Jazz Pharmaceuticals, Inc.

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Jazz Pharmaceuticals, Inc. Drugs

Cystadane

Cystadane

The usual dosage used in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams two times per day. Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day and then increased weekly by 50 mg/kg increments. In one study by Matthewsi et al., pharmacokinetic and pharmacodynamic simulation indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for betaine. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts. Plasma methionine concentrations should be monitored in patients with CBS-deficiency. See PRECAUTIONS: Hypermethioninemia.

The prescribed amount of Cystadane (betaine anhydrous for oral solution) should be measured with the measuring scoop provided (one level 1.7 cc scoop is equal to 1 gram of betaine anhydrous powder) and then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.
Oxytocin

Oxytocin

The patient dose of the radiolabel must be measured in a dose calibrator prior to administration.

The recommended dose of ProstaScint® (capromab pendetide) is 0.5 mg radiolabeled with 5 mCi of Indium In 111 chloride. Each dose is administered intravenously over 5 minutes and should not be mixed with any other medication during its administration. Indium In 111 ProstaScint® may be readministered following infiltration or a technically inadequate scan; however, it is not indicated for readministration for the purpose of assessment of response to treatment (see INDICATIONS AND USAGE).

Each ProstaScint® kit is a unit dose package. After radiolabeling with Indium In 111, the entire Indium In 111 ProstaScint® dose should be administered to the patient. Reducing the dose of Indium In 111, unlabeled ProstaScint®, or Indium In 111 ProstaScint® may adversely impact imaging results and is, therefore, not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Radiation Dosimetry

The estimated absorbed radiation doses to an average adult patient from an intravenous injection of ProstaScint® labeled with 5 mCi of Indium In 111 are shown in TABLE 6. Total dose estimates include absorbed radiation doses from both Indium In 111 and the Indium In 114m radiocontaminant. A level of 0.06% of Indium In 114m was utilized for the dose estimates presented in TABLE 6.
TABLE 6 - ESTIMATED AVERAGE ABSORBED RADIATION DOSE IN ADULT PATIENTS FROM INTRAVENOUS ADMINISTRATION OF PROSTASCINT® LABELED WITH 5 mCi (185 MBq) OF INDIUM IN 111 CHLORIDEa a Based on data from 21 patients who received doses of ProstaScint® labeled with a mean (± SD) Indium In 111 dose of 4.6 ± 1.0 mCi.
Organ

AverageDose(rad/5 mCi)

AverageDose(mGy/185 MBq)

Total body

2.7

27

Brain

1.1

11

Liver

18.5

185

Spleen

16.3

163

Kidneys

12.4

124

Lungs

5.6

56

Heart wall

7.8

78

Red marrow

4.3

43

Adrenals

5.2

52

Urine Bladder wall

2.2

22

Bone Surfaces

4.0

40

Stomach

3.1

31

Gall Bladder Wall

7.3

73

Small Intestine

3.3

33

Upper Large Intestine Wall

5.0

50

Lower Large Intestine Wall

7.6

76

Pancreas

5.1

51

Skin

1.1

11

Testes

5.6

56

Prostate

8.2

82

Thymus

2.6

26

Thyroid

1.4

14

Other Tissues

2.0

20

Directions for Radiolabeling ProstaScint® (capromab pendetide) with Indium In 111 Chloride

Proper aseptic techniques and precautions for handling radioactive materials should be employed. Waterproof gloves should be worn during the radiolabeling procedure. The preparation of the product should be done by the following procedure.
1. Required materials, not supplied: A. Indium In 111 Chloride from GE Healthcare, Inc. or Covidien, Inc. B. One sterile 1 mL syringe, one sterile 3 mL syringe C. Vial shield D. Dose calibrator set for Indium In 111 E. Biodex Dark Green Chromatography strips F. Developing chamber for chromatography (e.g. scintillation vial) G. 21-23 gauge sterile needles H. Shield for 10 mL syringe I. Waterproof gloves J. Alcohol wipe K. Water-soluble marker L. 0.9% sodium chloride solution M. 0.05 M solution of diethylenetriamine pentaacetic acid (DTPA) N. Gamma ray detector 2. Sterile, pyrogen-free Indium In 111 Chloride solution must be utilized in the preparation of the Indium In 111 ProstaScint ®. The use of high purity Indium In 111 Chloride manufactured by GE Healthcare, Inc. or by Covidien, Inc. is required. The Indium In 111 Chloride should be used only to radiolabel ProstaScint ® and should not be injected directly into the patient. The Indium In 111 Chloride should not be utilized after its expiration date. 3. Before radiolabeling, bring the refrigerated ProstaScint ® to room temperature. Note: ProstaScint ® is a protein solution which may develop translucent particulates. These particulates will be removed by filtration. 4. Clean the rubber stopper of each vial with an alcohol wipe. With a sterile 1 mL syringe add 0.1 mL of sodium acetate solution to the shielded vial of Indium In 111 chloride and mix. Retain remaining sodium acetate for use in Step 7. 5. With the same 1 mL syringe, withdraw between 6 and 7 mCi of the buffered Indium In 111 chloride and add to the ProstaScint ® vial. Flush the syringe to mix the preparation. Swirl gently to mix, and assay contents in a dose calibrator. On one of the labels provided, record the patient's identification, the date, time of preparation, and activity in the vial. Affix the label to the vial shield. 6. Allow the labeling reaction to proceed at room temperature for 30 minutes. 7. With a 3 mL syringe, add the remaining sodium acetate to the ProstaScint ® reaction vial. To normalize pressure, withdraw an equal volume of air. 8. Aseptically attach the 0.22 μm Millex ® GV sterile filter (provided) and a sterile hypodermic needle to a 10 mL sterile disposable syringe and withdraw the contents of the reaction vial through the filter into the syringe. Keep the needle immersed in the solution to avoid creating an air-lock in the filter. 9. Remove the filter and needle. Aseptically attach a fresh sterile hypodermic needle to the syringe. Assay syringe and contents in a dose calibrator. The syringe should contain not less than 4 mCi (148 MBq) of Indium In 111 ProstaScint ®. 10. Radiochemical purity (RCP) by Instant Thin Layer Chromatography (ITLC) can be determined by the following procedure: A. Mix equal parts (several drops of each) of Indium In 111 ProstaScint ® (capromab penditide) with DTPA solution. Allow the mixture to stand at room temperature for one minute. Spot a small drop of the mixture onto an ITLC strip at its origin. B. Add 0.9% sodium chloride solution to the developing chamber to a depth of about 0.5 cm. Place the strip in a chromatography chamber with the origin at the bottom (ensure the strip does not bend or touch the walls of the chamber) and allow the solvent to migrate to about 0.5 cm from the end of the strip. A small dot made with a felt tip pen at this distance can help indicate the arrival of the solvent front. Remove from the chamber and cut the strip in half and measure the counts per minute (CPM) of both halves with a gamma ray detector. C. Calculate the percent RCP as follows: %RCP = CPM bottom half x 100 CPM bottom half + CPM top half D. If the radiochemical purity is <90%, the ITLC procedure should be repeated. If repeat testing remains <90%, the preparation should not be administered. 11. On the second label provided in the kit, record the patient's identification, the date, time of assay, and activity in the syringe. Affix this label to the syringe shield. 12. Indium In 111 ProstaScint ® should be used within 8 hours of radiolabeling. 13. Discard vials, needles, and syringes in accordance with local, state, and federal regulations governing radioactive and biohazardous waste.
Image Acquisition and Interpretation

Images should be acquired using a large field of view gamma camera equipped with a parallel hole medium energy collimator. The gamma camera should be calibrated using the 172 and 247 keV photopeaks for Indium In 111 with a 15-20% symmetric window.

Whole body or spot planar views of the pelvis, abdomen, and thorax should be performed between 72 and 120 hours following Indium In 111 ProstaScint® (capromab penditide) infusion. A cathartic is required the evening before imaging and a cleansing enema should be administered within an hour prior to each 72-120 hour imaging session. In addition, the bladder should be catheterized and irrigated.

Whole body acquisition should be carried out from skull through mid-femur. The total scan time over this area should be no less than 35 minutes using a 128x512 or 256x1024 matrix.

Planar images should be acquired in anterior and posterior views for 7.5 minutes per view using a 128x128 or 256x256 matrix. Due to uptake of Indium In 111 ProstaScint® by the liver, planar images obtained with the liver in the field of view must be acquired with adequate counts to allow the detection of lesions in the adjacent extrahepatic abdomen and pelvis. This may result in pixel overflow with image degradation in the region of the liver.

Two SPECT imaging sessions are necessary. The first SPECT session should be of the pelvis and be performed approximately 30 minutes after infusion to obtain a blood pool image. The second SPECT session should include both the pelvis and abdomen, including the lower liver margin through the prostatic fossa and be performed between 72 and 120 hours after infusion for detection of benign and malignant prostate tissue sites. Depending upon the capability of the camera field of view to include both pelvis and abdomen, either one or two separate acquisitions may be necessary during the second session.

To resolve imaging ambiguities possibly resulting from activity in blood pool, stool or urinary bladder, follow-up imaging sessions with full patient preparation should be performed.

The SPECT Images should be acquired using a 64x64 or 128x128 matrix for a minimum of 60 or 120 stops, respectively, over 360 degrees rotation for approximately 25 seconds per view at the first session and 50 seconds per view at the second session. Reconstruction should be performed using a Butterworth filter or equivalent in the transverse, coronal and sagittal views. An order of 5 and cut off of 0.5 may be used as a starting point. Slice thickness should be in the range of 6 to 12 mm.

Following Indium In 111 ProstaScint® (capromab penditide) administration, some of the radiolabel localizes in normal liver, spleen, bone marrow and genitalia.

It has been reported that Indium In 111 labeled antibodies may localize non-specifically in colostomy sites, degenerative joint disease, abdominal aneurysms, post-operative bowel adhesions, and local inflammatory lesions, including those typically associated with inflammatory bowel disease or secondary to surgery or radiation. Indium In 111 ProstaScint® can demonstrate apparent localization to sites of tortuous blood vessels. Careful review of the patient's medical history and other diagnostic information should aid in the interpretation of the images.

The diagnostic images acquired with Indium In 111 ProstaScint® should be interpreted in conjunction with other appropriate diagnostic tests.
Quadramet

Quadramet

The recommended dose of QUADRAMET® is 1.0 mCi/kg, administered intravenously over a period of one minute through a secure in-dwelling catheter and followed with a saline flush. Dose adjustment in patients at the extremes of weight have not been studied. Caution should be exercised when determining the dose in very thin or very obese patients.

The dose should be measured by a suitable radioactivity calibration system, such as a radioisotope dose calibrator, immediately before administration.

The dose of radioactivity to be administered and the patient should be verified before administering QUADRAMET®. Patients should not be released until their radioactivity levels and exposure rates comply with federal and local regulations.

The patient should ingest (or receive by i.v. administration) a minimum of 500 mL (2 cups) of fluids prior to injection and should void as often as possible after injection to minimize radiation exposure to the bladder.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should not be used if it is cloudy or if it contains particulate matter.

QUADRAMET® contains calcium and may be incompatible with solutions that contain molecules that can complex with and form calcium precipitates.

QUADRAMET® should not be diluted or mixed with other solutions.

Thaw at room temperature before administration and use within 8 hours of thawing.

Radiation Dosimetry

The estimated absorbed radiation doses to an average 70 kg adult patient from an i.v. injection of QUADRAMET® are shown in Table 7. The dosimetry estimates were based on clinical biodistribution studies using methods developed for radiation dose calculations by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine.

Radiation exposure is based on a urinary voiding interval of 4.8 hours. Radiation dose estimates for bone and marrow assume that radioactivity is deposited on bone surfaces, as noted in autoradiograms of biopsy bone samples in 7 patients who received QUADRAMET®. Although electron emissions from 153Sm are abundant, with energies up to 810 keV, rapid blood clearance of QUADRAMET® and low energy and abundant photon emissions generally result in low radiation doses to those parts of the body where the complex does not localize.

When blastic osseous lesions are present, significantly enhanced localization of the radiopharmaceutical will occur, with correspondingly higher doses to the lesions compared with normal bones and other organs. (See Clinical Pharmacology, Skeletal Uptake and Pharmacodynamics Sections).
TABLE 7 RADIATION ABSORBED DOSES

70 kg ADULT

Target Organ

    Rad/mCi

mGy/MBq

Bone Surfaces

    25.0

    6.76

Red Marrow

    5.70

    1.54

Urinary Bladder Wall

    3.60

    0.097

Kidneys

    0.065

    0.018

Whole Body

    0.040

    0.011

Lower large intestine

    0.037

    0.010

Ovaries

    0.032

    0.0086

Muscle

    0.028

    0.0076

Small Intestine

    0.023

    0.0062

Upper Large Intestine

    0.020

    0.0054

Testes

    0.020

    0.0054

Liver

    0.019

    0.0051

Spleen

    0.018

    0.0049

Stomach

    0.015

    0.0041
Parcopa

Parcopa

Instructions for Use/Handling PARCOPA® Tablets

Just prior to administration, GENTLY remove the tablet from the bottle with dry hands. IMMEDIATELY place the PARCOPA® Tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

The optimum daily dosage of PARCOPA® must be determined by careful titration in each patient. PARCOPA® is available in a 1:4 ratio of carbidopa to levodopa (PARCOPA® 25/100) as well as 1:10 ratio (PARCOPA® 25/250 and PARCOPA® 10/100). Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.

Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.

Usual Initial Dosage

Dosage is best initiated with one tablet of PARCOPA® 25/100 three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other day, as necessary, until a dosage of eight tablets of PARCOPA® 25/100 a day is reached.

If PARCOPA® 10/100 is used, dosage may be initiated with one tablet three or four times a day. However, this will not provide an adequate amount of carbidopa for many patients. Dosage may be increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is reached.

How to Transfer Patients from Levodopa

Levodopa must be discontinued at least twelve hours before starting PARCOPA® (carbidopa and levodopa orally disintegrating tablets). A daily dosage of PARCOPA® should be chosen that will provide approximately 25 percent of the previous levodopa dosage. Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of PARCOPA® 25/100 three or four times a day. The suggested starting dosage for most patients taking more than 1500 mg of levodopa is one tablet of PARCOPA® 25/250 three or four times a day.

Maintenance

Therapy should be individualized and adjusted according to the desired therapeutic response. At least 70 to 100 mg of carbidopa per day should be provided. When a greater proportion of carbidopa is required, one tablet of PARCOPA® 25/100 may be substituted for each tablet of PARCOPA® 10/100. When more levodopa is required, PARCOPA® 25/250 should be substituted for PARCOPA® 25/100 or PARCOPA® 10/100. If necessary, the dosage of PARCOPA® 25/250 may be increased by one-half or one tablet every day or every other day to a maximum of eight tablets a day. Experience with total daily dosages of carbidopa greater than 200 mg is limited.

Because both therapeutic and adverse responses occur more rapidly with PARCOPA® than with levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly with PARCOPA® than with levodopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients.

Addition of Other Antiparkinsonian Medications

Standard drugs for Parkinson’s disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while PARCOPA® is being administered, although dosage adjustments may be required.

Interruption of Therapy

Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been associated with dose reductions and withdrawal of carbidopa and levodopa. Patients should be observed carefully if abrupt reduction or discontinuation of PARCOPA® is required, especially if the patient is receiving neuroleptics. (See WARNINGS.)

If general anesthesia is required, PARCOPA® may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient is able to take oral medication.
Niravam

Niravam

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg per day. In such cases, the dosage should be increased cautiously to avoid adverse reactions. In general, benzodiazepines should be prescribed for short periods. Reevaluate the need for continued therapy before extending the treatment period.

2.1 Generalized Anxiety Disorder

Initiate treatment with a dose of 0.25 mg to 0.5 mg three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose, and periodically reassess the need for continued treatment. The risk of dependence can increase with dose and duration of treatment.

The dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

2.2 Panic Disorder

The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg per day, including approximately 100 patients who received maximum dosages of greater than 9 mg per day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration

Initiate treatment with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg per day may be advisable to allow full expression of the pharmacodynamic effect of NIRAVAM. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, (i.e., administered three or four times daily).

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. The dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

For patients receiving doses greater than 4 mg per day, periodically reassess treatment and consider a reduction of dosage. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg per day for 3 months were able to taper to 50% of their total daily maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, avoid abrupt discontinuation of treatment. [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

The necessary duration of treatment for panic disorder patients responding to NIRAVAM is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, reinstitute the previous stable dosing schedule. After stabilization, consider using a less rapid schedule of discontinuation. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, there was no difference between the groups in the proportion of patients who tapered and completely discontinued treatment with alprazolam; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. Reduce the dose by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

2.3 Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease (e.g., severe pulmonary disease), the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dose, the dose may be lowered.

2.4 Instructions to be Given to Patients for Use/Handling NIRAVAM Tablets

Just prior to administration, with dry hands, remove the tablet from the bottle. Immediately place the NIRAVAM tablet on top of the tongue where it will disintegrate and be swallowed with saliva. Administration with liquid is not necessary.

Discard any cotton that was included in the bottle and reseal the bottle tightly to prevent introducing moisture that might cause the tablets to disintegrate.
Prialt

Prialt

2.1 General Information

PRIALT is intended for administration by or under the direction of a physician experienced in the technique of intrathecal administration and who is familiar with the drug and device labeling.

PRIALT is not intended for intravenous administration.

PRIALT is intended for intrathecal delivery using the Medtronic SynchroMed® II Infusion System and CADD-Micro Ambulatory Infusion Pump [see Warnings and Precautions (5.2)]. Refer to the manufacturer's manual for specific instructions and precautions for programming the microinfusion device and/or refilling the reservoir.

PRIALT may be used for therapy undiluted (25 mcg/mL in 20 mL vial) or diluted (100 mcg/mL in 1 or 5 mL vials). The 100 mcg/mL formulation may be administered undiluted once an appropriate dose has been established.

Dilute PRIALT with 0.9% Sodium Chloride Injection, USP (preservative free) using aseptic procedures to the desired concentration prior to placement in the microinfusion pump.
• Saline solutions containing preservatives are not appropriate for intrathecal drug administration and should not be used due to risk of neurotoxicity. • Refrigerate but do not freeze all PRIALT solutions after preparation and begin infusion within 24 hours.
Inspect vials of PRIALT visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any PRIALT solution with observed particulate matter or discoloration and any unused portion left in the vial.

2.2 Dosing

Dose Initiation

Initiate dosing with PRIALT via intrathecal device at no more than 2.4 mcg/day (0.1 mcg/hr).

Dose Titration

Titrate doses by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2 to 3 times per week based on analgesic response and adverse events. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing.

The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr).

Adjust the dose of intrathecal PRIALT according to the severity of pain, the patient’s response to therapy, and the occurrence of adverse reactions.

2.3 Instructions for Use with the Medtronic SynchroMed II Infusion System

Refer to the manufacturer's manuals for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir, and programming. [see Warnings and Precautions (5.2)]

Naïve Pump Priming (i.e., first time use with PRIALT)

Use only the undiluted 25 mcg/mL formulation for naïve pump priming. Rinse the internal surfaces of the pump with 2 mL of PRIALT at 25 mcg/mL. Repeat twice for a total of three rinses.

Initial Pump Fill

Use only the undiluted 25 mcg/mL formulation for the initial pump fill. Fill the naïve pump after priming with the appropriate volume of PRIALT 25 mcg/mL. Begin dosing at a delivery rate no higher than 2.4 mcg/day (0.1 mcg/hr). In a naïve pump, PRIALT is lost due to two factors that do not occur upon subsequent refills: adsorption on internal device surfaces, such as titanium, and by dilution in the residual space of the device. Consequently, the pump reservoir should be refilled with PRIALT within 14 days of the initial fill to ensure appropriate dose administration.

Pump Refills

For subsequent pump refills, fill the pump at least every 40 days if PRIALT is used diluted. For undiluted PRIALT, fill the pump at least every 84 days. To ensure aseptic transfer of PRIALT into the device, use the Medtronic refill kit. Empty the pump contents prior to refill with PRIALT.

If the internal infusion system must be surgically replaced while the person is receiving PRIALT, rinse the replacement pump with PRIALT according to Naïve Pump Priming [see Dosage and Administration (2.4)], and replace the initial fill solution within 14 days according to Initial Pump Fill [see Dosage and Administration (2.4)].

PRIALT (ziconotide) solution, intrathecal infusion

Initial Fill      Expiry

Refill Expiry

25 mcg/mL, undiluted

14 Days

84 Days

100 mcg/mL, undiluted

N/A

84 Days

100 mcg/mL, diluted

N/A

40 Days

2.4 Instructions for Use in the CADD-Micro Ambulatory Infusion Pump

Refer to the manufacturer's manuals for specific instructions and precautions for performing the initial filling, refilling of the reservoir or replacement of the drug cartridge, and operation. The CADD-Micro Ambulatory Infusion Pump is filled for the first time with PRIALT solution at a concentration of 5 mcg/mL. This solution is prepared by diluting PRIALT with 0.9% Sodium Chloride, USP (preservative free).

The recommended initial flow rate for the external microinfusion is 0.02 mL/hr to deliver the initial dose rate of 2.4 mcg/day (0.1 mcg/hr) of PRIALT. Changes in dose rate are made by adjusting the flow rate of the infusion system and/or the concentration of PRIALT solution. [see Warnings and Precautions (5.2)]
Versacloz

Versacloz

2.1 Required Laboratory Testing Prior to Initiation and During Therapy

Prior to initiating treatment with VERSACLOZ, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1)].

2.2 Dosing Information

The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3)].

2.3 Important Administration Instructions

VERSACLOZ Oral Suspension is administered to the mouth by the oral syringes provided (1 mL or 9 mL). After shaking the bottle for 10 seconds prior to each use, the syringe adaptor is pressed on top of the bottle. The oral syringe (1 mL or 9 mL) is filled with air, and inserted into the adaptor. The air is dispelled into the bottle and then the bottle is turned upside down. The prescribed amount of the suspension is drawn from the bottle and dispensed directly to the mouth. The prescribed dose should be administered immediately after it is prepared. Do not draw a dose and store it in the syringe for later use. After use, the oral syringe may be washed with warm water and dried for next use. The bottle may be closed with the same cap without removing the bottle adaptor. Educate patients and caregivers on the steps to administer VERSACLOZ as described in the Patient Instructions for Use.

VERSACLOZ can be taken with or without food [see Pharmacokinetics (12.3)].

2.4 Maintenance Treatment

Generally, patients responding to VERSACLOZ should continue maintenance treatment on their effective dose beyond the acute episode.

2.5 Discontinuation of Treatment

Method of treatment discontinuation will vary depending on the patient's last ANC:
• See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. • Reduce the dose gradually over a period of 1 to 2 weeks if termination of VERSACLOZ therapy is planned and there is no evidence of moderate to severe neutropenia. • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/µL and for BEN patients until their ANC is ≥1000/µL or above their baseline. • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1)] . • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.
2.6 Re-Initiation of Treatment

When restarting VERSACLOZ in patients who have discontinued VERSACLOZ (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].

Table 1: Dose Adjustment in Patients Taking Concomitant Medications

Co-medications

Scenarios

Initiating VERSACLOZ while taking a co-medication

Adding a co-medication while taking VERSACLOZ

Discontinuing a co-medication while continuing VERSACLOZ

Strong CYP1A2 Inhibitors

Use one third of the VERSACLOZ dose.

Increase VERSACLOZ dose based on clinical response.

Moderate or Weak CYP1A2 Inhibitors

Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary.

Monitor for lack of effectiveness. Consider increasing VERSACLOZ dose if necessary.

CYP2D6 or CYP3A4 Inhibitors

Strong CYP3A4 Inducers

Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the VERSACLOZ dose. Monitor for decreased effectiveness.

Reduce VERSACLOZ dose based on clinical response.

Moderate or weak CYP1A2 or CYP3A4 Inducers

Monitor for decreased effectiveness. Consider increasing the VERSACLOZ dose if necessary.

Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary.

2.8 Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers

It may be necessary to reduce the VERSACLOZ dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].
Xyrem

Xyrem

Healthcare professionals who prescribe Xyrem must enroll in the Xyrem REMS Program and must comply with the requirements to ensure safe use of Xyrem [see Warnings and Precautions (5.3)].

2.1 Dosing Information

The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

Table 1: Xyrem Dose Regimen (g = grams)

If A Patient’s Total Nightly Dose is:

Take at Bedtime:

Take 2.5 to 4 Hours Later:

4.5 g per night

2.25 g

2.25 g

6 g per night

3 g

3 g

7.5 g per night

3.75 g

3.75 g

9 g per night

4.5 g

4.5 g

2.2 Important Administration Instructions

Take the first dose of Xyrem at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate.

Prepare both doses of Xyrem prior to bedtime. Prior to ingestion, each dose of Xyrem should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy vials provided. Patients should take both doses of Xyrem while in bed and lie down immediately after dosing as Xyrem may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Xyrem, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5 to 4 hours after the first dose. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

2.3 Dose Modification in Patients with Hepatic Impairment

The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later [see Use in Specific Populations (8.6); Clinical Pharmacology (12.3)].

2.4 Dose Adjustment with Co-administration of Divalproex Sodium

Pharmacokinetic and pharmacodynamic interactions have been observed when Xyrem is co-administered with divalproex sodium. For patients already stabilized on Xyrem, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of Xyrem by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting Xyrem dose with introducing Xyrem. Prescribers should monitor patient response and adjust dose accordingly [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Fazaclo

Fazaclo

2.1 Required Laboratory Testing Prior to Initiation and During Therapy

Prior to initiating treatment with FAZACLO, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1)].

2.2 Important Administration Instructions

FAZACLO orally disintegrating tablets should be immediately placed in the mouth after removing the tablet from the blister pack or bottle. The tablet disintegrates rapidly after placement in the mouth. The tablets can be allowed to disintegrate, or they may be chewed. They may be swallowed with saliva. No water is necessary for administration.

The orally disintegrating tablets in a blister pack should be left in the unopened blister until the time of use. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet. Do not push the tablets through the foil, because this could damage the tablet.

2.3 Dosing Information

The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3)].

FAZACLO can be taken with or without food [see Pharmacokinetics (12.3)].

2.4 Maintenance Treatment

Generally, patients responding to FAZACLO should continue maintenance treatment on their effective dose beyond the acute episode.

2.5 Discontinuation of Treatment

Method of treatment discontinuation will vary depending on the patient's last ANC:
• See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. • Reduce the dose gradually over a period of 1 to 2 weeks if termination of FAZACLO therapy is planned and there is no evidence of moderate to severe neutropenia. • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/µL and for BEN patients until their ANC is ≥1000/µL or above their baseline. • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1) ]. • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.
2.6 Re-Initiation of Treatment

When restarting FAZACLO in patients who have discontinued FAZACLO (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well-tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].

Table 1: Dose Adjustment in Patients Taking Concomitant Medications

Co-medications

Scenarios

Initiating FAZACLO while taking a

co-medication

Adding a

co-medication

while taking FAZACLO

Discontinuing a

co-medication

while continuing FAZACLO

Strong CYP1A2 Inhibitors

Use one third of the FAZACLO dose.

Increase FAZACLO dose based on clinical response.

Moderate or Weak CYP1A2 Inhibitors

Monitor for adverse reactions. Consider reducing the FAZACLO dose if necessary.

Monitor for lack of effectiveness. Consider increasing FAZACLO dose if necessary.

CYP2D6 or CYP3A4 Inhibitors

Strong CYP3A4 Inducers

Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the FAZACLO dose. Monitor for decreased effectiveness.

Reduce FAZACLO dose based on clinical response.

Moderate or Weak CYP1A2 or CYP3A4 Inducers

Monitor for decreased effectiveness. Consider increasing the FAZACLO dose if necessary.

Monitor for adverse reactions. Consider reducing the FAZACLO dose if necessary.

2.8 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers

It may be necessary to reduce the FAZACLO dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].
Erwinaze

Erwinaze

2.1 Recommended Dose

To substitute for a dose of pegaspargase:

The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m2 administered intramuscularly or intravenously three times a week (Monday/Wednesday/Friday) for six doses.

To substitute for a dose of native E. coli asparaginase:

The recommended dose is 25,000 International Units/m2 administered intramuscularly or intravenously for each scheduled dose of native E. coli asparaginase within a treatment.

When administering ERWINAZE intravenously, consider monitoring nadir (pre-dose) serum asparaginase activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved [see Clinical Pharmacology (12.3)].

2.2 Preparation and Handling Instructions

1. Visually inspect the ERWINAZE powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.

2. Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection (USP) against the inner vial wall.

3. Do not forcefully inject solution for reconstitution directly onto or into the powder. When reconstituted with 1 mL the resultant concentration is 10,000 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.

4. Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.

5. When reconstituted, ERWINAZE should be a clear, colorless solution. Inspect the solution after reconstitution and discard if any visible particles or protein aggregates are present.

6. Calculate the dose needed and the volume needed to obtain the calculated dose.

7. Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution. For intravenous use, slowly inject the reconstituted ERWINAZE into an IV infusion bag containing 100 mL of normal saline acclimatized to room temperature. Do not shake or squeeze the IV bag.8. If partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.9. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard [see How Supplied/Storage and Handling (16)].

2.3 Administration Instructions

ERWINAZE solution can be administered by intramuscular injection or by intravenous infusion.
• For intramuscular use, limit the volume of reconstituted ERWINAZE at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites. • For intravenous use, infuse ERWINAZE in 100 mL of normal saline over 1 hour. Do not infuse other intravenous drugs through the same intravenous line while infusing ERWINAZE.
Luvox Cr

Luvox Cr

2.1 OCD (Obsessive Compulsive Disorder)

     The recommended starting dose is 100 mg at bedtime, with weekly increases of 50 mg as tolerated to maximum therapeutic benefit, not to exceed 300 mg per day.

     Capsules should not be crushed or chewed.

2.2 Pediatric Patients Naïve to Fluvoxamine Maleate

     Physicians should consider that the lowest available dose of LUVOX CR Capsules may not be appropriate for pediatric patients naïve to fluvoxamine maleate.

2.3 Dosage for Elderly or Hepatically Impaired Patients

     Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to titrate slowly following the initial dose of 100 mg in these patient groups.

2.4 Maintenance/Continuation of Extended Treatment

     Although the efficacy of LUVOX CR Capsules beyond 12 weeks of dosing has not been documented in controlled trials, OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. The benefit of maintaining patients with OCD on immediate-release fluvoxamine maleate tablets after achieving a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a controlled trial (see CLINICAL TRIALS [14.2]). 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 continued treatment.

2.5 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 LUVOX CR Capsules. Conversely, at least 14 days should be allowed after stopping LUVOX CR Capsules before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS [4.1]).

2.6 Use of LUVOX CR Capsules with Other MAOIs such as Linezolid or Methylene Blue

     Do not start LUVOX CR Capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is an 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 [4.1]).

     In some cases, a patient already receiving LUVOX CR 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, LUVOX CR 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 LUVOX CR may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS AND PRECAUTIONS [5.2]).

     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 LUVOX CR is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS AND PRECAUTIONS [5.2]).

2.7 Discontinuation of Treatment with LUVOX CR Capsules

     Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported (see WARNINGS AND PRECAUTIONS [5.10]). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the health care provider may continue decreasing the dose but at a more gradual rate.

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