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.
Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination
Coadministration of these anti-retroviral agents resulted in increased clearance or decrease plasma levels of methadone. Methadone-maintained patients beginning treatment with above antiretroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly.
Didanosine and Stavudine
Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.
Experimental evidence demonstrated that methadone increased the AUC of zidovudine which could result in toxic effects.
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.
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 opioid 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.
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.
Methadone Hydrochloride Oral Concentrate, USP is contraindicated in patients with a known hypersensitivity to methadone hydrochloride or any other ingredient in Methadone Hydrochloride Oral Concentrate, USP.
Methadone Hydrochloride Oral Concentrate, USP is contraindicated in any situation where opioids are contraindicated, such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute bronchial asthma or hypercarbia.
Methadone is contraindicated in any patient who has or is suspected of having a paralytic ileus.
DRUG ABUSE AND DEPENDENCE
Methadone Hydrochloride Oral Concentrate, USP, contains methadone, a potent 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 Oral Concentrate, USP, poses a risk of overdose and death. This risk is increased with concurrent abuse of Methadone Hydrochloride Oral Concentrate, USP with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV.
Since Methadone Hydrochloride Oral Concentrate, USP, may be diverted for non-medical use, careful record keeping of ordering and dispensing information, including quantity, frequency, and renewal requests 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 Oral Concentrate, USP, 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).
Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see
PRECAUTIONS, Pregnancy, Labor and Delivery).
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