Xanodyne Pharmaceuticals, Inc.

Xanodyne Pharmaceuticals, Inc. Drugs

• Methadone
  

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  Methadone

  

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  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 μ-opioid agonists makes determination of dosing during opioid conversion complex.

  All of these characteristics make methadone dosing complex and 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.

  Treatment of Pain

  Optimal methadone initiation and dose titration strategies for the treatment of pain have not been determined. Published equianalgesic conversion ratios between methadone and other opioids are imprecise, providing at best, only population averages that cannot be applied consistently to all patients. It should be noted that many commonly cited equianalgesia tables only present relative analgesic potencies of single opioid doses in non-tolerant patients, thus greatly underestimating methadone's analgesic potency, and its potential for adverse effects in repeated-dose settings. Regardless of the dose determination strategy employed, methadone is most safely initiated and titrated using small initial doses and gradual dose adjustments.

  As with all opioid drugs, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. The following dosing recommendations should 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. Prescribers should always follow appropriate pain management principles of careful assessment and ongoing monitoring.

  In the selection of an initial dose of Methadone Hydrochloride Injection, attention should be given to the following:

  The total daily dose, potency and specific characteristics of the opioid the patient had been taking previously, if any; The relative potency estimate used to calculate an equianalgesic starting methadone dose, in particular, whether it is intended for use in acute or chronic methadone dosing; The patient's degree of opioid tolerance; The age, general condition and medical status of the patient; Concurrent medications, particularly other CNS and respiratory depressants; The type, severity and expected duration of the patient's pain; The acceptable balance between pain control and adverse side effects.

  Methadone Hydrochloride Injection may be administered intravenously, subcutaneously or intramuscularly. The absorption of subcutaneous and intramuscular methadone has not been well characterized and appears to be unpredictable. Local tissue reactions may occur.

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Initiation of Therapy in Opioid Non-Tolerant Patients

  When parenteral methadone is used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, the usual intravenous methadone starting dose is 2.5 mg to 10 mg every 8 to 12 hours, slowly titrated to effect. More frequent administration may be required during methadone initiation in order to maintain adequate analgesia, and extreme caution is necessary to avoid overdosage, taking into account methadone's long elimination half life.

  Conversion from Oral Methadone to Parenteral Methadone

  Conversion from oral methadone to parenteral methadone should initially use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone).

  Switching Patients to Parenteral Methadone from other Chronic Opioids

  Switching a patient from another chronically administered opioid to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete cross-tolerance. Deaths have occurred in opioid tolerant patients during conversion to methadone.

  Conversion ratios in many commonly used equianalgesic dosing tables do not apply in the setting of repeated methadone dosing. Although with single-dose administration the onset and duration of analgesic action, as well as the analgesic potency of methadone and morphine, are similar methadone's potency increases over time with repeated dosing. Furthermore, the conversion ratio between methadone and other opiates varies dramatically depending on baseline opiate (morphine equivalent) use as shown in the table below.

  The dose conversion scheme below is derived from various consensus guidelines for converting chronic pain patients to methadone from morphine. The guidelines used to construct this table, however, were all designed for converting patients from oral morphine to oral methadone. The third column assumes a 2:1 ratio for converting from oral to intravenous methadone. Clinicians should consult published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids.

  Table 1. Oral Morphine to Intravenous Methadone Conversion for Chronic Administration

  *The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).

  Total Daily Baseline Oral Estimated Daily Oral Methadone Estimated Daily Intravenous Morphine Dose Reguirement as Percent of Methadone as Percent of Total Daily Total Daily Morphine Dose Oral Morphine Dose* < 100mg 20% to 30% 10% to 15% 100 to 300 mg 10% to 20% 5% to 10% 300 to 600 mg 8% to 12% 4% to 6% 600 mg to 1000 mg 5% to 10% 3% to 5% > 1000 mg < 5% < 3% Table 2. Parenteral Morphine to Intravenous Methadone Conversion for Chronic Administration (Derived from Table 1, assuming a 3:1 oral:parenteral morphine ratio)

  *The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).

  Total Daily Baseline Parenteral Estimated Daily Parenteral Methadone Morphine Dose Requirement as Percent of Total Daily Morphine Dose* 10 mg to 30 mg 40% to 66% 30 mg to 50 mg 27% to 66% 50 mg to 100 mg 22% to 50% 100 mg to 200 mg 15% to 34% 200 mg to 500 mg 10% to 20%

  Note: Equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on baseline morphine (or other opioid) dose. Tables 1 and 2 have been included in order to illustrate this concept and to provide a safe starting point for opioid conversion. Methadone dosing should not be based solely on these tables. Methadone conversion and dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use. The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects. If a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased.

  Methadone conversion and dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use. The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects. If a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased.

  Dosage Adjustment During Pregnancy

  Methadone clearance may be increased during pregnancy. Several small studies have demonstrated significantly lower trough methadone plasma concentrations and shorter methadone half-lives in women during their pregnancy compared to after their delivery. During pregnancy a woman's methadone dose may need to be increased, or their dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

  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 42CFR Section 8.12, including limitations on unsupervised administration. Injectable methadone products are not approved for the outpatient treatment of opioid dependence. Parenteral methadone should be used only for patients who are unable to take oral medication, such as during hospitalization. The patient's oral methadone dose should be converted to an equivalent parenteral dose using the considerations above.

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• Zipsor
  

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  Zipsor

  

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  2.1 Initiating Therapy

  For treatment of mild to moderate acute pain, the dosage is 25 mg four times a day. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

  2.2 Non-Interchangeability with Other Formulations of Diclofenac

  Different formulations of oral diclofenac are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulation of diclofenac to Zipsor. The only approved dosing regimen for Zipsor is 25 mg four times a day.

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• Roxicodone
  

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  Roxicodone

  

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  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 4-6 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.

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