Methadone Hydrochloride Injection

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 C21H27NO•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:

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.

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 major hazards of methadone are res piratory depression and, to a lesser degree, systemic hypotens ion. Respiratoryarrest, s hock, cardiacarrest, and death have occurred.

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:

Body as a Whole: asthenia (weakness), edema, headache

Cardiovascular: Arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, Torsade de Pointes, ventricular fibrillation, ventricular tachycardia. ECG abnormalities, prolonged QT interval, Twave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope.

Digestive: Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Hematologic and Lymphatic: Reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis.

Metabolic and Nutritional: Hypokalemia, hypomagnesemia, weight gain

Nervous: Agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia

Respiratory: Pulmonary edema

Intramuscular and Subcutaneous: Local tissue reactions (pain, erythema, swelling), particularly with continuous subcutaneous infusion

Intravenous: Pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Special senses: Visual disturbances

Urogenital: Antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency

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.

Drug Abuse And Dependence

Methadone is a μ-agonist opioid with an abuse liability similar to that of morphine and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.

Drug addiction is characterized by a preoccupation with the procurement, hoarding, and abuse of drugs for non-medicinal purposes. Drug addiction is treatable, utilizing a multi-disciplinary approach, but relapse is common.

“Drug seeking” behavior is very common to addicts and drug abusers. Drug seeking tactics include emergency calls or visits near the end of the office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addictions.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Methadone Hydrochloride Injection, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Abuse of Methadone Hydrochloride Injection poses a risk of overdose and death. This risk is increased with concurrent abuse of Methadone Hydrochloride Injection with alcohol and other substances. In  addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (See PRECAUTIONS; Pregnancy and Labor and Delivery)

Signs And Symptoms

Serious overdosage of methadone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Treatment

Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person takes a large dose of methadone, effective opioid antagonists are available to counteract the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (36 to 48 hours ), whereas the antagonists act for much shorter periods (one to three hours ). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and may need to be treated repeatedly with the narcotic antagonist. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of other respiratory stimulants is not indicated.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If antagonists must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Intravenously administered naloxone or nalmefene may be used to reverse signs of intoxication. Because of the relatively short half-life of naloxone as compared with methadone, repeated injections may be required until the status of the patient remains satisfactory. Naloxone may also be administered by continuous intravenous infusion.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated.

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

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.

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.

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.

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 (t ½) 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

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 opioiddependent 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).

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.

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.

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

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

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

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)

Methadone, like all opioids, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery. The patient should be cautioned accordingly.

Methadone, like other opioids, may produce orthostatic hypotension in ambulatory patients.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with methadone, and should be avoided.

If a patient taking methadone experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, or syncope), that patient should seek immediate medical attention.