impairment

In patients with renal impairment start with one tablet and adjust dosage as needed. Monitor closely for respiratory depression [see Clinical Pharmacology (12.3)].

2.4       Cessation of Therapy

When a patient who has been taking XARTEMIS XR regularly and may be physically dependent no longer requires therapy with XARTEMIS XR use a gradual downward titration of the dose of 50% every 2 to 4 days to prevent signs and symptoms of withdrawal. Do not stop XARTEMIS XR abruptly in patients who may be physically dependent.
Ultratag Rbc

Ultratag Rbc

The Instructions for Preparation must be carefully followed for preparing technetium Tc 99m-labeled red blood cells using UltraTag™ RBC. The suggested dose range of technetium Tc 99m-labeled red blood cells in the average patient (70 kg) is 370 MBq (10 mCi) to 740 MBq (20 mCi).The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aseptic procedures and a shielded syringe should be employed in preparing and withdrawing doses for administration to patients. The user should wear waterproof gloves during the administration procedure.
Kit For The Preparation...

Kit For The Preparation Of Tc 99m Pyrophosphate

Bone and Cardiac Imaging

The recommended adult doses of Technetium Tc 99m Pyrophosphate Injection are:
Indication Doses asTechnetium Tc 99 Fraction ofVial Contents Required Skeletal Imaging 185 to 555 megabecquerels(5 to 15 mCi) 0.07 to 0.91 Cardiac Imaging 370 to 555 megabecquerels(10 to 15 mCi) 0.26 to 0.45
Technetium Tc 99m Pyrophosphate Injection is injected intravenously over a 10- to 20-second period. For optimal results, bone imaging should be done one to six hours following administration. Cardiac imaging should be done 60 to 90 minutes following administration. The acute myocardial infarct can be visualized from 24 hours to nine days following onset of symptoms, with maximum localization at 48 to 72 hours. Cardiac imaging should be done with a gamma scintillation camera. It is recommended that images be made of the anterior, left anterior oblique and left lateral projections.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. It is also recommended that the radiochemical purity be checked prior to administration.

Blood Pool Imaging

The recommended adult dose of TechneScan PYP is one-third (0.33) to the entire vial contents, followed by 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. Cardiac imaging should be done 10 minutes following the administration of sodium pertechnetate Tc 99m (in vivo method) or Tc 99m labeled red blood cells (modified in vivo/in vitro method) utilizing a scintillation camera interfaced to an electrocardiographic gating device.

In Vivo Method: TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives. The patient dose is administered intravenously 15 to 30 minutes prior to the intravenous administration of 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. TechneScan PYP should be injected by direct venipuncture. Heparinized catheter systems should be avoided.

Modified In Vivo/In Vitro Method Using Acid-Citrate-Dextrose (ACD): TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives, and the patient dose is administered intravenously. An intravenous line containing a 3-way stopcock is inserted in a large peripheral vein and kept patent with a continuous drip of sterile, non-pyrogenic normal saline containing no preservatives. Thirty minutes after TechneScan PYP injection, the infusion line and stopcock are cleared by withdrawing and discarding approximately 5 milliliters of whole blood. Immediately following, approximately 5 milliliters of whole blood are withdrawn into a syringe containing 1 milliliter preservative-free acid-citrate-dextrose (ACD) and 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. The stopcock is then turned, residual blood is flushed from the intravenous line, and the normal saline flow is readjusted. The syringe is gently rotated to mix and allowed to incubate at room temperature for 10 minutes prior to injection via the 3-way stopcock.

Modified In Vivo/In Vitro Method Using Heparin: TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives, and the patient dose is administered intravenously. An infusion set fitted with a 3-way stopcock is placed in a large peripheral vein, and the intravenous line is heparinized with a saline solution containing 5-10 units preservative-free heparin per milliliter. Thirty minutes after TechneScan PYP injection, 3 milliliters of blood are withdrawn into a syringe containing 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. Anticoagulation of the blood is provided by residual heparin in the intravenous line. The syringe is gently rotated to mix and allowed to incubate at room temperature for 10 minutes prior to injection via the 3-way stopcock.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if contents are turbid.
Flecainide Acetate

Flecainide Acetate

IF THERE IS ANY QUESTION OF OCCULT OPIOID DEPENDENCE, PERFORM A NALOXONE CHALLENGE TEST AND DO NOT INITIATE NALTREXONE THERAPY UNTIL THE NALOXONE CHALLENGE IS NEGATIVE.

Treatment of Alcoholism

A dose of 50 mg once daily is recommended for most patients (see CLINICAL PHARMACOLOGY, Individualization of Dosage). The placebo-controlled studies that demonstrated the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not evaluated in these trials.A patient is a candidate for treatment with naltrexone if:
the patient is willing to take a medicine to help with alcohol dependence the patient is opioid free for 7 to 10 days the patient does not have severe or active liver or kidney problems (Typical guidelines suggest liver function tests no greater than 3 times the upper limits of normal, and bilirubin normal.) the patient is not allergic to naltrexone, and no other contraindications are present
Refer to CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections for additional information.Naltrexone should be considered as only one of many factors determining the success of treatment of alcoholism. Factors associated with a good outcome in the clinical trials with naltrexone were the type, intensity, and duration of treatment; appropriate management of comorbid conditions; use of community-based support groups; and good medication compliance. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, especially medication compliance.

Treatment of Opioid Dependence

Initiate treatment with naltrexone using the following guidelines –
Treatment should not be attempted unless the patient has remained opioid-free for at least 7 to 10 days. Self-reporting of abstinence from opioids in opioid addicts should be verified by analysis of the patient’s urine for absence of opioids. The patient should not be manifesting withdrawal signs or reporting withdrawal symptoms. If there is any question of occult opioid dependence, perform a naloxone challenge test. If signs of opioid withdrawal are still observed following naloxone challenge, treatment with naltrexone should not be attempted. The naloxone challenge can be repeated in 24 hours. Treatment should be initiated carefully, with an initial dose of 25 mg of naltrexone hydrochloride. If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter.
Naloxone Challenge Test – The naloxone challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The naloxone challenge test may be administered by either the intravenous or subcutaneous routes.Intravenous:

Inject 0.2 mg naloxone.Observe for 30 seconds for signs or symptoms of withdrawal. If no evidence of withdrawal, inject 0.6 mg of naloxone. Observe for an additional 20 minutes.

Subcutaneous:

Administer 0.8 mg naloxone.Observe for 20 minutes for signs or symptoms of withdrawal.

Note: Individual patients, especially those with opioid dependence, may respond to lower doses of naloxone. In some cases, 0.1 mg IV naloxone has produced a diagnostic response.Interpretation of the Challenge – Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal. These may include but are not limited to: nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy nose, craving for opioids, poor appetite, abdominal cramps, sense of fear, skin erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to focus, mental lapses, muscle aches or cramps, pupillary dilation, piloerection, fever, changes in blood pressure, pulse or temperature, anxiety, depression, irritability, backache, bone or joint pains, tremors, sensations of skin crawling, or fasciculations. If signs or symptoms of withdrawal appear, the test is positive and no additional naloxone should be administered.Warning: If the test is positive, do NOT initiate naltrexone therapy. Repeat the challenge in 24 hours. If the test is negative, naltrexone therapy may be started if no other contraindications are present. If there is any doubt about the result of the test, hold naltrexone and repeat the challenge in 24 hours.

Alternative Dosing Schedules

Once the patient has been started on naltrexone hydrochloride, 50 mg every 24 hours will produce adequate clinical blockade of the actions of parenterally administered opioids (i.e., this dose will block the effects of a 25 mg intravenous heroin challenge). A flexible approach to a dosing regimen may need to be employed in cases of supervised administration. Thus, patients may receive 50 mg of naltrexone hydrochloride every weekday with a 100 mg dose on Saturday, 100 mg every other day, or 150 mg every third day. The degree of blockade produced by naltrexone may be reduced by these extended dosing intervals.There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits (see WARNINGS and CLINICAL PHARMACOLOGY, Individualization of Dosage).

Patient Compliance

Naltrexone should be considered as only one of many factors determining the success of treatment. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, including medication compliance.
Gallium Citrate Ga-67

Gallium Citrate Ga-67

The recommended adult (70 kg) dose of Gallium Citrate Ga 67 Injection is 74 to 185 megabecquerels (2 to 5 millicuries). Gallium Citrate Ga 67 Injection is intended for intravenous administration only.

Approximately 10 percent of the administered dose is excreted in the feces during the first week after injection. Daily laxatives and/or enemas are recommended from the day of injection until the final images are obtained in order to cleanse the bowel of radioactive material and minimize the possibility of false positive studies.

Studies indicate the optimal tumor to background concentration ratios are often obtained 48 hours post injection. However, considerable biological variability may occur in individuals and acceptable images may be obtained as early as 6 hours and as late as 120 hours after injection.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if contents are turbid.

Instructions for the handling of Gallium Citrate Ga 67:
Waterproof gloves should be used during the entire handling and administration procedure. Using proper shielding, the vial containing the Gallium Citrate Ga 67 should be visually inspected to insure that it is free of particulate matter and discoloration prior to use. Maintain adequate shielding during the life of the product and use a sterile, shielded syringe for withdrawing and injecting the preparation.
Ultratag Rbc

Ultratag Rbc

The Instructions for Preparation must be carefully followed for preparing technetium Tc 99m-labeled red blood cells using UltraTag™ RBC. The suggested dose range of technetium Tc 99m-labeled red blood cells in the average patient (70 kg) is 370 MBq (10 mCi) to 740 MBq (20 mCi).The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aseptic procedures and a shielded syringe should be employed in preparing and withdrawing doses for administration to patients. The user should wear waterproof gloves during the administration procedure.
Kit For The Preparation...

Kit For The Preparation Of Tc 99m Pyrophosphate

Bone and Cardiac Imaging

The recommended adult doses of Technetium Tc 99m Pyrophosphate Injection are:
Indication Doses asTechnetium Tc 99 Fraction ofVial Contents Required Skeletal Imaging 185 to 555 megabecquerels(5 to 15 mCi) 0.07 to 0.91 Cardiac Imaging 370 to 555 megabecquerels(10 to 15 mCi) 0.26 to 0.45
Technetium Tc 99m Pyrophosphate Injection is injected intravenously over a 10- to 20-second period. For optimal results, bone imaging should be done one to six hours following administration. Cardiac imaging should be done 60 to 90 minutes following administration. The acute myocardial infarct can be visualized from 24 hours to nine days following onset of symptoms, with maximum localization at 48 to 72 hours. Cardiac imaging should be done with a gamma scintillation camera. It is recommended that images be made of the anterior, left anterior oblique and left lateral projections.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. It is also recommended that the radiochemical purity be checked prior to administration.

Blood Pool Imaging

The recommended adult dose of TechneScan PYP is one-third (0.33) to the entire vial contents, followed by 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. Cardiac imaging should be done 10 minutes following the administration of sodium pertechnetate Tc 99m (in vivo method) or Tc 99m labeled red blood cells (modified in vivo/in vitro method) utilizing a scintillation camera interfaced to an electrocardiographic gating device.

In Vivo Method: TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives. The patient dose is administered intravenously 15 to 30 minutes prior to the intravenous administration of 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. TechneScan PYP should be injected by direct venipuncture. Heparinized catheter systems should be avoided.

Modified In Vivo/In Vitro Method Using Acid-Citrate-Dextrose (ACD): TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives, and the patient dose is administered intravenously. An intravenous line containing a 3-way stopcock is inserted in a large peripheral vein and kept patent with a continuous drip of sterile, non-pyrogenic normal saline containing no preservatives. Thirty minutes after TechneScan PYP injection, the infusion line and stopcock are cleared by withdrawing and discarding approximately 5 milliliters of whole blood. Immediately following, approximately 5 milliliters of whole blood are withdrawn into a syringe containing 1 milliliter preservative-free acid-citrate-dextrose (ACD) and 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. The stopcock is then turned, residual blood is flushed from the intravenous line, and the normal saline flow is readjusted. The syringe is gently rotated to mix and allowed to incubate at room temperature for 10 minutes prior to injection via the 3-way stopcock.

Modified In Vivo/In Vitro Method Using Heparin: TechneScan PYP is reconstituted with sterile, non-pyrogenic normal saline containing no preservatives, and the patient dose is administered intravenously. An infusion set fitted with a 3-way stopcock is placed in a large peripheral vein, and the intravenous line is heparinized with a saline solution containing 5-10 units preservative-free heparin per milliliter. Thirty minutes after TechneScan PYP injection, 3 milliliters of blood are withdrawn into a syringe containing 555 to 740 megabecquerels (15 to 20 millicuries) of sodium pertechnetate Tc 99m. Anticoagulation of the blood is provided by residual heparin in the intravenous line. The syringe is gently rotated to mix and allowed to incubate at room temperature for 10 minutes prior to injection via the 3-way stopcock.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if contents are turbid.
Technescan Mag3

Technescan Mag3

The suggested dose range employed in the average adult patient (70kg) for renal function and imaging studies is 185 MBq (5 mCi) to 370 MBq (10 mCi). In pediatric patients the recommended dose range is 2.6 MBq/kg (70 μCi/kg) to 5.2 MBq/kg (140 μCi/kg) with a minimum dose of 37 MBq (1 mCi).

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Aseptic procedures and a shielded syringe should be employed in withdrawing doses for administration to patients. The user should wear waterproof gloves during the administration procedure.
Technescan Mag3

Technescan Mag3

The suggested dose range employed in the average adult patient (70kg) for renal function and imaging studies is 185 MBq (5 mCi) to 370 MBq (10 mCi). In pediatric patients the recommended dose range is 2.6 MBq/kg (70 μCi/kg) to 5.2 MBq/kg (140 μCi/kg) with a minimum dose of 37 MBq (1 mCi).

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Aseptic procedures and a shielded syringe should be employed in withdrawing doses for administration to patients. The user should wear waterproof gloves during the administration procedure.
Kit For The Preparation...

Kit For The Preparation Of Technetium Tc 99m Sestamibi

For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient (70 Kg) is 370–1110 MBq (10–30 mCi).

For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m Sestamibi is a single dose of 740–1110 MBq (20–30 mCi).

2.1 Image Acquisition

Breast Imaging: It is recommended that images are obtained with a table overlay to separate breast tissue from the myocardium and liver, and to exclude potential activity that may be present in the opposite breast. For lateral images, position the patient prone with the isolateral arm comfortably above the head, shoulders flat against the table, head turned to the side and relaxed, with the breast imaged pendent through an overlay cutout. The breast should not be compressed on the overlay. For anterior images, position the patient supine with both arms behind the head. For either lateral or anterior images, shield the chest and abdominal organs, or remove them from the field of view.

For complete study, sets of images should be obtained five minutes after the injection, and in the following sequence:

Beginning five minutes after the injection of Technetium Tc 99m Sestamibi:
ten-minute lateral image of breast with abnormality ten-minute lateral image of contralateral breast ten-minute anterior image of both breasts
2.2 Radiation Dosimetry

The radiation doses to organs and tissues of an average patient (70 Kg) per 1110 MBq (30 mCi) of Technetium Tc 99m Sestamibi injected intravenously are shown in Table 1.
Table 1. Radiation Absorbed Doses from Tc 99m Sestamibi
Radiation dosimetry calculations performed by Radiation Internal Dose Information Center, Oak Ridge Institute for Science and Education, PO Box 117, Oak Ridge, TN 37831-0117, (865) 576-3448.
Estimated Radiation Absorbed Dose REST 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.9 Gallbladder Wall 2.0 20.0 2.0 20.0 Small Intestine 3.0 30.0 3.0 30.0 Upper LargeIntestine Wall 5.4 55.5 5.4 55.5 Lower LargeIntestine Wall 3.9 40.0 4.2 41.1 Stomach Wall 0.6 6.1 0.6 5.8 Heart Wall 0.5 5.1 0.5 4.9 Kidneys 2.0 20.0 2.0 20.0 Liver 0.6 5.8 0.6 5.7 Lungs 0.3 2.8 0.3 2.7 Bone Surfaces 0.7 6.8 0.7 6.4 Thyroid 0.7 7.0 0.7 2.4 Ovaries 1.5 15.5 1.6 15.5 Testes 0.3 3.4 0.4 3.9 Red Marrow 0.5 5.1 0.5 5.0 Urinary Bladder Wall 2.0 20.0 4.2 41.1 Total Body 0.5 4.8 0.5 4.8 Estimated Radiation Absorbed Dose STRESS 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.8 Gallbladder Wall 2.8 28.9 2.8 27.8 Small Intestine 2.4 24.4 2.4 24.4 Upper LargeIntestine Wall 4.5 44.4 4.5 44.4 Lower LargeIntestine Wall 3.3 32.2 3.3 32.2 Stomach Wall 0.6 5.3 0.5 5.2 Heart Wall 0.5 5.6 0.5 5.3 Kidneys 1.7 16.7 1.7 16.7 Liver 0.4 4.2 0.4 4.1 Lungs 0.3 2.6 0.2 2.4 Bone Surfaces 0.6 6.2 0.6 6.0 Thyroid 0.3 2.7 0.2 2.4 Ovaries 1.2 12.2 1.3 13.3 Testes 0.3 3.1 0.3 3.4 Red Marrow 0.5 4.6 0.5 4.4 Urinary Bladder Wall 1.5 15.5 3.0 30.0 Total Body 0.4 4.2 0.4 4.2
2.3 Instructions for Preparation

Preparation of the Technetium Tc 99m Sestamibi from the Kit for the Preparation of Technetium Tc 99m Sestamibi is done by the following aseptic procedure:
Prior to adding the Sodium Pertechnetate Tc 99m Injection to the vial, inspect the vial carefully for the presence of damage, particularly cracks, and do not use the vial if found. Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc from the vial and swab the top of the vial closure with alcohol to sanitize the surface. Place the vial in a suitable radiation shield with a fitted radiation cap. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc 99m Injection [925–5550 MBq, (25–150 mCi)] in approximately 1 to 3 mL. Aseptically add the Sodium Pertechnetate Tc 99m Injection to the vial in the lead shield. Without withdrawing the needle, remove an equal volume of headspace to maintain atmospheric pressure within the vial. Shake vigorously, about 5 to 10 quick upward-downward motions. Remove the vial from the lead shield and place upright in an appropriately shielded and contained boiling water bath, such that the vial is suspended above the bottom of the bath, and boil for 10 minutes. Timing for 10 minutes is begun as soon as the water begins to boil again. Do not allow the boiling water to come in contact with the aluminum crimp. Remove the vial from the water bath, place in the lead shield and allow to cool for fifteen minutes. Using proper shielding, the vial contents should be visually inspected. Use only if the solution is clear and free of particulate matter and discoloration. Assay the reaction vial using a suitable radioactivity calibration system. Record the Technetium Tc 99m concentration, total volume, assay time and date, expiration time and lot number on the radioassay information label and affix the label to the shield. Store the reaction vial containing the Technetium Tc 99m Sestamibi at 15° to 25°C (59° to 77°F) until use; at such time the product should be aseptically withdrawn. Technetium Tc 99m Sestamibi should be used within six hours of preparation. The vial contains no preservative.
Note: Adherence to the above product reconstitution instructions is recommended.

Mallinckrodt Inc.'s Kit for the Preparation of Technetium Tc 99m Sestamibi Injection is not to be used with the Recon-o-Stat™ thermal cycler due to the smaller vial size requirements of this heating device.

The potential for cracking and significant contamination exists whenever vials containing radioactive material are heated.

Product should be used within 6 hours after preparation.

Final product with radiochemical purity of at least 90% was used in the clinical trials that established safety and effectiveness. The radiochemical purity was determined by the following method.

2.4 Determination of Radiochemical Purity in Technetium Tc 99m Sestamibi
Obtain a Baker-Flex Aluminum Oxide coated, plastic TLC plate, #1 B-F, pre-cut to 2.5 cm x 7.5 cm. Dry the plate or plates at 100°C for 1 hour and store in a desiccator. Remove pre-dried plate from the desiccator just prior to use. Apply 1 drop of ethanol* using a 1 mL syringe with a 22–26 gauge needle, 1.5 cm from the bottom of the plate. THE SPOT SHOULD NOT BE ALLOWED TO DRY. Add 2 drops of Technetium Tc 99m Sestamibi solution, side by side on top of the ethanol* spot. Return the plate to a desiccator and allow the sample spot to dry (typically 15 minutes). The TLC tank is prepared by pouring ethanol* to a depth of 3–4 mm. Cover the tank and let it equilibrate for ~10 minutes. Develop the plate in the covered TLC tank in ethanol* for a distance of 5 cm from the point of application. Cut the TLC plate 4 cm from the bottom and measure the Tc 99m activity in each piece by appropriate radiation detector. Calculate the % Tc 99m Sestamibi as:

*The ethanol used in this procedure should be 95% or greater. Absolute ethanol (99%) should remain at ≥95% ethanol content for one week after opening if stored tightly capped, in a cool dry place.
Losartan Potassium

Losartan Potassium

Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia.Narcolepsy – Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response.Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate extended-release capsules may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Dextroamphetamine sulfate extended-release capsules may be used for once-a-day dosage wherever appropriate. Attention Deficit Disorder with Hyperactivity – The dextroamphetamine sulfate extended-release capsule formulation is not recommended for pediatric patients younger than 6 years of age.In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day.Dextroamphetamine sulfate extended-release capsules may be used for once-a-day dosage wherever appropriate.Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.
Acetaminophen And Codei...

Acetaminophen And Codeine Phosphate

Dosage should be adjusted according to severity of pain and response of the patient.

The usual adult dosage is:

Single Doses (Range)

Maximum 24-Hour Dose

Codeine Phosphate

15 mg to 60 mg

360 mg

Acetaminophen

300 mg to 1000 mg

4000 mg

Doses may be repeated up to every 4 hours.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours based upon the above dosage guidance. This information should be conveyed in the prescription.

It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.
Oxycodone And Acetamino...

Oxycodone And Acetaminophen Oral Solution

Dosage should be adjusted according to the severity of pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Oxycodone and acetaminophen oral solution is given orally.

Oral Solution

The usual adult dosage is 5 mL (one teaspoonful) every six hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. (Maximum daily dose is 12 teaspoonfuls or 60 mL.)

Cessation of Therapy

In patients treated with oxycodone and acetaminophen oral solution for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Oxycodone And Acetamino...

Oxycodone And Acetaminophen

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to oxycodone can develop with continued use and that the incidence of untoward effects is dose related. This product is inappropriate even in high doses for severe or intractable pain. Oxycodone and acetaminophen capsules are given orally.

The usual adult dosage is one capsule every 6 hours as needed for pain.
Thallous Chloride Tl 20...

Thallous Chloride Tl 201

2.1 Radiation Safety

Thallous Chloride Tl 201 Injection emits radiation and must be handled with appropriate safety measures and in accordance with the “as low as reasonably achievable” (ALARA) principle of radioactivity dosing.

Use the lowest dose of Thallous Chloride Tl 201 Injection necessary to obtain the intended diagnostic image. Individualize the dose and consider factors such as body size, and the equipment and technique to be employed.

2.2 Recommended Dose

Myocardial perfusion
Planar scintigraphy: 37 to 74 MBq (1 to 2 mCi) administered intravenously SPECT: 74 to 111 MBq (2 to 3 mCi) administered intravenously
Parathyroid hyperactivity localization

Planar or SPECT: 75 to 130 MBq (2 to 3.5 mCi) administered intravenously

2.3 Drug Administration and Imaging

For resting myocardial studies, begin imaging 10 to 20 minutes after injection of Thallous Chloride Tl 201. Myocardial-to-background ratios are improved when patients are injected upright and in the fasting state; the upright position reduces the hepatic and gastric Thallium Tl 201 concentration.

For exercise stress testing administer Thallous Chloride Tl 201 Injection at the start of a period of maximum stress which is sustained for approximately 30 seconds after injection. Begin imaging within ten minutes after administration to obtain maximum target-to-background ratios. Within two hours after the completion of the stress testing the target-to-background ratios may decrease in lesions that are attributable to transient ischemia.

For localization of parathyroid hyperactivity, administer Thallous Chloride Tl 201 Injection before, with or after a minimal dose of a thyroid imaging agent such as sodium pertechnetate Tc 99m or sodium iodide I 123 to enable thyroid subtraction imaging.

2.4 Radiation Dosimetry

The estimated absorbed radiation doses at calibration time to a 70 kg patient from an intravenous injection of Thallous Chloride Tl 201 are shown in Table 1. The estimates were calculated based on human data from Krahwinkel et al.1 and Thomas et al.2 Assumed percentages of 98.3% 201Tl, 0.3% 200Tl, 1.2% 202Tl, and 0.2% 203Pb. The effective dose was calculated using ICRP 103 tissue weighting factors and assumptions on the biodistribution data based on data from Krahwinkel et al. and Thomas et al.

Table 1. Radiation Dose Estimates for Thallous Chloride Tl 201 (includes contaminants)

Organ

Estimated Radiation Dose

mGy/MBq

rad/mCi

Adrenals

6.33E-02

2.34E-01

Brain

5.68E-02

2.10E-01

Breasts

3.39E-02

1.25E-01

GB Wall

8.31E-02

3.07E-01

LLI Wall

2.96E-01

1.09E+00

Small Intestine

3.79E-01

1.40E+00

Stomach

1.71E-01

6.34E-01

ULI Wall

2.97E-01

1.10E+00

Heart Wall

2.47E-01

9.14E-01

Kidneys

4.10E-01

1.52E+00

Liver

9.39E-02

3.47E-01

Lungs

4.73E-02

1.75E-01

Muscle

4.59E-02

1.70E-01

Ovaries

1.02E-01

3.76E-01

Pancreas

7.52E-02

2.78E-01

Red Marrow

4.44E-02

1.64E-01

Bone Surfaces

9.37E-02

3.47E-01

Skin

3.16E-02

1.17E-01

Spleen

1.66E-01

6.14E-01

Testes

2.09E-01

7.73E-01

Thymus

4.60E-02

1.70E-01

Thyroid

5.42E-01

2.00E+00

Urinary Bladder Wall

6.25E-02

2.31E-01

Uterus

8.63E-02

3.19E-01

Total Body

5.77E-02

2.14E-01

Effective Dose

0.145mSv/MBq

0.535rem/mCi
1 Krahwinkel W, Herzog H, Feinendegen LE. Pharmacokinetics of thallium-201 in normal individuals after routine myocardial scintigraphy. J Nucl Med, 1988; 29, 1582–1586. 2 Thomas SR, Stabin MG, Castronovo FP. Radiation-absorbed dose from 201Tl-thallous chloride . J Nucl Med, 2005; 46(3), 502-508.
2.5 Drug Handling
Do not use this drug after six (6) days from the calibration date, or nine (9) days from date of manufacture, whichever comes first. Limit the use of this drug, to physicians who are qualified by training and experience in the safe use and handling of radionuclides. Wear waterproof gloves during the handling procedures. Aseptically withdraw the material for use with a shielded sterile syringe. Measure the patient dose with a suitable radioactivity calibration system immediately prior to administration. Visually inspect the drug for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if contents are turbid. Minimize radiation exposure to the patient and insure minimum radiation exposure to occupational workers.
2.1 Radiation Safety

Thallous Chloride Tl 201 Injection emits radiation and must be handled with appropriate safety measures and in accordance with the “as low as reasonably achievable” (ALARA) principle of radioactivity dosing.

Use the lowest dose of Thallous Chloride Tl 201 Injection necessary to obtain the intended diagnostic image. Individualize the dose and consider factors such as body size, and the equipment and technique to be employed.

2.2 Recommended Dose

Myocardial perfusion
Planar scintigraphy: 37 to 74 MBq (1 to 2 mCi) administered intravenously SPECT: 74 to 111 MBq (2 to 3 mCi) administered intravenously
Parathyroid hyperactivity localization

Planar or SPECT: 75 to 130 MBq (2 to 3.5 mCi) administered intravenously

2.3 Drug Administration and Imaging

For resting myocardial studies, begin imaging 10 to 20 minutes after injection of Thallous Chloride Tl 201. Myocardial-to-background ratios are improved when patients are injected upright and in the fasting state; the upright position reduces the hepatic and gastric Thallium Tl 201 concentration.

For exercise stress testing administer Thallous Chloride Tl 201 Injection at the start of a period of maximum stress which is sustained for approximately 30 seconds after injection. Begin imaging within ten minutes after administration to obtain maximum target-to-background ratios. Within two hours after the completion of the stress testing the target-to-background ratios may decrease in lesions that are attributable to transient ischemia.

For localization of parathyroid hyperactivity, administer Thallous Chloride Tl 201 Injection before, with or after a minimal dose of a thyroid imaging agent such as sodium pertechnetate Tc 99m or sodium iodide I 123 to enable thyroid subtraction imaging.

2.4 Radiation Dosimetry

The estimated absorbed radiation doses at calibration time to a 70 kg patient from an intravenous injection of Thallous Chloride Tl 201 are shown in Table 1. The estimates were calculated based on human data from Krahwinkel et al.1 and Thomas et al.2 Assumed percentages of 98.3% 201Tl, 0.3% 200Tl, 1.2% 202Tl, and 0.2% 203Pb. The effective dose was calculated using ICRP 103 tissue weighting factors and assumptions on the biodistribution data based on data from Krahwinkel et al. and Thomas et al.

Table 1. Radiation Dose Estimates for Thallous Chloride Tl 201 (includes contaminants)

Organ

Estimated Radiation Dose

mGy/MBq

rad/mCi

Adrenals

6.33E-02

2.34E-01

Brain

5.68E-02

2.10E-01

Breasts

3.39E-02

1.25E-01

GB Wall

8.31E-02

3.07E-01

LLI Wall

2.96E-01

1.09E+00

Small Intestine

3.79E-01

1.40E+00

Stomach

1.71E-01

6.34E-01

ULI Wall

2.97E-01

1.10E+00

Heart Wall

2.47E-01

9.14E-01

Kidneys

4.10E-01

1.52E+00

Liver

9.39E-02

3.47E-01

Lungs

4.73E-02

1.75E-01

Muscle

4.59E-02

1.70E-01

Ovaries

1.02E-01

3.76E-01

Pancreas

7.52E-02

2.78E-01

Red Marrow

4.44E-02

1.64E-01

Bone Surfaces

9.37E-02

3.47E-01

Skin

3.16E-02

1.17E-01

Spleen

1.66E-01

6.14E-01

Testes

2.09E-01

7.73E-01

Thymus

4.60E-02

1.70E-01

Thyroid

5.42E-01

2.00E+00

Urinary Bladder Wall

6.25E-02

2.31E-01

Uterus

8.63E-02

3.19E-01

Total Body

5.77E-02

2.14E-01

Effective Dose

0.145mSv/MBq

0.535rem/mCi
1 Krahwinkel W, Herzog H, Feinendegen LE. Pharmacokinetics of thallium-201 in normal individuals after routine myocardial scintigraphy. J Nucl Med, 1988; 29, 1582–1586. 2 Thomas SR, Stabin MG, Castronovo FP. Radiation-absorbed dose from 201Tl-thallous chloride . J Nucl Med, 2005; 46(3), 502-508.
2.5 Drug Handling
Do not use this drug after six (6) days from the calibration date, or nine (9) days from date of manufacture, whichever comes first. Limit the use of this drug, to physicians who are qualified by training and experience in the safe use and handling of radionuclides. Wear waterproof gloves during the handling procedures. Aseptically withdraw the material for use with a shielded sterile syringe. Measure the patient dose with a suitable radioactivity calibration system immediately prior to administration. Visually inspect the drug for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if contents are turbid. Minimize radiation exposure to the patient and insure minimum radiation exposure to occupational workers.
Dextroamphetamine Sacch...

Dextroamphetamine Saccharate And Amphetamine Aspartate And Dextroamphetamine Sulfate And Amphetamine Sulfate

Regardless of indication, amphetamines should be administered at the lowest effective dosage, and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia.

Attention Deficit Hyperactivity Disorder

Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.

In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

Narcolepsy

Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response.

Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
Temazepam

Temazepam

While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined.
Methadose Dispersible

Methadose Dispersible

Consider the following important factors that differentiate methadone from other opioids:
The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic effect. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists. There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals. With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing. Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.1 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Methadone hydrochloride tablets for oral suspension are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid. Methadone hydrochloride tablets for oral suspension are cross-scored, allowing for flexible dosage adjustment. Each cross-scored tablet may be broken or cut in half to yield two 20 mg doses, or in quarters to yield four 10 mg doses. Prior to administration, the desired dose of methadone hydrochloride tablets for oral suspension should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (i.e., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, methadone hydrochloride tablets for oral suspension may not be the appropriate product for initial dosing in many patients. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use. Also consider concurrent medications and the general condition and medical status of the patient when selecting the initial dose.

Short-Term Detoxification For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, methadone hydrochloride tablets for oral suspension may not be the appropriate product for gradual dose reduction in many patients.

2.2 Titration and Maintenance Treatment of Opioid Dependence

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.3 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Because methadone hydrochloride tablets for oral suspension can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.4 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.5 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.6 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Ultra-technekow Dte

Ultra-technekow Dte

Sodium Pertechnetate Tc 99m is administered by intravenous injection. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose.

For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder.

The suggested dose ranges employed for various diagnostic indications in the average ADULT PATIENT (70 kg) are as follows:

Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi)Thyroid gland imaging: 37 to 370 MBq (1 to 10 mCi)Salivary gland imaging: 37 to 185 MBq (1 to 5 mCi)Nasolacrimal drainage system: Maximum dose of 3.7 MBq (100 µCi)

The recommended dosages in PEDIATRIC PATIENTS are:

Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi)Thyroid gland imaging: 2.22 to 2.96 MBq (60 to 80 µCi) per kg body weight

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution to be administered as the patient dose should be clear, colorless, and contain no particulate matter.
Eloxatin

Eloxatin

Methylphenidate HCl Extended-Release Capsules are administered once daily in the morning, before breakfast.

Methylphenidate HCl Extended-Release Capsules may be swallowed whole with the aid of liquids, or alternatively, the capsule may be opened and the capsule contents sprinkled onto a small amount (tablespoon) of applesauce and given immediately, and not stored for future use. Drinking some fluids, e.g. water, should follow the intake of the sprinkles with applesauce. The capsules and the capsule contents must not be crushed or chewed (see PRECAUTIONS: Information for Patients). Patients should be advised to avoid alcohol while taking Methylphenidate HCl Extended-Release Capsules.

Dosage should be individualized according to the needs and responses of the patient.

Initial Treatment

The recommended starting dose of Methylphenidate HCl Extended-Release Capsules is 20 mg once daily. Dosage may be adjusted in weekly 10 to 20 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending upon tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended.

Maintenance/Extended Treatment

There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Methylphenidate HCl Extended-Release Capsules. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Methylphenidate HCl Extended-Release Capsules for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
Menstrual Relief

Menstrual Relief

MD-76R should be at body temperature when injected, and may need to be warmed before use. If kept in a syringe for prolonged periods before injection, it should be protected from exposure to strong light.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If a minor reaction occurs during administration, the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs, the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Sodium Iodide I 123

Sodium Iodide I 123

The recommended oral dose for the average patient (70 kg) is 3.7 to 14.8 MBq (100 to 400 μCi). The lower part of the dosage range 3.7 MBq (100 μCi) is recommended for uptake studies alone, and the higher part 14.8 MBq (400 μCi) for thyroid imaging. The determination of I-123 concentration in the thyroid gland may be initiated at six hours after administering the dose and should be measured in accordance with standardized procedures.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. The capsules can be utilized up to 30 hours after calibration time and date. Thereafter, discard the capsules in accordance with standard safety procedures. The user should wear waterproof gloves at all times when handling the capsules or container.
Octreoscan

Octreoscan

Before administration, a patient should be well hydrated. After administration, the patient must be encouraged to drink fluids liberally. Elimination of extra fluid intake will help reduce the radiation dose by flushing out unbound, labelled pentetreotide by glomerular filtration. It is also recommended that a mild laxative (e.g., bisacodyl or lactulose) be given to the patient starting the evening before the radioactive drug is administered, and continuing for 48 hours. Ample fluid uptake is necessary during this period as a support both to renal elimination and the bowel-cleansing process. In a patient with an insulinoma, bowel-cleansing should be undertaken only after consultation with an endocrinologist.

The recommended intravenous dose for planar imaging is 111 MBq (3.0 mCi) of indium In 111 pentetreotide prepared from an OctreoScan kit. The recommended intravenous dose for SPECT imaging is 222 MBq (6.0 mCi) of indium In 111 pentetreotide.

The dose should be confirmed by a suitably calibrated radioactivity ionization chamber immediately before administration.

As with all intravenously administered products, OctreoScan should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparations containing particulate matter or discoloration should not be administered. They should be disposed of in a safe manner, in compliance with applicable regulations.

Aseptic techniques and effective shielding should be employed in withdrawing doses for administration to patients. Waterproof gloves should be worn during the administration procedure.

Do not administer OctreoScan in TPN solutions or through the same intravenous line.
Pennsaid

Pennsaid

2.1 General Instructions

For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops per knee, 4 times a day.

Apply PENNSAID to clean, dry skin.

To avoid spillage, dispense PENNSAID 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread PENNSAID evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution.

To treat the other knee, if symptomatic, repeat the procedure.

Application of PENNSAID in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

2.2 Special Precautions
Avoid showering/bathing for at least 30 minutes after the application of PENNSAID to the treated knee. Wash and dry hands after use. Do not apply PENNSAID to open wounds. Avoid contact of PENNSAID with eyes and mucous membranes. Do not apply external heat and/or occlusive dressings to treated knees. Avoid wearing clothing over the PENNSAID-treated knee(s) until the treated knee is dry. Protect the treated knee(s) from sunlight. Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with PENNSAID. Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
Dextroamphetamine Sulfa...

Dextroamphetamine Sulfate

Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia.

Narcolepsy

Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response.

Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate tablets may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.

Attention Deficit Disorder with Hyperactivity

Not recommended for pediatric patients under 3 years of age.

In pediatric patients from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until an optimal response is obtained.

In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day.

Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.
Hydromorphone Hydrochlo...

Hydromorphone Hydrochloride

The usual starting dose for hydromorphone hydrochloride tablets USP is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of hydromorphone hydrochloride tablets USP, 8 mg must be decided by careful evaluation of each clinical situation.

A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

Patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
Exalgo

Exalgo

2.1 Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

EXALGO should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, EXALGO is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning EXALGO therapy. As EXALGO is only for use in opioid-tolerant patients, do not begin any patient on EXALGO as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with EXALGO [see Warnings and Precautions (5.2)].

EXALGO tablets must be taken whole. Crushing, chewing, or dissolving EXALGO extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Conversion from Other Oral Hydromorphone Formulations to EXALGOPatients receiving oral immediate-release hydromorphone may be converted to EXALGO by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion from Other Oral Opioids to EXALGODiscontinue all other around-the-clock opioid drugs when EXALGO therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements, which could result in adverse reactions.

In an EXALGO clinical trial with an open-label titration period, patients were converted from their prior opioid to EXALGO using the Table 1 as a guide for the initial EXALGO dose. The recommended starting dose of EXALGO is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to EXALGO. The table cannot be used to convert from EXALGO to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1. Conversion Factors to EXALGO

Prior Oral Opioid

Approximate Oral Conversion Factor

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6

To calculate the estimated EXALGO dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate EXALGO strength(s) available.

Example conversion from a single opioid to EXALGO:

Step 1: Sum the total daily dose of the opioid
30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily
Step 3: Calculate the approximate starting dose of EXALGO to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate EXALGO tablet strengths available.
50% of 24 mg results in an initial dose of 12 mg of EXALGO once daily Adjust individually for each patient
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to EXALGO.

Conversion from Transdermal Fentanyl to EXALGOEighteen hours following the removal of the transdermal fentanyl patch, EXALGO treatment can be initiated. To calculate the 24-hour EXALGO dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of EXALGO. Then reduce the EXALGO dose by 50%.

For example:

Step 1: Identify the dose of transdermal fentanyl.
75 mg of transdermal fentanyl
Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of EXALGO.
75 mg of transdermal fentanyl : 36 mg total daily dose of EXALGO
Step 3: Calculate the approximate starting dose of EXALGO to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate EXALGO tablet strengths available.
50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of EXALGO once daily Adjust individually for each patient
Conversion from Methadone to EXALGOClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2 Titration and Maintenance of Therapy

Individually titrate EXALGO to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving EXALGO to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Plasma levels of EXALGO are sustained for 18 to 24 hours. Dosage adjustments of EXALGO may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.

Patients who experience breakthrough pain may require a dose increase of EXALGO, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the EXALGO dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of EXALGO

When a patient no longer requires therapy with EXALGO, taper doses gradually, by 25% to 50% every 2 or 3 days down to a dose of 8 mg before discontinuation of therapy, to prevent signs and symptoms of withdrawal in the opioid-tolerant patient.

To dispose of unused EXALGO flush all remaining tablets down the toilet or remit to authorities at a certified drug take-back program.

2.4 Hepatic Impairment

Start patients with moderate hepatic impairment on 25% of the EXALGO dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with EXALGO and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

2.5 Renal Impairment

Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the EXALGO dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with EXALGO and during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Use in Specific Populations (8.7)].

2.6 Administration of EXALGO

Instruct patients to swallow EXALGO tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5.2)].

2.1 Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

EXALGO should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, EXALGO is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning EXALGO therapy. As EXALGO is only for use in opioid-tolerant patients, do not begin any patient on EXALGO as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with EXALGO [see Warnings and Precautions (5.2)].

EXALGO tablets must be taken whole. Crushing, chewing, or dissolving EXALGO extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Conversion from Other Oral Hydromorphone Formulations to EXALGOPatients receiving oral immediate-release hydromorphone may be converted to EXALGO by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion from Other Oral Opioids to EXALGODiscontinue all other around-the-clock opioid drugs when EXALGO therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements, which could result in adverse reactions.

In an EXALGO clinical trial with an open-label titration period, patients were converted from their prior opioid to EXALGO using the Table 1 as a guide for the initial EXALGO dose. The recommended starting dose of EXALGO is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to EXALGO. The table cannot be used to convert from EXALGO to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1. Conversion Factors to EXALGO

Prior Oral Opioid

Approximate Oral Conversion Factor

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6

To calculate the estimated EXALGO dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate EXALGO strength(s) available.

Example conversion from a single opioid to EXALGO:

Step 1: Sum the total daily dose of the opioid
30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily
Step 3: Calculate the approximate starting dose of EXALGO to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate EXALGO tablet strengths available.
50% of 24 mg results in an initial dose of 12 mg of EXALGO once daily Adjust individually for each patient
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to EXALGO.

Conversion from Transdermal Fentanyl to EXALGOEighteen hours following the removal of the transdermal fentanyl patch, EXALGO treatment can be initiated. To calculate the 24-hour EXALGO dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of EXALGO. Then reduce the EXALGO dose by 50%.

For example:

Step 1: Identify the dose of transdermal fentanyl.
75 mg of transdermal fentanyl
Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of EXALGO.
75 mg of transdermal fentanyl : 36 mg total daily dose of EXALGO
Step 3: Calculate the approximate starting dose of EXALGO to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate EXALGO tablet strengths available.
50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of EXALGO once daily Adjust individually for each patient
Conversion from Methadone to EXALGOClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.
Imipramine Pamoate

Imipramine Pamoate

The following recommended dosages for imipramine pamoate capsules should be modified as necessary by the clinical response and any evidence of intolerance.
Xyntha

Xyntha

General

As with all radiopaque contrast agents, only the lowest dose necessary to obtain adequate visualization should be used. A lower dose may reduce the possibility of an adverse reaction. Most procedures do not require use of either the maximum volume or the highest concentration of Optiray. The combination of volume and concentration of Optiray to be used should be carefully individualized accounting for factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. Other factors such as anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed should be considered.

It is desirable that intravascularly administered iodinated contrast agents be at or close to body temperature when injected.

If during administration a reaction occurs, the injection should be stopped until the reaction has subsided.

Patients should be well hydrated prior to and following Optiray (ioversol injection) administration.

As with all contrast media, other drugs should not be mixed with ioversol solutions because of the potential for chemical incompatibility.

Sterile technique must be used in all vascular injections involving contrast media.

If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Withdrawal of contrast agents from their containers should be accomplished under strict aseptic conditions using only sterile syringes and transfer devices. Contrast agents which have been transferred into other delivery systems should be used immediately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and should not be used if particulates are observed or marked discoloration has occurred.

The Optiray formulations are supplied in single dose containers. Discard unused portion.
Oxymorphone Hydrochlori...

Oxymorphone Hydrochloride

Selection of patients for treatment with oxymorphone hydrochloride tablets should be governed by the same principles that apply to the use of similar opioid analgesics [see Indications and Usage (1)]. Physicians should individualize treatment in every case [see Dosage and Administration (2.1)], using non-opioid analgesics, opioids on an as needed basis, combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.Oxymorphone hydrochloride tablets should be administered on an empty stomach, at least one hour prior to or two hours after eating [see Clinical Pharmacology (12.3)].

2.1 Individualization of Dosage

As with any opioid drug product, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the selection of the initial dose of oxymorphone hydrochloride tablets, attention should be given to the following:
The total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; The relative potency estimate used to calculate the equivalent oxymorphone dose needed; The patient’s degree of opioid tolerance; The age, general condition, and medical status of the patient; Concurrent non-opioid analgesics and other medications; The type and severity of the patient's pain; The balance between pain control and adverse experiences; Risk factors for abuse or addiction, including a prior history of abuse or addiction.
Once therapy is initiated, frequently assess pain relief and other opioid effects. Titrate dose to adequate pain relief (generally mild or no pain). Patients who experience breakthrough pain may require dosage adjustment.If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. Adjust dosing to obtain an appropriate balance between pain relief and opioid-related adverse experiences. If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the events should be treated aggressively. Once adverse events are adequately managed, continue upward titration to an acceptable level of pain control.During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family. Advise patients and family members of the potential common adverse reactions associated with changing opioid doses.The dosing recommendations below, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

2.2 Initiation of Therapy

Titrate dose to adequate pain relief (generally mild or no pain).Opioid-Naïve Patients Patients who have not been receiving opioid analgesics should be started on oxymorphone hydrochloride tablets in a dosing range of 10 to 20 mg every four to six hours depending on the initial pain intensity. If deemed necessary to initiate therapy at a lower dose (e.g., for renal or hepatic impairment or for geriatric patients), patients may be started with oxymorphone hydrochloride tablets 5 mg. The dose should be titrated based upon the individual patient’s response to their initial dose of oxymorphone hydrochloride tablets. This dose can then be adjusted to an acceptable level of analgesia taking into account the pain intensity and adverse reactions experienced by the patient. Initiation of therapy with doses higher than 20 mg is not recommended because of potential serious adverse reactions [see Clinical Studies (14.1)].Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Tablets Given oxymorphone hydrochloride tablets’s absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to oxymorphone hydrochloride tablets by administering 10 times the patient’s total daily parenteral oxymorphone dose as oxymorphone hydrochloride tablets, in four or six equally divided doses (e.g., [IV dose x 10] divided by 4 or 6). For example, approximately 10 mg of oxymorphone hydrochloride tablets four times daily may be required to provide pain relief equivalent to a total daily IM dose of 4 mg oxymorphone. Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.Conversion from Other Oral Opioids to Oxymorphone Hydrochloride Tablets For conversion from other opioids to oxymorphone hydrochloride tablets, physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate. In general, it is safest to start oxymorphone hydrochloride tablets therapy by administering half of the calculated total daily dose of oxymorphone hydrochloride tablets in 4 to 6 equally divided doses, every 4 to 6 hours. The initial dose of oxymorphone hydrochloride tablets can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved.

2.3 Maintenance of Therapy

During therapy, continual reevaluation of the patient receiving oxymorphone hydrochloride tablets is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose [see Dosage and Administration (2.1)].

2.4 Cessation of Therapy

When the patient no longer requires therapy with oxymorphone hydrochloride tablets, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient [see Drug Abuse and Dependence (9.3)].

2.5 Patients with Hepatic Impairment

Oxymorphone hydrochloride tablets are contraindicated in patients with moderate or severe hepatic impairment. Use oxymorphone hydrochloride tablets with caution in patients with mild hepatic impairment, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring side effects [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

2.6 Patients with Renal Impairment

There are 57% and 65% increases in oxymorphone bioavailability in patients with moderate and severe renal impairment, respectively; treated with extended-release oxymorphone tablets [see Clinical Pharmacology (12.3)]. Accordingly, oxymorphone hydrochloride tablets should be administered cautiously and in reduced dosages to patients with creatinine clearance rates less than 50 mL/min.

2.7 Use with Central Nervous System Depressants

Oxymorphone hydrochloride tablets, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension and profound sedation, coma or death may result [see Warnings and Precautions (5.3) and Drug Interactions (7.1)]. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.Although no specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, oxymorphone hydrochloride tablets are not recommended for use in patients who have received MAO inhibitors within 14 days [see Drug Interactions (7.5)].

2.8 Geriatric Patients

Exercise caution in the selection of the starting dose of oxymorphone hydrochloride tablets for an elderly patient by starting at the low end of the dosing range (e.g., 5 mg) [see Use in Specific Populations (8.5)].
Fentanyl Transdermal Sy...

Fentanyl Transdermal System Patch

2.1 Initial Dosing

Fentanyl transdermal system should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with fentanyl transdermal system when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.2)].

The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose.

Discontinue all other around-the-clock opioid drugs when fentanyl transdermal system therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour fentanyl requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which could result in adverse reactions. In a fentanyl transdermal system clinical trial, patients were converted from their prior opioid to fentanyl transdermal system using Table 1 as a guide for the initial fentanyl transdermal system dose.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion doses in this table are only for the conversion from one of the listed oral or parenteral opioid analgesics to fentanyl transdermal system. The table cannot be used to convert from fentanyl transdermal system to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
To convert patients from oral or parenteral opioids to fentanyl transdermal system, use Table 1. Do not use Table 1 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.

Table 1*. Dose Conversion to Fentanyl Transdermal System

Current Analgesic

Daily Dosage (mg/day)

Oral morphine

60-134

135-224

225-314

315-404

Intramuscular or Intravenous morphine

10-22

23-37

38-52

53-67

Oral oxycodone

30-67

67.5-112

112.5-157

157.5-202

Oral codeine

150-447

Oral hydromorphone

8-17

17.1-28

28.1-39

39.1-51

Intravenous hydromorphone

1.5-3.4

3.5-5.6

5.7-7.9

8-10

Intramuscular meperidine

75-165

166-278

279-390

391-503

Oral methadone

20-44

45-74

75-104

105-134

Recommended Fentanyl Transdermal System Dose

25 mcg/hour

50 mcg/hour

75 mcg/hour

100 mcg/hour

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion methodology outlined above with Table 2.

* Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.3)].

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology:

1.    Calculate the previous 24-hour analgesic requirement. 2.    Convert this amount to the equianalgesic oral morphine dose using a reliable reference.

Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained.

3.    Do not use Table 2 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.

Table 2*. Recommended Initial Fentanyl Transdermal System Dose Based Upon Daily Oral Morphine Dose

Oral 24-hour Morphine (mg/day)

Fentanyl Transdermal SystemDose(mcg/hour)

60-134

25

135-224

50

225-314

75

315-404

100

405-494

125

495-584

150

585-674

175

675-764

200

765-854

225

855-944

250

945-1034

275

1035-1124

300

NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system.

* Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to           fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.5)].

For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Hepatic Impairment

Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.14), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Renal Impairment

Avoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.15), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.2 Titration and Maintenance of Therapy

Individually titrate fentanyl transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal system to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl transdermal system dose for the first time until at least 3 days after the initial application. Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.

It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.

Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

A small proportion of adult patients may not achieve adequate analgesia using a 72-hour dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen.

Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

2.3 Administration of Fentanyl Transdermal System

Fentanyl transdermal systems are for transdermal use, only.

Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions (5.3)].

Application and Handling Instructions
Patients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application. Patients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged. The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. Each fentanyl transdermal system may be worn continuously for 72 hours. The next patch is applied to a different skin site after removal of the previous transdermal system. If problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing. If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site. Patients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, sharing the same bed as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while applying or removing the patch. Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed.
Avoidance of Heat

Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions (5. 11)].

2.4 Disposal Instructions

Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures and deaths [see Warnings and Precautions (5.3)].

Patients should dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet.

Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.

2.5 Discontinuation of Fentanyl Transdermal System

Significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed [see Clinical Pharmacology (12.3)].

To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Withdrawal symptoms are possible in some patients after conversion or dose adjustment [see Warnings and Precautions (5.17)].

Do not use Tables 1 and 2 to convert from fentanyl transdermal system to other therapies to avoid overestimating the dose of the new agent resulting in overdose of the new analgesic and possibly death.

When discontinuing fentanyl transdermal system and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of withdrawal symptoms [see Warnings and Precautions (5.17)]. It is not known at what dose level fentanyl transdermal system may be discontinued without producing the signs and symptoms of opioid withdrawal.

2.1 Initial Dosing

Fentanyl transdermal system should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with fentanyl transdermal system when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.2)].

The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose.

Discontinue all other around-the-clock opioid drugs when fentanyl transdermal system therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour fentanyl requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which could result in adverse reactions. In a fentanyl transdermal system clinical trial, patients were converted from their prior opioid to fentanyl transdermal system using Table 1 as a guide for the initial fentanyl transdermal system dose.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion doses in this table are only for the conversion from one of the listed oral or parenteral opioid analgesics to fentanyl transdermal system. The table cannot be used to convert from fentanyl transdermal system to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
To convert patients from oral or parenteral opioids to fentanyl transdermal system, use Table 1. Do not use Table 1 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.

Table 1*. Dose Conversion to Fentanyl Transdermal System

Current Analgesic

Daily Dosage (mg/day)

Oral morphine

60-134

135-224

225-314

315-404

Intramuscular or Intravenous morphine

10-22

23-37

38-52

53-67

Oral oxycodone

30-67

67.5-112

112.5-157

157.5-202

Oral codeine

150-447

Oral hydromorphone

8-17

17.1-28

28.1-39

39.1-51

Intravenous hydromorphone

1.5-3.4

3.5-5.6

5.7-7.9

8-10

Intramuscular meperidine

75-165

166-278

279-390

391-503

Oral methadone

20-44

45-74

75-104

105-134

Recommended Fentanyl Transdermal System Dose

25 mcg/hour

50 mcg/hour

75 mcg/hour

100 mcg/hour

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion methodology outlined above with Table 2.

* Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.3)].

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology:

1.    Calculate the previous 24-hour analgesic requirement. 2.    Convert this amount to the equianalgesic oral morphine dose using a reliable reference.

Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained.

3.    Do not use Table 2 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.

Table 2*. Recommended Initial Fentanyl Transdermal System Dose Based Upon Daily Oral Morphine Dose

Oral 24-hour Morphine (mg/day)

Fentanyl Transdermal SystemDose(mcg/hour)

60-134

25

135-224

50

225-314

75

315-404

100

405-494

125

495-584

150

585-674

175

675-764

200

765-854

225

855-944

250

945-1034

275

1035-1124

300

NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system.

* Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to           fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.5)].

For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Hepatic Impairment

Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.14), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Renal Impairment

Avoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.15), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.2 Titration and Maintenance of Therapy

Individually titrate fentanyl transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal system to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl transdermal system dose for the first time until at least 3 days after the initial application. Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.

It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.

Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

A small proportion of adult patients may not achieve adequate analgesia using a 72-hour dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen.

Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

2.3 Administration of Fentanyl Transdermal System

Fentanyl transdermal systems are for transdermal use, only.

Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions (5.3)].

Application and Handling Instructions
Patients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application. Patients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged. The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. Each fentanyl transdermal system may be worn continuously for 72 hours. The next patch is applied to a different skin site after removal of the previous transdermal system. If problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing. If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site. Patients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, sharing the same bed as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while applying or removing the patch. Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed.
Avoidance of Heat

Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions (5. 11)].

2.4 Disposal Instructions

Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures and deaths [see Warnings and Precautions (5.3)].

Patients should dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet.

Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.

2.5 Discontinuation of Fentanyl Transdermal System

Significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed [see Clinical Pharmacology (12.3)].

To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Withdrawal symptoms are possible in some patients after conversion or dose adjustment [see Warnings and Precautions (5.17)].

Do not use Tables 1 and 2 to convert from fentanyl transdermal system to other therapies to avoid overestimating the dose of the new agent resulting in overdose of the new analgesic and possibly death.

When discontinuing fentanyl transdermal system and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of withdrawal symptoms [see Warnings and Precautions (5.17)]. It is not known at what dose level fentanyl transdermal system may be discontinued without producing the signs and symptoms of opioid withdrawal.
Methadone Hydrochloride...

Methadone Hydrochloride

2.1 Important General Information
The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

Methadone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with methadone hydrochloride tablets [see Warnings and Precautions (5.2)].

Use of Methadone Hydrochloride Tablets as the First Opioid Analgesic

Initiate treatment with methadone hydrochloride tablets with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone Hydrochloride Tablets

Discontinue all other around-the-clock opioid drugs when methadone hydrochloride tablets therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride tablets. The table cannot be used to convert from methadone hydrochloride tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadone Hydrochloride Tablets

Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone hydrochloride tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone hydrochloride tablets strength(s) available.

Example conversion from a single opioid to methadone hydrochloride tablets:

        Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

Step 2: Calculate the approximate equivalent dose of methadone hydrochloride tablets based on the total daily dose of Morphine using Table 1.

100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone hydrochloride tablets daily

        Step 3: Calculate the approximate starting dose of methadone hydrochloride tablets to be given every 12 hours. Round down, if necessary, to the appropriate methadone hydrochloride tablets strengths available.

15 mg daily / 2 = 7.5 mg methadone hydrochloride tablets every 12 hours

Then 7.5 mg is rounded down to 5 mg methadone hydrochloride tablets every 12 hours

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone hydrochloride tablets.

Conversion from Parenteral Methadone to Methadone Hydrochloride Tablets Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate methadone hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone hydrochloride tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate methadone hydrochloride tablets slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression). Patients who experience breakthrough pain may require a dose increase of methadone hydrochloride tablets, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone hydrochloride tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reations.

2.4 Discontinuation of Methadone Hydrochloride Tablets for Pain

When a patient no longer requires therapy with methadone hydrochloride tablets for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone hydrochloride tablets.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone hydrochloride tablets will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone hydrochloride tablets if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone hydrochloride tablets on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-Term Detoxification

For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone hydrochloride tablets. Decrease the dose of methadone hydrochloride tablets on a daily basis or at 2-day intervals, keeping the amount of methadone hydrochloride tablets sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

2.2 Initial Dosing for Management of Pain

Methadone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with methadone hydrochloride tablets [see Warnings and Precautions (5.2)].

Use of Methadone Hydrochloride Tablets as the First Opioid Analgesic

Initiate treatment with methadone hydrochloride tablets with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone Hydrochloride Tablets

Discontinue all other around-the-clock opioid drugs when methadone hydrochloride tablets therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride tablets. The table cannot be used to convert from methadone hydrochloride tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadone Hydrochloride Tablets

Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone hydrochloride tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone hydrochloride tablets strength(s) available.

Example conversion from a single opioid to methadone hydrochloride tablets:

        Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

Step 2: Calculate the approximate equivalent dose of methadone hydrochloride tablets based on the total daily dose of Morphine using Table 1.

100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone hydrochloride tablets daily

        Step 3: Calculate the approximate starting dose of methadone hydrochloride tablets to be given every 12 hours. Round down, if necessary, to the appropriate methadone hydrochloride tablets strengths available.

15 mg daily / 2 = 7.5 mg methadone hydrochloride tablets every 12 hours

Then 7.5 mg is rounded down to 5 mg methadone hydrochloride tablets every 12 hours

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone hydrochloride tablets.

Conversion from Parenteral Methadone to Methadone Hydrochloride Tablets Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate methadone hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone hydrochloride tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate methadone hydrochloride tablets slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression). Patients who experience breakthrough pain may require a dose increase of methadone hydrochloride tablets, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone hydrochloride tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reations.

2.4 Discontinuation of Methadone Hydrochloride Tablets for Pain

When a patient no longer requires therapy with methadone hydrochloride tablets for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone hydrochloride tablets.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Methadose

Methadose

2.1 Important General Information
The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

Methadose should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Methadose [see Warnings and Precautions (5.2)].

Use of Methadose as the First Opioid AnalgesicInitiate treatment with Methadose with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadose Discontinue all other around-the-clock opioid drugs when Methadose therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from another oral opioid analgesic to Methadose. The table cannot be used to convert from Methadose to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadose

Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated Methadose dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate Methadose strength(s) available.

Example conversion from a single opioid to Methadose:

        Step 1:    Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

        Step 2:    Calculate the approximate equivalent dose of Methadose based on the total daily dose of Morphine using Table 1.

100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadose daily

        Step 3:    Calculate the approximate starting dose of Methadose to be given every 12 hours. Round down, if necessary, to the     appropriate Methadose tablets strengths available.

15 mg daily / 2 = 7.5 mg Methadose every 12 hours

Then 7.5 mg is rounded down to 5 mg Methadose every 12 hours

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Methadose.

Conversion from Parenteral Methadone to Methadose

Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate Methadose to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Methadose to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because steady-state plasma concentrations are approximated within 24 to 36 hours, Methadose dosage adjustments may be done every 1 to 2 days.

Patients who experience breakthrough pain may require a dose increase of Methadose, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Methadose dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Methadose for Pain

When a patient no longer requires therapy with Methadose for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue Methadose.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of Methadose will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of Methadose if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of Methadose on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-Term Detoxification

For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of Methadose. Decrease the dose of Methadose on a daily basis or at 2-day intervals, keeping the amount of Methadose sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

2.1 Important General Information
The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

Methadose should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Methadose [see Warnings and Precautions (5.2)].

Use of Methadose as the First Opioid AnalgesicInitiate treatment with Methadose with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadose Discontinue all other around-the-clock opioid drugs when Methadose therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from another oral opioid analgesic to Methadose. The table cannot be used to convert from Methadose to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadose

Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated Methadose dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate Methadose strength(s) available.

Example conversion from a single opioid to Methadose:

        Step 1:    Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

        Step 2:    Calculate the approximate equivalent dose of Methadose based on the total daily dose of Morphine using Table 1.

100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadose daily

        Step 3:    Calculate the approximate starting dose of Methadose to be given every 12 hours. Round down, if necessary, to the     appropriate Methadose tablets strengths available.

15 mg daily / 2 = 7.5 mg Methadose every 12 hours

Then 7.5 mg is rounded down to 5 mg Methadose every 12 hours

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Methadose.

Conversion from Parenteral Methadone to Methadose

Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate Methadose to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Methadose to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because steady-state plasma concentrations are approximated within 24 to 36 hours, Methadose dosage adjustments may be done every 1 to 2 days.

Patients who experience breakthrough pain may require a dose increase of Methadose, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Methadose dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Methadose for Pain

When a patient no longer requires therapy with Methadose for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue Methadose.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of Methadose will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of Methadose if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of Methadose on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-Term Detoxification

For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of Methadose. Decrease the dose of Methadose on a daily basis or at 2-day intervals, keeping the amount of Methadose sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Hexabrix

Hexabrix

It is advisable that HEXABRIX be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors prior to the injection of the contrast medium.

If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately.

Under no circumstances should other drugs be administered concomitantly in the same syringe or IV administration set because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

PEDIATRIC ANGIOCARDIOGRAPHY

HEXABRIX may be administered by catheter injection into the chambers of the heart or associated large blood vessels. Rapid injection is essential and satisfactory results usually require injection of the total dosage in 1-2 seconds.

Precautions

In addition to the general precautions previously described, it is advisable to monitor for ECG and vital signs changes throughout the procedure.

When large individual doses are administered sufficient time should be allowed for any observed changes to return to or near baseline prior to making the next injection.

Caution should be used when making right heart injections in patients with pulmonary hypertension or incipient heart failure since this may lead to increased right side pressures with subsequent bradycardia and systemic hypotension. Patients with pulmonary disease present additional risks.

Caution is advised in cyanotic infants since apnea, bradycardia, other arrhythmias and a tendency to acidosis are more likely to occur.

Since infants are more likely to respond with convulsions than are adults, the amount of total dosage is of particular importance. Repeated injections are hazardous in infants weighing less than 7 kg, particularly when these infants have pre-existing compromised right heart function or obliterated pulmonary vascular beds.

Adverse Reactions

In addition to the adverse reactions previously listed, this procedure has been complicated by intramural injection with marked adverse effects on cardiac function.

Usual Dosage

The volume of individual doses should be determined by the size of the structure to be visualized and the anticipated degree of hemodilution at the site of injection. Valvular competence should also be taken into consideration.

Older Children: Catheter angiocardiography usually requires single doses of 30-45 mL of HEXABRIX.

Infants and Young Children: The recommended single dose of HEXABRIX is about 1.5 mL/kg (range 1 mL/kg to 2 mL/kg). In addition, small test volumes of about 2 mL may be used for catheter placement.

The usual total dose of HEXABRIX per procedure, which includes diagnostic and test doses is about 4 mL/kg. This dosage may be as small as 1.5 mL/kg and should not normally exceed 5 mL/kg.

SELECTIVE CORONARY ARTERIOGRAPHY WITH OR WITHOUT LEFT VENTRICULOGRAPHY

Precautions

During the administration of large doses of HEXABRIX, continuous monitoring of vital signs is desirable. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the pre-existing condition. Hypotension should be corrected promptly since it may result in serious arrhythmias.

Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary hypertension, or stenotic pulmonary vascular beds because of hemodynamic changes which may occur after injection into the right heart outflow tract.

Adverse Reactions

Patients may have clinically insignificant ECG changes during the procedure. The following adverse effects have occurred in conjunction with the administration of iodinated intravascular contrast agents for this procedure: hypotension, shock, anginal pain, myocardial infarction, cardiac arrhythmias (bradycardia, ventricular tachycardia, ventricular fibrillation) and cardiac arrest. Fatalities have been reported.

Complications to the procedure include dissection of coronary arteries, dislodgement of atheromatous plaques, perforation, hemorrhage and thrombosis.

Usual Dosage

The usual adult dose for left coronary arteriography is 8 mL (range 2-14 mL) and for right coronary arteriography is 5 mL (range 1-10 mL). The doses may be repeated as necessary; doses up to a total of 150 mL have been given. For left ventriculography, the usual adult dose in a single injection is 45 mL (range 35-45 mL) and repeated as necessary. The total dose for combined selective coronary arteriography and left ventriculography should not exceed 250 mL.

PERIPHERAL ARTERIOGRAPHY

HEXABRIX may be injected to visualize the peripheral arterial circulation. Arteriograms of the upper and lower extremities may be obtained by any of the established techniques.

Patient Preparation

The procedure is normally performed with local anesthesia. Rarely, general anesthesia may be required. (See PRECAUTIONS, General.)

A preliminary radiograph is usually made prior to the injection of the contrast agent.

Precautions

In addition to the general precautions previously described, moderate decreases in blood pressure occur frequently with intra-arterial (brachial) injections. This change is usually transient and requires no treatment, however, the blood pressure should be monitored for approximately ten minutes following injection.

Extreme caution during injection of the contrast agent is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial disease.

Adverse Reactions

In addition to the general adverse reactions previously described, hemorrhage and thrombosis have occurred at the puncture site of the percutaneous injection. Brachial plexus injury has been reported following axillary artery injection.

Usual Dosage

The single adult dose for aorto-iliac runoff studies is 45 mL (range 20-80 mL). The single adult dose for the common iliac, the external iliac and the femoral arteries is 30 mL (range 10-50 mL). These doses may be repeated as necessary. For the upper limb, the usual single adult dose is 20 mL (range 15-30 mL), repeated as necessary. The total procedural dose should not exceed 250 mL.

AORTOGRAPHY AND SELECTIVE VISCERAL ARTERIOGRAPHY

HEXABRIX may be used to visualize the aorta and its major abdominal branches.

Usual Dosage

The usual dose for injections into the aorta is 25 to 50 mL; the celiac artery is 40 mL; the superior mesenteric artery is 20 to 40 mL; the inferior mesenteric artery is 8 to 15 mL. These doses may be repeated as necessary. The total dose should not exceed 250 mL.

CEREBRAL ANGIOGRAPHY

HEXABRIX may be used to visualize the cerebral vasculature by any of the accepted techniques.

Patient Preparation

Cerebral angiography is normally performed with local or general anesthesia. (See PRECAUTIONS, General.)

Precautions

In addition to the general precautions previously described, cerebral angiography should be performed with special caution in patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, senility, recent cerebral thrombosis or embolism, and migraine.

Adverse Reactions

The major causes of cerebral arteriographic adverse reactions appear to be repeated injections of the contrast material, administration of doses higher than those recommended, the presence of occlusive atherosclerotic vascular disease and the method and technique of injection.

Adverse reactions are normally mild and transient. A feeling of warmth in the face and neck is frequently experienced. Infrequently, a more severe burning discomfort is observed. Transient visual hallucinations have been reported.

Serious neurological reactions that have been associated with cerebral angiography and not listed under Adverse Reactions, General, include stroke, amnesia and respiratory difficulties.

Visual field defects with anopsia and reversible neurological deficit lasting from 24 hours to 48 hours have been reported. Confusion, disorientation with hallucination, and absence of vision sometimes lasting for one week have also been reported.

Cardiovascular reactions that may occur with some frequency are bradycardia and either an increase or decrease in systemic blood pressure. The blood pressure change is transient and usually requires no treatment.

Usual Dosage

The usual dosage employed varies with the site and method of injection and the age and condition of the patient. In adults, cerebral angiography is usually performed by a selective injection of 9 mL (range 6-12mL) for the common carotid arteries and 8 mL (range 5-12 mL) for the vertebral arteries. Additional injections may be made as indicated. When aortic arch injections (four vessel studies) are performed in conjunction with cerebral angiography, the usual dose is 40 mL (range 30-50 mL). Other dosages may be employed for more selective injections, depending upon the vessel injected. The total dose per procedure should not exceed 150 mL.

INTRA-ARTERIAL DIGITAL SUBTRACTION ANGIOGRAPHY (IA-DSA)

Intra-arterial digital subtraction angiography (IA-DSA) is a radiographic modality which produces arterial images similar to conventional film-screen systems following arterial injection. The advantages include: the use of less contrast medium; the use of lower iodine concentrations; a decreased need for selective arterial catheterization; and a shortened examination time.

Patient Preparation

No special patient preparation is required for IA-DSA. However, it is advisable to insure that patients are well hydrated prior to examination.

Precautions

In addition to the general precautions described, the risks associated with IA-DSA are those usually attendant with catheter procedures. Following the procedure, gentle pressure hemostasis is required, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies.

Usual Dosage

As a general rule, the volume and concentration used for IA-DSA are about 50%, or less, of that used for conventional procedures. The actual dosage and flow rate will vary depending on the selectivity of the injection site and the area being examined.

The most versatile concentration of HEXABRIX is a 1:1 dilution with Sterile Water for Injection, U.S.P. This dilution provides 16% iodine and is isotonic.

The following suggested volumes per injection are intended only as a guide. Injections may be repeated as necessary. It is advisable to inject at rates approximately equal to the flow rate of the vessel being injected.
Carotid Arteries 6-10 mL Vertebral Arteries 4-8 mL Aorta 25-50 mL Subclavian or Brachial Arteries 2-10 mL Major Branches of the Abdominal Aorta 2-20 mL
INTRAVENOUS DIGITAL SUBTRACTION ANGIOGRAPHY

Intravenous digital subtraction angiography (IV DSA) is a radiographic modality which allows dynamic imaging of the arterial system following intravenous injection of iodinated x-ray contrast media through the use of image intensification, enhancement of the iodine signal and digital processing of the image data. Temporal subtraction of the images obtained prior to and during the “first arterial pass” of the injected contrast medium yields images which are devoid of bone and soft tissue.

IV DSA is most frequently used to examine the heart, including coronary by-pass grafts; the pulmonary arteries; arteries of the brachiocephalic circulation; the aortic arch; the abdominal aorta and its major branches; the iliac arteries; and the arteries of the extremities.

Patient Preparation

No special patient preparation is required for IV DSA. However it is advisable to insure that patients are well hydrated prior to examination.

Precautions

In addition to the general precautions previously described, the risks associated with IV DSA include those usually attendant with catheter procedures and include intramural injections, vessel dissection and tissue extravasation. The potential risk is reduced when small test injections of contrast medium are made under fluoroscopic observation to insure that the catheter tip is properly positioned and, in the case of peripheral placement, that the vein is of adequate size.

Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies.

Usual Dosage

HEXABRIX may be injected centrally, in either the superior or inferior vena cava or right atrium; or peripherally into an appropriate arm vein. For central injections, catheters may be introduced at the antecubital fossa into either the basilic or cephalic vein or at the leg into the femoral vein and advanced to the distal segment of the corresponding vena cava. For peripheral injections, the catheter is introduced at the antecubital fossa into an appropriate size arm vein. In order to reduce the potential for extravasation during peripheral injection, a catheter of approximately 20 cm in length should be employed.

Depending on the area to be imaged, the usual dose range per injection is 30-50 mL. Injections may be repeated as necessary. The total procedural dose should not exceed 250 mL.

Injection rates will vary depending on the site of catheter placement and vessel size. Central catheter injections are usually made at a rate of between 10 and 30 mL/second. Peripheral injections are usually made at a rate of between 12 and 20 mL/second. Since the injected medium can sometimes remain in the arm vein for an extended period, it may be advisable to flush the vein, immediately following injection with an appropriate volume (20-25 mL) of 5% Dextrose in water or normal saline.

PERIPHERAL VENOGRAPHY (PHLEBOGRAPHY)

HEXABRIX may be injected to visualize the peripheral venous circulation. Venograms are obtained by injection or infusion into an appropriate vein in the upper or lower extremity. Post-venography thrombophlebitis, as detected by fibrinogen I-125 uptake studies, is significantly less in patients receiving HEXABRIX when compared to conventional contrast agents.

Precautions

In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a totally obstructed venous system.

Extreme caution during injection of contrast media is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease.

Usual Dosage

The dose for adults will usually range from 50-100 mL per extremity of full strength (32% iodine) HEXABRIX as a single rapid injection. The dosage will vary according to the patient's size and condition and the technique employed. Smaller or larger volumes may be indicated in some cases.

Reduced concentrations to as low as 20% w/v iodine may be effectively employed. These dilute solutions may be prepared by addition of normal saline (Sodium Chloride Injection, U.S.P.), 5% Dextrose in water (D5W) or Water for Injection, U.S.P. To prepare a 20% w/v solution, dilute each milliliter of HEXABRIX with 0.6 milliliters of the diluent selected (e.g., 50 mL HEXABRIX plus 30 mL of diluent equals 80 mL of a 20% iodine concentration). The usual dose of dilute medium will range from 75-150 mL per extremity.

Following the procedure, the venous system should be flushed with any one of the diluents listed above. Massage and elevation are also helpful for clearing the contrast medium from the extremity.

EXCRETORY UROGRAPHY

Following intravenous injection, HEXABRIX is rapidly excreted by the kidneys. HEXABRIX may be visualized in the renal parenchyma one minute following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 7 to 12 minutes after injection. In patients with severe renal impairment, contrast visualization may be substantially delayed.

Patient Preparation

A low residue diet the day preceding the examination and a laxative the evening before the examination may be given, unless contraindicated.

Precautions

Infants and small children should not have any fluid restrictions prior to excretory urography. (See WARNINGS and PRECAUTIONS, General concerning preparatory dehydration.)

Usual Dosage

Adults — The usual adult dose is 50 to 75 mL (0.7 to 1.0 mL/kg). The total dose is normally injected within 30 to 90 seconds. A higher dosage may be indicated where poor visualization is anticipated (e.g., elderly patients, obese patients, patients with impaired renal function or patients in whom dense opacification of the pelvo-calyceal system and ureters is desired). In these patients, a dose of 100 to 150 mL (1.5 to 2.0 mL/kg) may be used.

Children — The following schedule is recommended for infants and children.
Under 6 months of age 3 mL/kg Over 6 months of age 2 mL/kg The total dosage in children should not exceed 5 mL/kg
CONTRAST ENHANCEMENT OF COMPUTED TOMOGRAPHIC (CT) HEAD IMAGING

HEXABRIX may be useful to enhance the presence and better define the extent of primary and metastatic malignancies of the head. In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement.

The use of HEXABRIX may also be beneficial in the image enhancement of non-neoplastic lesions, such as cerebral infarcts, sites of active infection, arterio-venous malformations and aneurysms.

The opacification of the inferior vermis occurs occasionally in normal studies.

Patient Preparation

No special preparation is required, however, it is advisable to insure that patients are well hydrated prior to examination.

Usual Dosage

For adults weighing up to 150 pounds, the usual dosage is 0.9 mL/lb. Patients weighing more than 150 pounds can usually undergo satisfactory examination with a dose of 135 mL not to exceed 150 mL.

CONTRAST ENHANCEMENT IN BODY COMPUTED TOMOGRAPHY

Patient Preparation

No special patient preparation is required. However, it is advisable to insure that patients are well hydrated. In patients undergoing abdominal or pelvic examination, opacification of the bowel may be valuable in scan interpretation.

Precautions

In addition to the general precautions described, patient cooperation is essential since patient motion, including respiration, can markedly affect image quality. The use of an intravascular contrast medium can obscure tumors in patients undergoing CT evaluation of the liver resulting in a false negative diagnosis. Dynamic CT scanning is the procedure of choice for malignant tumor enhancement. (See CLINICAL PHARMACOLOGY.)

Usual Dosage

HEXABRIX may be administered by bolus injection, rapid infusion or by a combination of both. Depending on the area to be examined, doses of 30-150 mL (0.4-0.9 mL/lb) may be administered. When prolonged enhancement is required up to 150 mL can be used, usually with 25-50 mL as a rapid bolus and the remainder as an infusion.

ARTHROGRAPHY

Due to the low osmolality of HEXABRIX, the concomitant use of epinephrine is not necessary since the rate of contrast medium absorption as well as the production of synovial fluid and consequent dilution of the medium are reduced.

Precautions

In addition to the general precautions previously described, strict aseptic technique is required to prevent the introduction of infection. Fluoroscopic control should be used to insure proper introduction of the needle into the synovial space and prevent extracapsular injection. Aspiration of excessive synovial fluid will reduce the pain on injection and prevent the dilution of the contrast agent. It is important that undue pressure not be exerted during the injection.

Adverse Reactions

In addition to the general adverse reactions previously described, arthrography may induce joint pain or discomfort which is usually mild and transient but occasionally may be severe and persist for 24 to 48 hours following the procedure. Effusion requiring aspiration may occur in patients with rheumatoid arthritis.

Usual Dosage

Arthrography is usually performed under local anesthesia. The amount of contrast agent required is solely dependent on the size of the joint to be injected and the technique employed.

The following dosage schedule for normal adult joints should serve only as a guide since joints may require more or less contrast medium for optimal visualization.
Knee, hip 5-15 mL Shoulder, ankle 5-20 mL Temporomandibular 0.5-0.7 mL
Passive or active manipulation is used to disperse the medium throughout the joint space.

The lower volumes of contrast medium are usually employed for double contrast examinations in which 30-100 cc of either filtered room air or carbon dioxide may be introduced for examination of the knee and lesser volumes for other joints.

HYSTEROSALPINGOGRAPHY

Patient Preparation

It is preferable to perform the procedure approximately eight to ten days after the onset of menses. The patient should empty the bladder before the examination.

Precautions

Caution should be exercised in patients suspected of having cervical or tubal carcinoma to avoid possible spread of the lesion by the procedure. Delayed onset of pain and fever (1-2 days) may be indicative of pelvic infection.

Adverse Reactions

In addition to the general adverse reactions described previously, fever and pain, cramping and tenderness of the abdomen have been reported.

Usual Dosage

The total volume administered will vary depending upon anatomical variations and/or disease processes. The usual dose varies from 5 to 15 mL, administered slowly under fluoroscopic control, without undue pressure.
Methylphenidate Hydroch...

Methylphenidate Hydrochloride

Dosage should be individualized according to the needs and responses of the patient.

Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

Extended-Release Tablets: Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.

Extended-Release Tablets: Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.

Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
Methylphenidate Hcl Ora...

Methylphenidate Hcl Oral Solution

Dosage should be individualized according to the needs and responses of the patient.

Adults

Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

Children (6 years and over)

Methylphenidate HCl Oral Solution should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.

Methylphenidate HCl Oral Solution should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
Hydromorphone Hydrochlo...

Hydromorphone Hydrochloride Extended-release

2.1          Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablets therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with hydromorphone hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Hydromorphone hydrochloride extended-release tablets must be taken whole. Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Conversion from Other Oral Hydromorphone Formulations to Hydromorphone Hydrochloride Extended-Release Tablets

Patients receiving oral immediate-release hydromorphone may be converted to hydromorphone hydrochloride extended-release tablets by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion from Other Oral Opioids to Hydromorphone Hydrochloride Extended-Release Tablets

Discontinue all other around-the-clock opioid drugs when hydromorphone hydrochloride extended-release tablets therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements, which could result in adverse reactions.

In a hydromorphone hydrochloride extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to hydromorphone hydrochloride extended-release tablets using the Table 1 as a guide for the initial hydromorphone hydrochloride extended-release tablets dose. The recommended starting dose of hydromorphone hydrochloride extended-release tablets is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to hydromorphone hydrochloride extended-release tablets. The table cannot be used to convert from hydromorphone hydrochloride extended-release tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1. Conversion Factors to Hydromorphone Hydrochloride Extended-Release Tablets

Prior Oral Opioid

Approximate Oral

Conversion Factor

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6
To calculate the estimated hydromorphone hydrochloride extended-release tablets dose using Table 1: For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablets strength(s) available.

Example conversion from a single opioid to hydromorphone hydrochloride extended-release tablets:

Step 1: Sum the total daily dose of the opioid
30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily
Step 3: Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablets strengths available.
50% of 24 mg results in an initial dose of 12 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to hydromorphone hydrochloride extended-release tablets.

Conversion from Transdermal Fentanyl to Hydromorphone Hydrochloride Extended-Release Tablets

Eighteen hours following the removal of the transdermal fentanyl patch, hydromorphone hydrochloride extended-release tablets treatment can be initiated. To calculate the 24-hour hydromorphone hydrochloride extended-release tablets dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets. Then reduce the hydromorphone hydrochloride extended-release tablets dose by 50%.

For example:

Step 1:    Identify the dose of transdermal fentanyl.
75 mg of transdermal fentanyl
Step 2:    Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets.
75 mg of transdermal fentanyl : 36 mg total daily dose of hydromorphone hydrochloride extended-release tablets
Step 3:    Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablets strengths available.
50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Conversion from Methadone to Hydromorphone Hydrochloride Extended-Release Tablets

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2        Titration and Maintenance of Therapy

Individually titrate hydromorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydromorphone hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Plasma levels of hydromorphone hydrochloride extended-release tablets are sustained for 18 to 24 hours. Dosage adjustments of hydromorphone hydrochloride extended-release tablets may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.

Patients who experience breakthrough pain may require a dose increase of hydromorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the hydromorphone hydrochloride extended-release tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3        Discontinuation of Hydromorphone Hydrochloride Extended-Release Tablets

When a patient no longer requires therapy with hydromorphone hydrochloride extended-release tablets, taper doses gradually, by 25% to 50% every 2 or 3 days down to a dose of 8 mg before discontinuation of therapy, to prevent signs and symptoms of withdrawal in the opioid-tolerant patient.

To dispose of unused hydromorphone hydrochloride extended-release tablets flush all remaining tablets down the toilet or remit to authorities at a certified drug take-back program.

2.4        Hepatic Impairment

Start patients with moderate hepatic impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

2.5        Renal Impairment

Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. As hydromorphone hydrochloride extended-release tablets are only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Use in Specific Populations (8.7)].

2.6        Administration of Hydromorphone Hydrochloride Extended-Release Tablets

Instruct patients to swallow hydromorphone hydrochloride extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5.2)].
Oxymorphone Hydrochlori...

Oxymorphone Hydrochloride Extended-release

2.1 Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg and 10 mg tablets and extended-release 5 mg and 10 mg tablets [see Dosage Forms and Strengths].

Oxymorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with oxymorphone hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Oxymorphone hydrochloride extended-release tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving oxymorphone hydrochloride extended-release tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Oxymorphone hydrochloride extended-release tablets are administered at a frequency of twice daily (every 12 hours). Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

Use of Oxymorphone Hydrochloride Extended-Release Tablets as the First Opioid AnalgesicInitiate treatment with oxymorphone hydrochloride extended-release tablets with the 5 mg tablet orally every 12 hours.

Use of Oxymorphone Hydrochloride Extended-Release Tablets in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is oxymorphone hydrochloride extended-release tablets 5 mg orally every 12 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Oxymorphone Hydrochloride Tablets to Oxymorphone Hydrochloride Extended-Release Tablets

Patients receiving oxymorphone hydrochloride tablets may be converted to oxymorphone hydrochloride extended-release tablets by administering half the patient's total daily oral oxymorphone hydrochloride tablets dose as oxymorphone hydrochloride extended-release tablets, every 12 hours.

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets

The absolute oral bioavailability of oxymorphone hydrochloride extended-release tablets is approximately 10%. Convert patients receiving parenteral oxymorphone to oxymorphone hydrochloride extended-release tablets by administering 10 times the patient's total daily parenteral oxymorphone dose as oxymorphone hydrochloride extended-release tablets in two equally divided doses (e.g., [IV dose x 10] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion monitor patients closely to evaluate for adequate analgesia and side effects.

Conversion from Other Oral Opioids to Oxymorphone Hydrochloride Extended-Release TabletsDiscontinue all other around-the-clock opioid drugs when oxymorphone hydrochloride extended-release tablets therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral oxymorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxymorphone requirements which could result in adverse reactions. In an oxymorphone hydrochloride extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to oxymorphone hydrochloride extended-release tablets using Table 1 as a guide for the initial oxymorphone hydrochloride extended-release tablets dose.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to oxymorphone hydrochloride extended-release tablets. This table cannot be used to convert from oxymorphone hydrochloride extended-release tablets to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.
CONVERSION FACTORS TO OXYMORPHONEHYDROCHLORIDE EXTENDED-RELEASE TABLETS

Prior Oral Opioid

Approximate Oral Conversion Factor

Oxymorphone

1

Hydrocodone

0.5

Oxycodone

0.5

Methadone

0.5

Morphine

0.333

To calculate the estimated oxymorphone hydrochloride extended-release tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral (active opioid) daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral (active opioid) dose for each opioid and sum the totals to obtain the approximate total (active opioid) daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion
Always round the dose down, if necessary, to the appropriate oxymorphone hydrochloride extended-release tablets strength(s) available.

Example conversion from a single opioid to oxymorphone hydrochloride extended-release tablets:

Step 1:   Sum the total daily dose of the opioid oxycodone 20 mg BID

               20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid

Step 2: Calculate the approximate equivalent dose of oral (active opioid) based on the total daily dose of the current opioid using Table 1

               40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily

Step 3: Calculate the approximate starting dose of oxymorphone hydrochloride extended-release tablets to be given every 12 hours. Round down, if necessary, to the appropriate oxymorphone hydrochloride extended-release tablets strengths available.

               10 mg oxymorphone hydrochloride extended-release tablets every 12 hours

Conversion from Methadone to Oxymorphone Hydrochloride Extended-Release TabletsClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2 Titration and Maintenance of Therapy

Individually titrate oxymorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving oxymorphone hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, and misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the oxymorphone hydrochloride extended-release tablets dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, oxymorphone hydrochloride extended-release tablets dosage adjustments, preferably at increments of 5 to 10 mg every 12 hours, may be done every 3 to 7 days.

Patients who experience breakthrough pain may require a dose increase of oxymorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing oxymorphone hydrochloride extended-release tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of Oxymorphone Hydrochloride Extended-Release Tablets

When a patient no longer requires therapy with oxymorphone hydrochloride extended-release tablets, use a gradual downward titration of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue oxymorphone hydrochloride extended-release tablets.

2.4 Administration of Oxymorphone Hydrochloride Extended-Release Tablets

Instruct patients to swallow oxymorphone hydrochloride extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of oxymorphone [see Warnings and Precautions (5.2)]. Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

2.5 Patients with Hepatic Impairment

Oxymorphone hydrochloride extended-release tablets are contraindicated in patients with moderate or severe hepatic impairment.

In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.6 Patients with Renal Impairment

In patients with creatinine clearance rates less than 50 mL/min, start oxymorphone hydrochloride extended-release tablets in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a patient with normal renal function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.7 Geriatric Patients

The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects. Initiate dosing with oxymorphone hydrochloride extended-release tablets in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating oxymorphone hydrochloride extended-release tablets to adequate analgesia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.

2.1 Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg and 10 mg tablets and extended-release 5 mg and 10 mg tablets [see Dosage Forms and Strengths].

Oxymorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with oxymorphone hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Oxymorphone hydrochloride extended-release tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving oxymorphone hydrochloride extended-release tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Oxymorphone hydrochloride extended-release tablets are administered at a frequency of twice daily (every 12 hours). Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

Use of Oxymorphone Hydrochloride Extended-Release Tablets as the First Opioid AnalgesicInitiate treatment with oxymorphone hydrochloride extended-release tablets with the 5 mg tablet orally every 12 hours.

Use of Oxymorphone Hydrochloride Extended-Release Tablets in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is oxymorphone hydrochloride extended-release tablets 5 mg orally every 12 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Oxymorphone Hydrochloride Tablets to Oxymorphone Hydrochloride Extended-Release Tablets

Patients receiving oxymorphone hydrochloride tablets may be converted to oxymorphone hydrochloride extended-release tablets by administering half the patient's total daily oral oxymorphone hydrochloride tablets dose as oxymorphone hydrochloride extended-release tablets, every 12 hours.

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets

The absolute oral bioavailability of oxymorphone hydrochloride extended-release tablets is approximately 10%. Convert patients receiving parenteral oxymorphone to oxymorphone hydrochloride extended-release tablets by administering 10 times the patient's total daily parenteral oxymorphone dose as oxymorphone hydrochloride extended-release tablets in two equally divided doses (e.g., [IV dose x 10] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion monitor patients closely to evaluate for adequate analgesia and side effects.

Conversion from Other Oral Opioids to Oxymorphone Hydrochloride Extended-Release TabletsDiscontinue all other around-the-clock opioid drugs when oxymorphone hydrochloride extended-release tablets therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral oxymorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxymorphone requirements which could result in adverse reactions. In an oxymorphone hydrochloride extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to oxymorphone hydrochloride extended-release tablets using Table 1 as a guide for the initial oxymorphone hydrochloride extended-release tablets dose.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to oxymorphone hydrochloride extended-release tablets. This table cannot be used to convert from oxymorphone hydrochloride extended-release tablets to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.
CONVERSION FACTORS TO OXYMORPHONEHYDROCHLORIDE EXTENDED-RELEASE TABLETS

Prior Oral Opioid

Approximate Oral Conversion Factor

Oxymorphone

1

Hydrocodone

0.5

Oxycodone

0.5

Methadone

0.5

Morphine

0.333

To calculate the estimated oxymorphone hydrochloride extended-release tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral (active opioid) daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral (active opioid) dose for each opioid and sum the totals to obtain the approximate total (active opioid) daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion
Always round the dose down, if necessary, to the appropriate oxymorphone hydrochloride extended-release tablets strength(s) available.

Example conversion from a single opioid to oxymorphone hydrochloride extended-release tablets:

Step 1:   Sum the total daily dose of the opioid oxycodone 20 mg BID

               20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid

Step 2: Calculate the approximate equivalent dose of oral (active opioid) based on the total daily dose of the current opioid using Table 1

               40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily

Step 3: Calculate the approximate starting dose of oxymorphone hydrochloride extended-release tablets to be given every 12 hours. Round down, if necessary, to the appropriate oxymorphone hydrochloride extended-release tablets strengths available.

               10 mg oxymorphone hydrochloride extended-release tablets every 12 hours

Conversion from Methadone to Oxymorphone Hydrochloride Extended-Release TabletsClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2 Titration and Maintenance of Therapy

Individually titrate oxymorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving oxymorphone hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, and misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the oxymorphone hydrochloride extended-release tablets dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, oxymorphone hydrochloride extended-release tablets dosage adjustments, preferably at increments of 5 to 10 mg every 12 hours, may be done every 3 to 7 days.

Patients who experience breakthrough pain may require a dose increase of oxymorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing oxymorphone hydrochloride extended-release tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of Oxymorphone Hydrochloride Extended-Release Tablets

When a patient no longer requires therapy with oxymorphone hydrochloride extended-release tablets, use a gradual downward titration of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue oxymorphone hydrochloride extended-release tablets.

2.4 Administration of Oxymorphone Hydrochloride Extended-Release Tablets

Instruct patients to swallow oxymorphone hydrochloride extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of oxymorphone [see Warnings and Precautions (5.2)]. Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

2.5 Patients with Hepatic Impairment

Oxymorphone hydrochloride extended-release tablets are contraindicated in patients with moderate or severe hepatic impairment.

In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.6 Patients with Renal Impairment

In patients with creatinine clearance rates less than 50 mL/min, start oxymorphone hydrochloride extended-release tablets in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a patient with normal renal function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.7 Geriatric Patients

The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects. Initiate dosing with oxymorphone hydrochloride extended-release tablets in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating oxymorphone hydrochloride extended-release tablets to adequate analgesia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start oxymorphone hydrochloride extended-release tablets at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.
Folic Acid

Folic Acid

METHADONE HYDROCHLORIDE POWDER MUST BE DISSOLVED IN AN APPROPRIATE LIQUID VEHICLE BEFORE ORAL ADMINISTRATION.

For Detoxification Treatment:

THE DRUG SHALL BE ADMINISTERED DAILY UNDER CLOSE SUPERVISION AS FOLLOWS:

A detoxification treatment course shall not exceed twenty-one days and may not be repeated earlier than four weeks after completion of the preceding course.

In detoxification, the patient may receive methadone when there are significant symptoms of withdrawal. The dosage schedules indicated below are recommended but could be varied in accordance with clinical judgment. Initially, a single oral dose of 15 to 20 mg. of methadone will often be sufficient to suppress withdrawal symptoms. Additional methadone may be provided if withdrawal symptoms are not suppressed or if symptoms reappear. When patients are physically dependent on high doses, it may be necessary to exceed these levels. Forty mg. per day in single or divided doses will usually constitute an adequate stabilizing dosage level. Stabilization can be continued for two to three days, and then the amount of methadone normally will be gradually decreased. The rate at which methadone is decreased will be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at two-day intervals, but the amount of intake shall always be sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20 percent of the total daily dose may be tolerated and may cause little discomfort. In ambulatory patients, a somewhat slower schedule may be needed. If methadone is administered for more than three weeks, the procedure is considered to have progressed from detoxification or treatment of the acute withdrawal syndrome to maintenance treatment, even though the goal and intent may be eventual total withdrawal.

For Maintenance Treatment:

In maintenance treatment, the initial dosage of methadone should control the abstinence symptoms that follow withdrawal of narcotic drugs but should not be so great as to cause sedation, respiratory depression, or other effects of acute intoxication. It is important that the initial dosage be adjusted on an individual basis to the narcotic tolerance of the new patient. If such a patient has been a heavy user of heroin up to the day of admission, he may be given 20 mg. four to eight hours later or 40 mg. in a single oral dose. If he enters treatment with little or no narcotic tolerance (e.g., if he has recently been released from jail or other confinement), the initial dosage maybe one-half these quantities. When there is any doubt, the smaller dose should be used initially. The patient should then be kept under observation, and, if symptoms of abstinence are distressing, additional 10 mg. doses may be administered as needed. Subsequently, the dosage should be adjusted individually, as tolerated and required, up to a level of 120 mg. daily. The patient will initially ingest the drug under observation daily, or at least six days a week, for the first three months. After demonstrating satisfactory adherence to the program regulations for at least three months, the patient may be permitted to reduce to three times weekly the occasions when he must ingest the drug under observation. He shall receive no more than a two-day take-home supply. With continuing adherence to the program’s requirements for at least two years, he may then be permitted twice-weekly visits to the program for drug ingestion under observation with a three-day take-home supply. A daily dose of 120 mg. or more shall be justified in the medical record. Prior approval from state authority and the Food and Drug Administration is required for any dose above 120 mg. administered at the clinic and for any dose above 100 mg. to be taken at home. A regular review of dosage level should be made by the responsible physician, with careful consideration given to reduction of dosage as indicated on an individual basis. A new dosage level is only a test level until stability is achieved.

Special Consideration for a Pregnant Patient:

Caution shall be taken in the maintenance treatment of pregnant patients. Dosage levels shall be kept as low as possible if continued methadone treatment is deemed necessary. It is the responsibility of the program sponsor to assure that each female patient be fully informed concerning the possible risks to a pregnant woman or her unborn child from the use of methadone.

Special Limitations:

Treatment of Patients Under Age Eighteen

1. The safety and effectiveness of methadone for use in the treatment of adolescents have not been proven by adequate clinical study. Special procedures are therefore necessary to assure that patients under age sixteen will not be admitted to a program and that patients between sixteen and eighteen years of age will be admitted to maintenance treatment only under limited conditions.

2. Patients between sixteen and eighteen years of age who were enrolled and under treatment in approved programs on December 15, 1972, may continue in maintenance treatment. No new patients between sixteen and eighteen years of age may be admitted to a maintenance treatment program after March 15, 1973, unless a parent, legal guardian, or responsible adult designated by the state authority completes and signs Form FD 2635, “Consent for Methadone Treatment.”

Methadone treatment of new patients between the ages of sixteen and eighteen years will be permitted after December 15, 1972, only with a documented history of two or more unsuccessful attempts at detoxification and a documented history of dependence on heroin or other morphine-like drugs beginning two years or more prior to application for treatment. No patient under age sixteen may be continued or started on methadone treatment after December 15, 1972, but these patients may be detoxified and retained in the program in a drug-free state for follow-up and aftercare.

3. Patients under age eighteen who are not placed on maintenance treatment may be detoxified. Detoxification may not exceed three weeks. A repeat episode of detoxification may not be initiated until four weeks after the completion of the previous detoxification.
Methadose

Methadose

Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

While methadone's duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone's plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex.

The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.

Detoxification and Maintenance Treatment of Opiate Dependence

For detoxification and maintenance of opiate dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Induction/Initial Dosing

The initial methadone dose should be administered, under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days' dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use.

For Short-term Detoxification

For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.

For Maintenance Treatment

Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

For Medically Supervised Withdrawal After a Period of Maintenance Treatment

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
Anafranil

Anafranil

The treatment regimens described below are based on those used in controlled clinical trials of Anafranil in 520 adults, and 91 children and adolescents with OCD. During initial titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.

Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change (see CLINICAL PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.

Initial Treatment/Dose Adjustment (Adults)

Treatment with Anafranil should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Initial Treatment/Dose Adjustment (Children and Adolescents)

As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS, Pediatric Use). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Maintenance/Continuation Treatment (Adults, Children, and Adolescents)

While there are no systematic studies that answer the question of how long to continue Anafranil, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Anafranil after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Anafranil. Conversely, at least 14 days should be allowed after stopping Anafranil before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Anafranil With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start Anafranil in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving Anafranil therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Anafranil should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Anafranil may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Anafranil is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Pamelor

Pamelor

Pamelor is not recommended for children.

Pamelor is administered orally in the form of capsules. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission.

If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur.

Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dosage may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg/day are not recommended.

Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily dosage may be given once a day.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Pamelor. Conversely, at least 14 days should be allowed after stopping Pamelor before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Pamelor With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start Pamelor in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving Pamelor therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Pamelor should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Pamelor may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Pamelor is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Tofranil-pm

Tofranil-pm

The following recommended dosages for Tofranil-PM should be modified as necessary by the clinical response and any evidence of intolerance.

Initial Adult Dosage

Outpatients – Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day.

Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Hospitalized Patients – Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day.

Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Adult Maintenance Dosage – Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.

The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.

Adolescent and Geriatric Patients – Therapy in these age groups should be initiated with Tofranil™, brand of imipramine hydrochloride tablets, at a total daily dosage of 25 to 50 mg, since Tofranil-PM capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Tofranil-PM capsules may be used when total daily dosage is established at 75 mg or higher.

The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.

The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Tofranil-PM. Conversely, at least 14 days should be allowed after stopping Tofranil-PM before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Tofranil-PM With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start Tofranil-PM in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving Tofranil-PM therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Tofranil-PM should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Tofranil-PM may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Tofranil-PM is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Tofranil

Tofranil

Depression

Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission.

Usual Adult Dose

Hospitalized Patients – Initially, 100 mg/day in divided doses gradually increased to 200 mg/day as required. If no response after two weeks, increase to 250 to 300 mg/day.

Outpatients – Initially, 75 mg/day increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance, 50 to 150 mg/day.

Adolescent and Geriatric Patients – Initially, 30 to 40 mg/day; it is generally not necessary to exceed 100 mg/day.

Childhood Enuresis

Initially, an oral dose of 25 mg/day should be tried in children aged 6 and older. Medication should be given one hour before bedtime. If a satisfactory response does not occur within one week, increase the dose to 50 mg nightly in children under 12 years; children over 12 may receive up to 75 mg nightly. A daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. Evidence suggests that in early night bedwetters, the drug is more effective given earlier and in divided amounts, i.e., 25 mg in midafternoon, repeated at bedtime. Consideration should be given to instituting a drug free period following an adequate therapeutic trial with a favorable response. Dosage should be tapered off gradually rather than abruptly discontinued; this may reduce the tendency to relapse. Children who relapse when the drug is discontinued do not always respond to a subsequent course of treatment.

A dose of 2.5 mg/kg/day should not be exceeded. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

The safety and effectiveness of Tofranil as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.
Sodium Iodide I 131

Sodium Iodide I 131

2.1 Radiation Safety

Sodium iodide I-131 capsules emit radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)].
Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Wear waterproof gloves during the entire sodium iodide I-131 capsule handling and administration procedure. Maintain adequate shielding during the radiation-emitting life of the product. Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration.
2.2 Hyperthyroidism

For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations.   Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)].

2.3 Thyroid Carcinoma

For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi).

2.4 Individualization of Therapy

Individualize sodium iodide I-131 therapy, including dose selection, based upon patient-specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)].

2.5 Radiation Dosimetry

The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1.

Table 1. Absorbed Radiation Doses

Tissue

Thyroid Uptake

5%

15%

25%

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

Thyroid

72

266

210

777

360

1300

Stomach Wall

0.45

1.7

0.46

1.7

0.46

1.7

Red Marrow

0.038

0.14

0.054

0.20

0.07

0.26

Liver

0.03

0.11

0.032

0.12

0.035

0.13

Testes

0.029

0.11

0.028

0.10

0.027

0.10

Ovaries

0.044

0.16

0.043

0.16

0.043

0.16

Urinary Bladder

0.58

2.1

0.52

1.9

0.46

1.7

Salivary Glands2

0.5

1.85

0.5

1.85

0.5

1.85

Other

0.040

0.15

0.065

0.24

0.090

0.33

2.1 Radiation Safety

Sodium iodide I-131 capsules emit radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)].
Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Wear waterproof gloves during the entire sodium iodide I-131 capsule handling and administration procedure. Maintain adequate shielding during the radiation-emitting life of the product. Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration.
2.2 Hyperthyroidism

For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations.   Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)].

2.3 Thyroid Carcinoma

For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi).

2.4 Individualization of Therapy

Individualize sodium iodide I-131 therapy, including dose selection, based upon patient-specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)].

2.5 Radiation Dosimetry

The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1.

Table 1. Absorbed Radiation Doses

Tissue

Thyroid Uptake

5%

15%

25%

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

Thyroid

72

266

210

777

360

1300

Stomach Wall

0.45

1.7

0.46

1.7

0.46

1.7

Red Marrow

0.038

0.14

0.054

0.20

0.07

0.26

Liver

0.03

0.11

0.032

0.12

0.035

0.13

Testes

0.029

0.11

0.028

0.10

0.027

0.10

Ovaries

0.044

0.16

0.043

0.16

0.043

0.16

Urinary Bladder

0.58

2.1

0.52

1.9

0.46

1.7

Salivary Glands2

0.5

1.85

0.5

1.85

0.5

1.85

Other

0.040

0.15

0.065

0.24

0.090

0.33
Sodium Iodide I-131 The...

Sodium Iodide I-131 Therapeutic

2.1 Radiation Safety

Sodium iodide I-131 solution emits radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)].
Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Wear waterproof gloves during the entire sodium iodide I-131 solution handling and administration procedure. Maintain adequate shielding during the radiation-emitting life of the product. Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration.
2.2 Hyperthyroidism

For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations. Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)].

2.3 Thyroid Carcinoma

For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi).

2.4 Individualization of Therapy

Individualize sodium iodide I-131 therapy, including dose selection, based upon patient-specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)].

2.5 Radiation Dosimetry

The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1.

Table 1. Absorbed Radiation Doses

Tissue

Thyroid Uptake

5%

15%

25%

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

Thyroid

72

266

210

777

360

1300

Stomach Wall

0.45

1.7

0.46

1.7

0.46

1.7

Red Marrow

0.038

0.14

0.054

0.20

0.07

0.26

Liver

0.03

0.11

0.032

0.12

0.035

0.13

Testes

0.029

0.11

0.028

0.10

0.027

0.10

Ovaries

0.044

0.16

0.043

0.16

0.043

0.16

Urinary Bladder

0.58

2.1

0.52

1.9

0.46

1.7

Salivary Glands2

0.5

1.85

0.5

1.85

0.5

1.85

Other

0.040

0.15

0.065

0.24

0.090

0.33

2.1 Radiation Safety

Sodium iodide I-131 solution emits radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)].
Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Wear waterproof gloves during the entire sodium iodide I-131 solution handling and administration procedure. Maintain adequate shielding during the radiation-emitting life of the product. Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration.
2.2 Hyperthyroidism

For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations. Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)].

2.3 Thyroid Carcinoma

For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi).

2.4 Individualization of Therapy

Individualize sodium iodide I-131 therapy, including dose selection, based upon patient-specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)].

2.5 Radiation Dosimetry

The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1.

Table 1. Absorbed Radiation Doses

Tissue

Thyroid Uptake

5%

15%

25%

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

mGy/

MBq

rads/

mCi

Thyroid

72

266

210

777

360

1300

Stomach Wall

0.45

1.7

0.46

1.7

0.46

1.7

Red Marrow

0.038

0.14

0.054

0.20

0.07

0.26

Liver

0.03

0.11

0.032

0.12

0.035

0.13

Testes

0.029

0.11

0.028

0.10

0.027

0.10

Ovaries

0.044

0.16

0.043

0.16

0.043

0.16

Urinary Bladder

0.58

2.1

0.52

1.9

0.46

1.7

Salivary Glands2

0.5

1.85

0.5

1.85

0.5

1.85

Other

0.040

0.15

0.065

0.24

0.090

0.33
Restoril

Restoril

While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined.
Lisinopril

Lisinopril

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Oxycodone and acetaminophen tablets are given orally.

The total daily dose of acetaminophen should not exceed 4 grams.
Strength UsualAdult Dosage MaximalDaily Dose Oxycodone and acetaminophen tablets 5 mg/325 mg 1 tablet every 6 hours as needed for pain 12Tablets Oxycodone and acetaminophen tablets 7.5 mg/325 mg 1 tablet every 6 hours as needed for pain 8Tablets Oxycodone and acetaminophen tablets 10 mg/325 mg 1 tablet every 6 hours as needed for pain 6Tablets
In patients treated with oxycodone and acetaminophen tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Methylphenidate Hydroch...

Methylphenidate Hydrochloride Extended-release

2.1 General Dosing Information

Methylphenidate hydrochloride extended-release tablets should be administered orally once daily in the morning with or without food.

Methylphenidate hydrochloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17)].

2.2 Patients New to Methylphenidate

The recommended starting dose of methylphenidate hydrochloride extended-release tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1).

Table 1. Methylphenidate Hydrochloride Extended-Release Tablets Recommended Starting Doses and Dose Ranges

Patient Age

Recommended Starting Dose

Dose Range

Children6-12 years of age

18 mg/day

18 mg - 54 mg/day

Adolescents13-17 years of age

18 mg/day

18 mg - 72 mg/day not to exceed 2 mg/kg/day

Adults18-65 years of age

18 or 36 mg/day

18 mg - 72 mg/day

2.3 Patients Currently Using Methylphenidate

The recommended dose of methylphenidate hydrochloride extended-release tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily.

Table 2. Recommended Dose Conversion from Methylphenidate Regimens to Methylphenidate Hydrochloride Extended-Release Tablets

Previous Methylphenidate Daily Dose

Recommended Methylphenidate Hydrochloride Extended-Release Tablets Starting Dose

5 mg Methylphenidate twice daily or three times daily

18 mg every morning

10 mg Methylphenidate twice daily or three times daily

36 mg every morning

15 mg Methylphenidate twice daily or three times daily

54 mg every morning

20 mg Methylphenidate twice daily or three times daily

72 mg every morning

Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.

2.4 Dose Titration

Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended.

A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages.

2.5 Maintenance/Extended Treatment

There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with methylphenidate hydrochloride extended-release tablets. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods.

The effectiveness of methylphenidate hydrochloride extended-release tablets for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use methylphenidate hydrochloride extended-release tablets for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

2.6 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
Conray 30

Conray 30

It is advisable that Conray 30 be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Conray

Conray

It is advisable that Conray be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If a minor reaction occurs during administration, the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs, the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Optimark

Optimark

2.1 Directions for Proper use of Pharmacy Bulk Package
NOT FOR DIRECT INFUSION
The 50 mL Pharmacy Bulk Package is used as a multiple dose container with an appropriate transfer device to fill empty sterile syringes. Use the following procedure when transferring Optimark from the pharmacy bulk package to individual syringes:
Use of this product is restricted to a suitable work area, such as a laminar flow hood, utilizing aseptic technique. Prior to entering the vial, remove the seal and cleanse the rubber closure with a suitable antiseptic agent. Once the pharmacy bulk package is punctured, do not remove from the aseptic work area during the entire period of use. Penetrate the container closure only one time, utilizing a suitable transfer device or dispensing set that allows measured dispensing of the contents. Withdrawal of container contents should be accomplished without delay. A maximum time of 24 hours from initial closure entry is permitted to complete fluid transfer operations. Discard any unused Optimark 24 hours after the initial puncture of the bulk package.
2.2 Dosing Guidelines
Administer Optimark as a bolus peripheral intravenous injection at a dose of 0.2 mL/kg (0.1 mmol/kg) and at a rate of 1 to 2 mL/sec delivered by manual or by power injection (see Table 1). Follow injection with a 5 mL normal saline flush to ensure complete administration of the contrast. Discard unused portions of the drug.
Table 1 Dosage Chart for Optimark Injection

Body Weight Kilograms (kg)

0.1 mmol/kgVolume (mL)

40

8

50

10

60

12

70

14

80

16

90

18

100

20

110

22

120

24

130

26

140

28

150

30

2.3 Drug Handling
Visually inspect Optimark for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix Optimark with other medications or parenteral nutrition and do not administer Optimark in the same intravenous line as other medications because of the potential for chemical incompatibility.
2.4 Imaging
Complete the imaging procedure within 1 hour of the injection of Optimark. Paramagnetic contrast agents may impair the visualization of lesions seen on non-contrast MRI. Interpret Optimark MR images with companion non-contrast MR images [see Clinical Pharmacology (12.2)].
Optimark

Optimark

2.1 Dosing Guidelines
Administer Optimark as a bolus peripheral intravenous injection at a dose of 0.2 mL/kg (0.1 mmol/kg) and at a rate of 1 to 2 mL/sec delivered by manual or by power injection (see Table 1). Use sterile technique to withdraw and administer Optimark. Follow injection with a 5 mL normal saline flush to ensure complete administration of the contrast. Discard unused portions of the drug.
Table 1 Dosage Chart for Optimark Injection

Body Weight Kilograms (kg)

0.1 mmol/kgVolume (mL)

40

8

50

10

60

12

70

14

80

16

90

18

100

20

110

22

120

24

130

26

140

28

150

30

2.2 Drug Handling
Visually inspect Optimark for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix Optimark with other medications or parenteral nutrition and do not administer Optimark in the same intravenous line as other medications because of the potential for chemical incompatibility.
2.3 Imaging
Complete the imaging procedure within 1 hour of the injection of Optimark. Paramagnetic contrast agents may impair the visualization of lesions seen on non-contrast MRI. Interpret Optimark MR images with companion non-contrast MR images [see Clinical Pharmacology (12.2)].
2.1 Dosing Guidelines
Administer Optimark as a bolus peripheral intravenous injection at a dose of 0.2 mL/kg (0.1 mmol/kg) and at a rate of 1 to 2 mL/sec delivered by manual or by power injection (see Table 1). Use sterile technique to withdraw and administer Optimark. Follow injection with a 5 mL normal saline flush to ensure complete administration of the contrast. Discard unused portions of the drug.
Table 1 Dosage Chart for Optimark Injection

Body Weight Kilograms (kg)

0.1 mmol/kgVolume (mL)

40

8

50

10

60

12

70

14

80

16

90

18

100

20

110

22

120

24

130

26

140

28

150

30

2.2 Drug Handling
Visually inspect Optimark for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix Optimark with other medications or parenteral nutrition and do not administer Optimark in the same intravenous line as other medications because of the potential for chemical incompatibility.
2.3 Imaging
Complete the imaging procedure within 1 hour of the injection of Optimark. Paramagnetic contrast agents may impair the visualization of lesions seen on non-contrast MRI. Interpret Optimark MR images with companion non-contrast MR images [see Clinical Pharmacology (12.2)].
Optimark

Optimark

2.1 Dosing Guidelines
Administer Optimark as a bolus peripheral intravenous injection at a dose of 0.2 mL/kg (0.1 mmol/kg) and at a rate of 1 to 2 mL/sec delivered by manual or by power injection (see Table 1). Use sterile technique to withdraw and administer Optimark. Follow injection with a 5 mL normal saline flush to ensure complete administration of the contrast. Discard unused portions of the drug.
Table 1 Dosage Chart for Optimark Injection

Body Weight Kilograms (kg)

0.1 mmol/kgVolume (mL)

40

8

50

10

60

12

70

14

80

16

90

18

100

20

110

22

120

24

130

26

140

28

150

30

2.2 Drug Handling
Visually inspect Optimark for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix Optimark with other medications or parenteral nutrition and do not administer Optimark in the same intravenous line as other medications because of the potential for chemical incompatibility.
2.3 Imaging
Complete the imaging procedure within 1 hour of the injection of Optimark. Paramagnetic contrast agents may impair the visualization of lesions seen on non-contrast MRI. Interpret Optimark MR images with companion non-contrast MR images [see Clinical Pharmacology (12.2)].
2.1 Dosing Guidelines
Administer Optimark as a bolus peripheral intravenous injection at a dose of 0.2 mL/kg (0.1 mmol/kg) and at a rate of 1 to 2 mL/sec delivered by manual or by power injection (see Table 1). Use sterile technique to withdraw and administer Optimark. Follow injection with a 5 mL normal saline flush to ensure complete administration of the contrast. Discard unused portions of the drug.
Table 1 Dosage Chart for Optimark Injection

Body Weight Kilograms (kg)

0.1 mmol/kgVolume (mL)

40

8

50

10

60

12

70

14

80

16

90

18

100

20

110

22

120

24

130

26

140

28

150

30

2.2 Drug Handling
Visually inspect Optimark for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix Optimark with other medications or parenteral nutrition and do not administer Optimark in the same intravenous line as other medications because of the potential for chemical incompatibility.
2.3 Imaging
Complete the imaging procedure within 1 hour of the injection of Optimark. Paramagnetic contrast agents may impair the visualization of lesions seen on non-contrast MRI. Interpret Optimark MR images with companion non-contrast MR images [see Clinical Pharmacology (12.2)].
Heparin Sodium

Heparin Sodium

2.1 General Instructions

For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day.

The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required.

After the priming procedure, PENNSAID is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee.

Apply PENNSAID to clean, dry skin.

Application of PENNSAID in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

2.2 Special Precautions
Avoid showering/bathing for at least 30 minutes after the application of PENNSAID to the treated knee. Wash and dry hands after use. Do not apply PENNSAID to open wounds. Avoid contact of PENNSAID with eyes and mucous membranes. Avoid wearing clothing over the PENNSAID-treated knee(s) until the treated knee is dry. Protect the treated knee(s) from natural and artificial sunlight. PENNSAID was not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise; therefore, concurrent use of PENNSAID under these conditions is not recommended. Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with PENNSAID. Do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Sodium Chloride

Sodium Chloride

The 50 mL syringe and the 125 mL syringe are for single patient use only. Determine the volume of the saline flush for each patient individually based, in part, on the imaging procedure, the location of the vascular access device, the length of tubing between the Mallinckrodt contrast agent power injector and the vascular access device and the recommendations made on the package insert for the contrast agent. Typical Sodium Chloride Injection USP 0.9% flush volumes following contrast agent administration in adults are 10 to 25 mL per injection at rates not to exceed 10 mL/sec. Use of some Mallinckrodt contrast agent power injectors allows for additional infusion of Sodium Chloride Injection USP 0.9% to maintain the patency of vascular access. Typical infusion rates used for this purpose are in the range of 0.5 to 1 mL per minute. Individualize infusion rates and flush volumes for each patient based on their body weight, fluid status and concomitant medical conditions. Consult the Mallinckrodt contrast agent power injector manual for proper use.

2.1 Drug Handling
Inspect the syringe for signs of break in sterility. Do not use if the syringe or its tip cap shows signs of damage, leakage or displacement. Do not use if the solution is hazy, cloudy, discolored or contains particulate matter. Use aseptic technique. Expel residual air in both the syringe and tubing prior to connection with the patient’s vascular access. Instructions for assembly and inspection of the Sodium Chloride Injection USP 0.9% syringes prior to use are printed on this sheet.

2.2 50 mL Syringe Assembly and Inspection

NOTE: Exterior of syringe is not sterile. Contents of syringe and area under tip cap and piston ribs are sterile and should be treated accordingly.

Remove syringe from carton and inspect the area around the tip cap and outside of piston for signs of leakage. Do not use if leakage is observed.

After screwing the push rod into the syringe piston, it is important to turn the push rod an additional ½ turn so that the piston rotates freely.

Prior to using the syringe, twist off tip cap and discard. The area under the tip cap is sterile, caution should now be used when handling. Syringe is now ready for needle or infusion tubing attachment.

2.3 125 mL Syringe Assembly and Inspection

NOTE: Exterior of syringe is not sterile. Contents of syringe and area under tip cap and piston ribs are sterile and should be treated accordingly.

Remove syringe from carton and inspect the area around the tip cap and outside of piston for signs of leakage. Do not use if leakage is observed. Load syringe into power injector.

To remove tip cap from syringe, push in and twist off, then discard. The area under the cap is sterile. Caution should now be used when handling.

Next remove cap from luer locknut dust cover by twisting to break tamper evident seal. Discard cap.

Attach luer locknut to syringe by holding dust cover and screwing to the stop.Remove and discard dust cover when ready to attach sterile connector tubing.
Md-gastroview

Md-gastroview

General

This medium is not to be used for the preparation of solutions for parenteral administration. Oral or rectal use only.
The routine preparatory measures employed for barium studies are also appropriate for this agent. For pediatric and severely cachectic patients, the maintenance of an intravenous fluid line may be advisable.
Radiographic Examination of Segments of the Gastrointestinal Tract

Oral Administration: Adult oral dosage may range from 30 to 90 mL (11 to 33 g iodine), depending on the nature of the examination and the size of the patient. For infants and children less than 5 years of age, 30 mL (11 g iodine) are usually adequate; for children 5 to 10 years of age, the suggested dose is 60 mL (22 g iodine). These pediatric doses may be diluted 1:1, if desired, with water, carbonated beverage, milk, or mineral oil. When used in infants, the solution may be given in a nursing bottle. Pediatric doses may also be used in dehydrated and/or debilitated adult patients. A 1:1 dilution is also recommended when the contrast medium is used in elderly cachectic individuals.

For very young (under 10 kg) and debilitated children the dose should be diluted: 1 part MD-Gastroview (Diatrizoate Meglumine and Diatrizoate Sodium Solution) in 3 parts water is recommended.

For Enemas or Enterostomy Instillations: MD-Gastroview should be diluted when it is used for enemas and enterostomy instillations.
When used as an enema, the suggested dilution for adults is 240 mL (88 g iodine) in 1,000 mL of tap water. For children under 5 years of age, a 1:5 dilution in tap water is suggested; for children over 5 years of age, 90 mL (33 g iodine) in 500 mL of tap water is a suitable dilution.
Tomography (Body Imaging)

A usual adult dose is 240 mL of a dilute MD-Gastroview solution prepared by diluting 25 mL (9.17 g iodine) to one liter with tap water. Less dilute solutions [up to 77 mL (28.26 g iodine) diluted to one liter with tap water] may be used when indicated. The dose is administered orally about 15 to 30 minutes prior to imaging in order to permit the contrast medium to reach the pelvic loops.
Conray 43

Conray 43

Intravascular Administration

It is advisable that Conray 43 be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Hydrocodone Bitartrate ...

Hydrocodone Bitartrate And Acetaminophen

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The usual adult dosage for Hydrocodone Bitartrate and Acetaminophen Tablets USP is:

Product Strength

Usual Adult Dosage as needed for pain

The total 24-hour dosage should not exceed

5 mg/325 mg

One to two tablets every four to six hours

12 tablets

7.5 mg/325 mg

One tablet every four to six hours

8 tablets

10 mg/325 mg

One tablet every four to six hours

6 tablets
Cysto-conray Ii

Cysto-conray Ii

Patient Preparation

Unless contraindicated, an appropriate laxative is given the night before the examination.

Radiographic Technique

The radiographic procedure normally employed for cystography and cystourethrography should be employed. A preliminary radiograph is recommended before the contrast agent is administered.

Administration

Sterile catherization is essential. Cysto-Conray II may be introduced by gravity flow using an appropriate venoclysis set or by syringe. Excessive pressure should be avoided with any method of administration.

Usual Dosage

Cystography and Cystourethrography – Either Conray 43 supplied at 43% w/v or Cysto-Conray II supplied at a 17.2% w/v concentration may be used for these procedures. The desired concentration will vary depending upon the patient’s size and age and also with the technique and equipment used. (SEE CONRAY 43 PACKAGE INSERT FOR SPECIFIC INFORMATION ABOUT THE USE OF THIS PRODUCT.) Sufficient volume of contrast medium is administered to adequately fill the urinary bladder. The volume of solution required will vary depending upon the individual patient. Adults usually require a volume in the range of 200 to 400 mL. Children require a volume in proportion to their body size. The usual dose ranges from 30 to 300 mL.
Amlodipine Besylate And...

Amlodipine Besylate And Atorvastatin Calcium

Morphine sulfate oral solution is available in one concentration: 100 mg per 5 mL (20 mg/mL).

Take care when prescribing and administering morphine sulfate oral solution to avoid dosing errors due to confusion between different concentrations and between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated oral syringe when administering morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL) to ensure the dose is measured and administered accurately.

Selection of patients for treatment with morphine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of morphine sulfate, give attention to the following:
the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; the reliability of the relative potency estimate used to calculate the equivalent morphine sulfate dose needed; the patient’s degree of opioid tolerance; the general condition and medical status of the patient; concurrent medications; the type and severity of the patient’s pain; risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual reevaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy in Opioid-Naïve Patients

Start patients who have not been receiving opioid analgesics on morphine sulfate in the following dosing range using morphine sulfate oral solution, 10 mg per 5 mL or 20 mg per 5 mL strengths:

Morphine sulfate oral solution: 10 to 20 mg every 4 hours as needed for pain.

Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate. Adjust the dose to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the morphine by the patient.

The 100 mg per 5 mL (20 mg/mL) oral solution formulation is for use in opioid-tolerant patients only who have already been receiving opioid therapy. Use this strength only for patients that have already been titrated to a stable analgesic regimen using lower strengths of morphine sulfate and who can benefit from use of a smaller volume of oral solution.

2.3 Conversion to Oral Morphine Sulfate

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of morphine sulfate. It is better to underestimate a patient’s 24-hour oral morphine sulfate dose and make available rescue medication than to overestimate the 24-hour oral morphine sulfate dose and manage an adverse experience of overdose.

Consider the following general points regarding opioid conversions.

Conversion from Parenteral Morphine to Oral Morphine Sulfate

For conversion from parenteral to oral morphine sulfate, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Parenteral Oral Non-Morphine Opioids to Oral Morphine Sulfate

In converting patients from other opioids to morphine sulfate, close observation and adjustment of dosage based upon the patient’s response to morphine sulfate is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

Conversion from Controlled-Release Oral Morphine to Oral Morphine Sulfate

For a given dose, the same total amount of morphine sulfate is available from morphine sulfate oral solution, morphine sulfate tablets, and controlled-release and extended-release morphine capsules. The extended duration of release of morphine sulfate from controlled-release tablets or extended-release tablets results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from oral solution or immediate-release tablets to the same total daily dose of controlled-release tablets or extended-release tablets could lead to excessive sedation at peak serum levels. Therefore, dosage adjustment with close observation is necessary.

2.4 Maintenance of Therapy

Continual reevaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

2.5 Cessation of Therapy

When the patient no longer requires therapy with morphine sulfate, gradually taper the dose to prevent signs and symptoms of withdrawal in the physically dependent patient.

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