*'''Phenytoin''': In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d initially for 1 day followed by 300 mg QD for 3-4 days) resulted in ~50% reduction in methadone exposure and concurrently withdrawal symptoms occurred. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and the methadone exposure increased and was comparable to pre-phenytoin dose scenario.
*'''Phenytoin''': In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d initially for 1 day followed by 300 mg QD for 3-4 days) resulted in ~50% reduction in methadone exposure and concurrently withdrawal symptoms occurred. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and the methadone exposure increased and was comparable to pre-phenytoin dose scenario.
St. John's Wort, phenobarbital, carbamazepine: Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms.
*'''St. John's Wort, phenobarbital, carbamazepine''': Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms.
Cytochrome P450 inhibitors: Since the metabolism of methadone is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), while receiving methadone should be carefully monitored and dosage adjustment made if warranted. Some selective serotonin reuptake inhibitors (SSRI's) (i.e., sertraline, fluvoxamine) upon coadministration may increase methadone plasma levels and result in increased opiate effects or toxicity.
*'''Cytochrome P450 inhibitors''': Since the metabolism of methadone is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), while receiving methadone should be carefully monitored and dosage adjustment made if warranted. Some selective serotonin reuptake inhibitors (SSRI's) (i.e., sertraline, fluvoxamine) upon coadministration may increase methadone plasma levels and result in increased opiate effects or toxicity.
Others:
Others:
Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient's condition and vital signs are under careful observation.
*'''Monoamine Oxidase (MAO) Inhibitors''': Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient's condition and vital signs are under careful observation.
Desipramine: Blood levels of desipramine have increased with concurrent methadone therapy.
*'''Desipramine''': Blood levels of desipramine have increased with concurrent methadone therapy.
Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing concomitant drugs capable of inducing electrolyte disturbances that may prolong the QT interval (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and in rare cases mineralocorticoid hormones.
*'''Potentially Arrhythmogenic Agents''': Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing concomitant drugs capable of inducing electrolyte disturbances that may prolong the QT interval (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and in rare cases mineralocorticoid hormones.
Interactions with other CNS Depressants: Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma.
*'''Interactions with other CNS Depressants''': Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma.
Use with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist, such as Methadone Hydrochloride Injection. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Methadone Hydrochloride Injection and/or may precipitate withdrawal symptoms.
*'''Use with Mixed Agonist/Antagonist Opioid Analgesics''': Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist, such as Methadone Hydrochloride Injection. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Methadone Hydrochloride Injection and/or may precipitate withdrawal symptoms.
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
For the treatment of moderate to severe pain not responsive to non-narcotic analgesics.
For use in temporary treatment of opioid dependence in patients unable to take oral medication.
Outpatient maintenance and outpatient detoxification treatment may be provided only by opioid treatment programs (OTPs) certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). This does not preclude the maintenance treatment of a patient with concurrent opioid addiction who is hospitalized for conditions other than opioid addiction and who requires temporary maintenance during the critical period of hospitalization, or of a patient whose enrollment has been verified in a program which has been certified for maintenance treatment with methadone.
NOTE: INJECTABLE METHADONE PRODUCTS ARE NOT APPROVED FOR THE OUTPATIENT TREATMENT OF OPIOID DEPENDENCE. IN THIS PATIENT POPULATION, PARENTERAL METHADONE IS TO BE USED ONLY FOR PATIENTS UNABLE TO TAKE ORAL MEDICATION, SUCH AS HOSPITALIZED PATIENTS.
Dosage
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.
This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methadone (injection) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methadone (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Methadone (injection) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methadone (injection) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methadone (injection) in pediatric patients.
Contraindications
There is limited information regarding Methadone (injection) Contraindications in the drug label.
Warnings
There is limited information regarding Methadone (injection) Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
Initial Administration: The initial methadone dose should be carefully titrated to the individual. Induction too rapid for the patient's sensitivity is more likely to produce adverse effects.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses of methadone are advisable.
Other adverse reactions that have been reported in patients (including opioid addicts taking methadone for detoxification or maintenance) receiving methadone include the following:
Maintenance on a Stabilized Dose: During prolonged administration of methadone, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Methadone (injection) in the drug label.
Drug Interactions
In vitro results indicate that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, and to a lesser extent CYP2D6. Coadministration of methadone with inducers of these enzymes may result in a more rapid metabolism and potential for decreased effects of methadone, whereas administration with inhibitors may reduce metabolism and potentiate methadone's effects. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy.
Opioid antagonists, mixed agonist/antagonists, and partial agonists: As with other μ-agonists, patients maintained on methadone may experience withdrawal symptoms when given these agents. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.
Anti-retroviral agents:
Nevirapine: Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Opioid withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Efavirenz: Coadministration of efavirenz in HIV-infected methadone-maintenance patients has resulted in decreased methadone plasma concentrations of methadone associated with signs of opiod withdrawal, and necessitating increases in methadone dose.
Ritonavir and Ritonavir/Lopinavir: Reduced plasma methadone levels have been observed after administration of ritonavir alone or ritonavir/lopinavir combination. Withdrawal symptoms were however, inconsistently observed. Caution is warranted when administering methadone to patients receiving ritonavir-containing regimens in addition to other drugs known to decrease methadone plasma levels.
Zidovudine: Experimental evidence suggests that methadone increases the area under the concentration-time curve (AUC) of zidovudine with possible toxic effects.
Didanosine and Stavudine: Experimental evidence suggests that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.
Cytochrome P450 inducers: The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes.
Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in marked reduction in serum methadone levels and concurrent appearance of withdrawal symptoms.
Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d initially for 1 day followed by 300 mg QD for 3-4 days) resulted in ~50% reduction in methadone exposure and concurrently withdrawal symptoms occurred. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and the methadone exposure increased and was comparable to pre-phenytoin dose scenario.
St. John's Wort, phenobarbital, carbamazepine: Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms.
Cytochrome P450 inhibitors: Since the metabolism of methadone is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), while receiving methadone should be carefully monitored and dosage adjustment made if warranted. Some selective serotonin reuptake inhibitors (SSRI's) (i.e., sertraline, fluvoxamine) upon coadministration may increase methadone plasma levels and result in increased opiate effects or toxicity.
Others:
Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient's condition and vital signs are under careful observation.
Desipramine: Blood levels of desipramine have increased with concurrent methadone therapy.
Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing concomitant drugs capable of inducing electrolyte disturbances that may prolong the QT interval (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and in rare cases mineralocorticoid hormones.
Interactions with other CNS Depressants: Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma.
Use with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist, such as Methadone Hydrochloride Injection. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Methadone Hydrochloride Injection and/or may precipitate withdrawal symptoms.
01.png){kind=link}