Methadone Hydrocloride (Page 4 of 6)

ADVERSE REACTIONS

The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, 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. In such individuals, lower doses are advisable.

Other adverse reactions include the following: (listed alphabetically under each subsection)

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

Cardiovascular (see WARNINGS, Cardiac Conduction Effects) arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia

Central Nervous System – agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus)

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

Respiratory pulmonary edema, respiratory depression (see WARNINGS, Respiratory Depression)

Skin and Appendages pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Special Senses hallucinations, visual disturbances

Urogenital – amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Methadone Hydrochloride.

Serotonin Syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs (see WARNINGS and PRECAUTIONS, Drug Interactions).

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use (see WARNINGS).

Anaphylaxis Anaphylactic reaction has been reported with ingredients contained in Methadone Hydrochloride (see CONTRAINDICATIONS).

Androgen Deficiency Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY).

DRUG ABUSE AND DEPENDENCE

Methadone hydrochloride oral concentrate contains methadone, a Schedule II opioid agonist. Schedule II opioid substances, which also include hydromorphone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.

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

Because Methadone Hydrochloride may be diverted for non-medical use, careful record keeping of ordering and dispensing information, including quantity and frequency is strongly advised.

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.

Methadone Hydrochloride, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners or institutions by formal agreement with the program sponsor).

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy (see WARNINGS, Neonatal Opioid Withdrawal Syndrome, and PRECAUTIONS, Pregnancy).

Physical dependence can develop during chronic opioid therapy.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Physical dependence is expected during opioid agonist therapy of opioid addiction.

Methadone Hydrochloride should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION). If Methadone Hydrochloride is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate (see DOSAGE ANDADMINISTRATION, Medically Supervised Withdrawal After a Period of Maintenance Treatment).

OVERDOSAGE

Clinical Presentation

Acute overdosage with methadone can be manifested by respiratory depression somnolence progressing to stupor or coma, skeletal-muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Methadone overdosage is associated with rhabdomyolysis. Seek medical attention, especially if abuse/misuse results in prolonged immobilization. Acute toxic leukoencephalopathy has been reported after methadone overdose, often weeks after apparent recovery from the initial intoxication. Hearing loss has been reported after methadone overdose, in some cases permanent.

Treatment of Overdose

In the case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

The physician must remember that methadone is a long-acting depressant (36 to 48 hours), whereas opioid antagonists act for much shorter periods (one to three hours). Because the duration of opioid reversal is expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

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