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Methadone (Methadone Hydrochloride) - Description and Clinical Pharmacology

 
 



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 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis.
  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 21 CFR 1306.07(b)).

DESCRIPTION

Methadone Hydrochloride Oral Concentrate, USP, is supplied in two formulations. The first is supplied as a cherry flavored liquid concentrate. The second is a dye-free, sugar-free, unflavored liquid concentrate. Each liquid concentrate contains 10 mg of methadone hydrochloride per mL.

Methadone hydrochloride is chemically described as 3-heptanone, 6-(dimethylamino)-4, 4-diphenyl-, hydrochloride. Methadone hydrochloride is a white, essentially odorless, bitter-tasting crystalline powder. It is very soluble in water, soluble in isopropranolol and in chloroform, and practically insoluble in ether and in glycerine. It is present in Methadone Hydrochloride Oral Concentrate, USP, as the racemic mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water. Its structural formula is:

C21H27NO•HCl    MW= 345.91

Other ingredients of Methadone Hydrochloride Oral Concentrate, USP: Artificial Cherry Flavor; Sorbic Acid, NF; Potassium Sorbate, NF; FD&C Red No. 40; D&C Red No. 33; Poloxamer 188, NF; Propylene Glycol, USP; Glycerin, USP; Sucrose, NF, and Purified Water, USP.

Other ingredients of Methadone Hydrochloride Oral Concentrate, USP (Dye-Free, Sugar-Free, Unflavored): Citric Acid Anhydrous, USP; Purified Water, USP, and Sodium Benzoate, NF.

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 actions of therapeutic value are analgesia and sedation and 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

Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.

Distribution

Methadone is a lipophilic drug and the steady state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 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, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in urine.

Excretion

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 to 126 L/h and the terminal half-life (T1/2) was highly variable and ranged between 8 and 59 hours in different studies. Since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Pharmacokinetics in Special Populations

Pregnancy

The disposition of oral methadone has been studied in approximately 30 pregnant patients in the second and third 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 PRECAUTIONS: Pregnancy, Labor and Delivery, and DOSAGE AND ADMINISTRATION.)

Renal Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in 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 the elimination of methadone or its metabolites.

Hepatic Impairment

Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways, therefore 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 the geriatric population.

Pediatric

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

Drug Interactions

( see PRECAUTIONS, Drug Interactions)

Methadone undergoes hepatic N-demethylation by cytochrome P-450 isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and 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 CYP inhibitors may reduce metabolism and potentiate methadone's effects. Pharmacokinetics of methadone may be unpredictable when coadministered with drugs that are known to both induce and inhibit CYP enzymes. Although anti-retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy before making a dosage adjustment.

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