METHADONE HYDROCHLORIDE (methadone hydrochloride 10 mg) Dailymed

• • Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.8)
• • Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Methadone Hydrochloride Tablets if serotonin syndrome is suspected. (5.9)
• • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.10)
• • Severe Hypotension: Monitor during dose initiation and titration. Avoid use in patients with circulatory shock. (5.11)
• • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Methadone Hydrochloride Tablets in patients with impaired consciousness or coma. (5.12)

5.1 Addiction, Abuse and Misuse

Methadone Hydrochloride Tablets contain methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Tablets expose users to the risks of addiction, abuse, and misuse. As long-acting opioids such as Methadone Hydrochloride Tablets have pharmacological effects over an extended period of time, there is a greater risk for overdose and death [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Tablets. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Tablets, and monitor all patients receiving Methadone Hydrochloride Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Methadone Hydrochloride Tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Methadone Hydrochloride Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Methadone Hydrochloride Tablets along with the intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Methadone Hydrochloride Tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the methadone and can result in overdose and death [see Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Methadone Hydrochloride Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• •Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
• •Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• •Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• •Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a ul of accredited REMS CME/CE, call 1-800-503- 0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.3 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Methadone Hydrochloride Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Monitor patients closely for respiratory depression, when initiating therapy with Methadone Hydrochloride Tablets and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of Methadone Hydrochloride Tablets are essential [see Dosage and Administration (2.3, 2.4)]. Overestimating the Methadone Hydrochloride Tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Methadone Hydrochloride Tablets, especially by children, can result in respiratory depression and death due to an overdose of methadone.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.4 )].

5.4 Life-Threatening QT Prolongation

Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies.

Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.

Evaluate patients developing QT prolongation while on methadone treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism.

Only initiate Methadone Hydrochloride Tablets therapy for pain in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone.

The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.

5.5 Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Specific Populations (8.1)].

The balance between the risks of NOWS and the benefits of maternal Methadone Hydrochloride Tablets use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.

• •For management of pain, prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options.
• •Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.6 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

Concomitant use of Methadone Hydrochloride Tablets with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of Methadone Hydrochloride Tablets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Tablets-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone Hydrochloride Tablets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation [see Drug Interactions (7)].

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone Hydrochloride Tablets may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using Methadone Hydrochloride Tablets with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone Hydrochloride Tablets dosage as needed [see Drug Interactions (7)].

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone Hydrochloride Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).

For Patients Being Treated for Pain:

Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone Hydrochloride Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

For Patients Being Treated for Opioid Addiction:

Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation, and delays or omits the methadone dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions ( 7 )].

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Methadone Hydrochloride Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease:

Methadone Hydrochloride Tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Methadone Hydrochloride Tablets [see Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients:

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

Monitor such patients closely, particularly when initiating and titrating Methadone Hydrochloride Tablets and when Methadone Hydrochloride Tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Methadone Hydrochloride Tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue methadone if serotonin syndrome is suspected.

5.10 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.11 Severe Hypotension

Methadone Hydrochloride Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Methadone Hydrochloride Tablets. In patients with circulatory shock, Methadone Hydrochloride Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Methadone Hydrochloride Tablets in patients with circulatory shock.

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors) Methadone Hydrochloride Tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Methadone Hydrochloride Tablets.

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of Methadone Hydrochloride Tablets in patients with impaired consciousness or coma.

5.13 Risks of Use in Patients with Gastrointestinal Conditions

Methadone Hydrochloride Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The methadone in Methadone Hydrochloride Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

The methadone in Methadone Hydrochloride Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Methadone Hydrochloride Tablets therapy.

5.15 Withdrawal

Do not abruptly discontinue Methadone Hydrochloride Tablets in a patient physically dependent on opioids. When discontinuing Methadone Hydrochloride Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5 ), Drug Abuse and Dependence ( 9.3 )].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including Methadone Hydrochloride Tablets. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

5.16 Risks Driving and Operating Machinery

Methadone Hydrochloride Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Methadone Hydrochloride Tablets and know how they will react to the medication [see Patient Counseling Information (17)].

5.17 Laboratory Test Interactions

False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.

6 Adverse Reactions

The following serious adverse reactions are described, or described in greater detail, in other sections:

• •Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• •Life Threatening Respiratory Depression [see Warnings and Precautions (5.3)]
• •QT Prolongation [see Warnings and Precautions (5.4)]
• •Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]
• •Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions (5.7)]
• •Serotonin Syndrome [see Warnings and Precautions (5.9)]
• •Adrenal Insufficiency [see Warnings and Precautions (5.10)]
• •Severe Hypotension [see Warnings and Precautions (5.11)]
• •Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]
• •Seizures [see Warnings and Precautions (5.14)]
• •Withdrawal [see Warnings and Precautions (5.15)]

The following adverse reactions associated with the use of methadone were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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:

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

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

Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances

Endocrine: hypogonadism, decreased testosterone

Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis

Metabolic: hypokalemia, hypomagnesemia, weight gain

Renal: antidiuretic effect, urinary retention or hesitancy

Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology

Respiratory: pulmonary edema, respiratory depression

Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Hypersensitivity: Anaphylaxis has been reported with ingredients contained in Methadone Hydrochloride Tablets.

Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].


Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 Drug Interactions

Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of Methadone Hydrochloride Tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride Tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes uled above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of Methadone Hydrochloride Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the Methadone Hydrochloride Tablets dosage until stable drug effects are achieved.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of Methadone Hydrochloride Tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the Methadone Hydrochloride Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	For Patients Being Treated for Pain: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)]. For Patients Being Treated for Opioid Addiction: Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments.
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.9)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Methadone Hydrochloride Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.9)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
Intervention:	The use of Methadone Hydrochloride Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Methadone Hydrochloride Tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Methadone Hydrochloride Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Methadone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.

Paradoxical Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets:

Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of Methadone Hydrochloride Tablets 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 Methadone Hydrochloride Tablets 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.

Effects of Methadone Hydrochloride Tablets on Antidepressants:

Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.

• • Anti-Retroviral Agents: May result in decreased efficacy or, in certain cases, increased toxicity. (7)
• • Potentially Arrhythmogenic Agents: Pharmacodynamic interactions may occur. Monitor patients closely for cardiac conduction changes. (7)
• • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Methadone Hydrochloride Tablets because they may reduce analgesic effect of Methadone Hydrochloride Tablets or precipitate withdrawal symptoms. (5.15, 7)
• • Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of methadone hydrochloride. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. (7)