Methadone

METHADONE- methadone hydrochloride injection, solution
Xanodyne Pharmaceuticals Inc.

Rx only

CII

CONDITIONS FOR DISTRIBUTION AND USE

CONDITIONS FOR DISTRIBUTION AND USE OF METHADONE PRODUCTS FOR THE TREATMENT OF OPIOID ADDICTION

Code of Federal Regulations, Title 42, Sec 8

METHADONE PRODUCTS WHEN USED FOR THE TREATMENT OF OPIOID ADDICTION IN DETOXIFICATION OR MAINTENANCE PROGRAMS, SHALL BE DISPENSED ONLY BY OPIOID TREATMENT PROGRAMS (AND AGENCIES, PRACTITIONERS OR INSTITUTIONS BY FORMAL AGREEMENT WITH THE PROGRAM SPONSOR) CERTIFIED BY THE SUBSTANCE ABUSE AND MENTAL HEALTH SERVICES ADMINISTRATION AND APPROVED BY THE DESIGNATED STATE AUTHORITY. CERTIFIED TREATMENT PROGRAMS SHALL DISPENSE AND USE METHADONE IN ORAL FORM ONLY AND ACCORDING TO THE TREATMENT REQUIREMENTS STIPULATED IN THE FEDERAL OPIOID TREATMENT STANDARDS (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.

FAILURE TO ABIDE BY THE REQUIREMENTS IN THESE REGULATIONS MAY RESULT IN CRIMINAL PROSECUTION, SEIZURE OF THE DRUG SUPPLY, REVOCATION OF THE PROGRAM APPROVAL, AND INJUNCTION PRECLUDING OPERATION OF THE PROGRAM.

Regulatory Exceptions To The General Requirement For Certification To Provide Opioid Agonist Treatment:

  1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis). For patients unable to take oral medication, parenteral methadone may be used.
  2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21CFR 1306.07(b)).

DESCRIPTION

Methadone Hydrochloride Injection, USP, 10 mg/mL is an opioid analgesic.

Each milliliter of Methadone Hydrochloride Injection contains 10 mg (0.029 mmol) of methadone hydrochloride, equivalent to 8.95 mg of methadone free base.

Methadone hydrochloride is a white, crystalline material that is water-soluble.

Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Its molecular formula is C21 H27 NO•HCl and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235° C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5.

It has the following structural formula:

Image from Drug Label Content

Methadone Hydrochloride Injection is a sterile injectable solution containing the following inactive ingredients: chlorobutanol, 0.5%, as a preservative, and sodium chloride. The pH of the sterile injectable solution may have been adjusted during manufacturing with sodium hydroxide and/or hydrochloric acid.

CLINICAL PHARMACOLOGY

Mechanism of Action

Methadone hydrochloride is a μ agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.

Pharmacokinetics

Absorption:

Methadone Hydrochloride Injection is intended for parenteral (intravenous, subcutaneous and intramuscular) administration. Methadone pharmacokinetics following subcutaneous and intramuscular administration have not been systematically studied and differences among the various parenteral routes have not been well characterized. As with many drugs, absorption into the systemic circulation may vary with subcutaneous and intramuscular administration.

Distribution:

Methadone is a lipophilic drug and the steady state volume of distribution ranges between 2 -6 L/kg. In plasma, methadone is predominantly bound to α1 -acid glycoprotein (85% — 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma.

Metabolism:

Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4 and to a lesser extent CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in urine.

Excretion:

Elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. After single intravenous dose administration the plasma clearance of methadone ranged between 3-10 L/h and the terminal half-life (t½ ) ranged between 8 — 59 hours. Methadone has been known to persist in the liver and other tissues. Slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Pharmacokinetics in Special Populations:

Pregnancy

There are no pharmacokinetic studies of parenteral methadone in pregnancy. The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Elimination of methadone was significantly changed in pregnancy. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during second and third trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone (See DOSAGE AND ADMINISTRATION).

Renal Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Unchanged methadone and its metabolites are excreted in urine to a variable degree. Methadone is a basic (pKa=9.2) compound and the luminal pH of the urinary tract can affect its extraction from plasma. Urine acidification has been shown to increase renal elimination of methadone. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for increasing methadone or metabolite elimination.

Hepatic Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing.

Gender

The pharmacokinetics of methadone have not been evaluated for gender specificity.

Race

The pharmacokinetics of methadone have not been evaluated for race specificity.

Geriatric

The pharmacokinetics of methadone have not been evaluated in geriatric population.

Pediatric

The pharmacokinetics of methadone have not been evaluated in pediatric population.

Drug Interactions

(see PRECAUTIONS, Drug Interactions)

Methadone undergoes hepatic N-demethylation by cytochrome P-450 isoforms, principally CYP3A4, and to a lesser extent CYP2D6. Coadministration of methadone with inducers of these enzymes may result in more rapid methadone metabolism and potentially, decreased effects of methadone. Conversely, administration with CYP3A4 or CYP2D6 inhibitors may reduce metabolism and potentiate methadone’s effects. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential (see Drug Interactions)

INDICATIONS AND USAGE

  1. For the treatment of moderate to severe pain not responsive to non-narcotic analgesics.
  2. 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.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.