FDA label 3f607a9a-9b07-0a32-e054-00144ff8d46c

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, ABUSE POTENTIAL and TREATMENT FOR OPIOID ADDICTION Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, have been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions ( 5.1 )] . Proper dosing and titration are essential and methadone hydrochloride tablets for oral suspension should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone hydrochloride tablets for oral suspension or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Life-Threatening QT Prolongation QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone [see Warnings and Precautions ( 5.2 )] . 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. Closely monitor patients for changes in cardiac rhythm during initiation and titration of methadone hydrochloride tablets for oral suspension. Accidental Exposure Accidental ingestion of methadone hydrochloride tablets for oral suspension, especially in children, can result in fatal overdose of methadone [see Warnings and Precautions ( 5.3 )] . Abuse Potential Methadone hydrochloride tablets for oral suspension contain methadone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions ( 5.4 )] . Routinely monitor all patients receiving methadone hydrochloride tablets for oral suspension for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence ( 9 )] . Conditions For Distribution And Use Of Methadone Products For The Treatment of Opioid Addiction For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration [see Indications and Usage ( 1 )] . WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, ABUSE POTENTIAL and TREATMENT FOR OPIOID ADDICTION See full prescribing information for complete boxed warning. Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of methadone hydrochloride tablets for oral suspension to reduce the risk. ( 5.1 ) QT Interval prolongation and serious arrhythmia (torsades de pointes) have occurred with treatment with methadone. ( 5.2 ) Accidental ingestion of methadone hydrochloride tablets for oral suspension can result in fatal overdose of methadone, especially in children. ( 5.3 ) Methadone hydrochloride tablets for oral suspension contain methadone, a Schedule II controlled substance and can be abused and criminally diverted. ( 5.4 , 9 ) Methadone products, when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by certified opioid treatment programs as stipulated in 42 CFR 8.12. ( 1 )

5.11 Use in Patients with Convulsive or Seizure Disorders Methadone may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during methadone hydrochloride tablets for oral suspension therapy.

5 WARNINGS AND PRECAUTIONS Methadone hydrochloride tablets for oral suspension are for oral administration only. The preparation must not be injected. Methadone should be kept out of reach of children to prevent accidental ingestion. Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.5 , 5.6 ) Interactions with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.7 , 7.2 ) Hypotensive effect: Monitor during dose initiation and titration. ( 5.8 ) Patients with head injury and increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of methadone in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.9 ) 5.1 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of methadone. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. 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 )] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Closely monitor patients with respiratory depression when initiating therapy with methadone and following dose increases. Instruct patients against use by individuals other than the patient for whom methadone was prescribed and to keep methadone out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential [see Dosage and Administration ( 2.1 )] . Overestimating the methadone dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of methadone when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Proper dosing and titration are essential and methadone should be prescribed only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. Methadone is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications ( 4 )] . 5.2 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 hydrochloride tablets for oral suspension treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. Only initiate therapy with methadone hydrochloride tablets for oral suspension 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. 5.3 Accidental Exposure Accidental ingestion of methadone hydrochloride tablets for oral suspension, especially in children, can result in a fatal overdose of methadone. Methadone hydrochloride tablets for oral suspension should be kept out of reach of children to prevent accidental ingestion. 5.4 Abuse Potential Methadone hydrochloride tablets for oral suspension contain methadone, an opioid agonist and a Schedule II controlled substance. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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. 5.5 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating methadone hydrochloride tablets for oral suspension and when methadone hydrochloride tablets for oral suspension are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.1 )] . 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with methadone hydrochloride tablets for oral suspension, as in these patients, even usual therapeutic doses of methadone may decrease respiratory drive to the point of apnea [see Warnings and Precautions ( 5.1 )] . 5.7 Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if methadone is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of methadone hydrochloride tablets for oral suspension in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If methadone therapy is to be initiated in a patient taking a CNS depressant, start with a lower methadone dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions ( 7.2 )] . Deaths associated with illicit use of methadone have frequently involved concomitant benzodiazepine abuse. 5.8 Hypotensive Effect Methadone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain normal blood pressure is compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions ( 7.2 )] . Monitor these patients for signs of hypotension after initiating or titrating the dose of methadone hydrochloride tablets for oral suspension. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking methadone hydrochloride tablets for oral suspension who may be susceptible to the intracranial effects of CO 2 retention (e.g. those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with methadone. Methadone may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure . Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of methadone in patients with impaired consciousness or coma. 5.10 Use in Patients with Gastrointestinal Conditions Methadone hydrochloride tablets for oral suspension are contraindicated in patients with paralytic ileus. Avoid the use of methadone hydrochloride tablets for oral suspension in patients with other gastrointestinal obstruction. Methadone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders Methadone may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during methadone hydrochloride tablets for oral suspension therapy. 5.12 Avoidance of Withdrawal Avoid the use of partial agonists or mixed agonist/antagonist analgesics (i.e., buprenorphine, pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including methadone. In these patients, partial agonists or mixed agonists/antagonists analgesics may precipitate withdrawal symptoms [see Drug Interactions ( 7.4 )] . When discontinuing methadone hydrochloride tablets for oral suspension, gradually taper the dose [see Dosage and Administration ( 2.3 , 2.4 )] . Do not abruptly discontinue methadone hydrochloride tablets for oral suspension. 5.13 Driving and Operating Machinery Methadone 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 for oral suspension and know how they will react to the medication.

5.1 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of methadone. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. 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 )] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Closely monitor patients with respiratory depression when initiating therapy with methadone and following dose increases. Instruct patients against use by individuals other than the patient for whom methadone was prescribed and to keep methadone out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential [see Dosage and Administration ( 2.1 )] . Overestimating the methadone dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of methadone when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Proper dosing and titration are essential and methadone should be prescribed only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. Methadone is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications ( 4 )] .

5.2 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 hydrochloride tablets for oral suspension treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. Only initiate therapy with methadone hydrochloride tablets for oral suspension 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.

6 ADVERSE REACTIONS The following adverse reactions have been identified during post-approval use of methadone. Because these reactions are 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 following serious adverse reactions and/or conditions are discussed elsewhere in the labeling: Respiratory Depression [see Warnings and Precautions ( 5.1 )] QT Prolongation [see Warnings and Precautions ( 5.2 )] Chronic Pulmonary Disease [see Warnings and Precautions ( 5.6 )] Interactions with CNS Depressants [see Warnings and Precautions ( 5.7 )] Hypotensive Effect [see Warnings and Precautions ( 5.8 )] Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions ( 5.9 )] Gastrointestinal Effects [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] 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, torsade de pointes, ventricular fibrillation, ventricular tachycardia Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances Endocrine: hypogonadism 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 Musculoskeletal: decreased muscle mass and strength, osteoporosis and fractures 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 for oral suspension. Advise patients how to recognize such a reaction and when to seek medical attention. 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. Methadone Hydrochloride Tablets for Oral Suspension 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. Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Inc. at 1-888-744-1414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch