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Details with Side Effects
The following serious adverse reactions and/or conditions are discussed elsewhere in the labeling:
- Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see WARNINGS AND PRECAUTIONS]
- Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS]
- Head Injuries and Increased Intracranial Pressure [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effect [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
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 and in those who are not suffering severe pain. In such individuals, lower doses are advisable.
Other adverse reactions include the following:
Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia
Renal: antidiuretic effect, urinary retention or hesitancy
Respiratory: pulmonary edema, respiratory depression
Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and reproductive effects are thought to be related to chronic opioid use.
DOLOPHINE for the Detoxification and Maintenance Treatment of Opioid Dependence
During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated.
Read the Dolophine (methadone) Side Effects Center for a complete guide to possible side effects
Cytochrome P450 Interactions
Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6 [see CLINICAL PHARMACOLOGY].
Cytochrome P450 Inducers
Concurrent use of DOLOPHINE and drugs that induce cytochrome P450 enzymes (such as rifampicin, phenytoin, phenobarbital, carbamazepine, and St. John's Wort) may result in reduced efficacy of DOLOPHINE and could precipitate a withdrawal syndrome. Closely monitor patients receiving DOLOPHINE and an enzyme inducer closely for signs of withdrawal and adjust the DOLOPHINE dose accordingly.
Cytochrome P450 Inhibitors
Coadministration of drugs that inhibit CYP3A4 (such as ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, telithromycin) and/or drugs that inhibit CYP2C9 (such as sertraline and fluvoxamine) may cause decreased clearance of methadone, which could increase or prolong adverse drug effects and may cause fatal respiratory depression [see CLINICAL PHARMACOLOGY]. Monitor patients closely for signs of respiratory or central nervous system depression when DOLOPHINE is prescribed with a CYP3A4 inhibitor and reduce the dosage if necessary.
Paradoxical Effects of Antiretroviral Agents on DOLOPHINE
Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of DOLOPHINE and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
Effects of DOLOPHINE on Antiretroviral Agents
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.
Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects.
Concurrent use of DOLOPHINE and other central nervous system (CNS) depressants (e.g. sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, alcohol and drugs of abuse) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and DOLOPHINE for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines.
Potentially Arrhythmogenic Agents
Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
Similarly, monitor patients closely when prescribing methadone concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists
As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.
Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are carefully observed.
Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when DOLOPHINE is used concurrently with anticholinergic drugs.
Laboratory Test Interactions
Drug Abuse And Dependence
Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Methadone and other opioids used in analgesia have the potential for being abused and are subject to criminal diversion [see WARNINGS AND PRECAUTIONS].
All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost 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 addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
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.
DOLOPHINE, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised.
Abuse of DOLOPHINE poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. Methadone is for oral use only and must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment and selection 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 Use in Specific Populations].
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 such as analgesia (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 a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
DOLOPHINE should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If DOLOPHINE is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].
Read the Dolophine Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/19/2012
This monograph has been modified to include the generic and brand name in many instances.
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