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warnings and cautions
5 WARNINGS AND PRECAUTIONS Respiratory Depression: The peak respiratory depressant effect typically occurs later, and persists longer than the peak analgesic effect, which can contribute to iatrogenic overdose. Patients who are tolerant to other opioids may be incompletely tolerant to methadone hydrochloride. (5.2) May cause QT interval prolongation and serious arrhythmia. (5.3) Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. (5.5, 5.6) Interaction 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 or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of methadone hydrochloride in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. (5.9) 5.1 Abuse Potential Methadone hydrochloride tablets 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. Consider these risks when prescribing or dispensing methadone hydrochloride in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. For each patient prescribed methadone hydrochloride for pain management, assess the risk for opioid abuse or addiction prior to prescribing methadone hydrochloride. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. 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 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of methadone hydrochloride. 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 hydrochloride, 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 analgesic effect, especially during the initial dosing period. Closely monitor patients for respiratory depression when initiating therapy with methadone hydrochloride and following dose increases. Instruct patients against use by individuals other than the patient for whom methadone hydrochloride was prescribed and to keep methadone hydrochloride 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 hydrochloride are essential [see Dosage and Administration (2.1, 2.2)] . Overestimating the methadone hydrochloride 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 hydrochloride should be prescribed only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone, especially when converting patients from other opioids, and in the use of potent opioids for the management of chronic pain. Methadone hydrochloride is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)] . 5.3 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 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. 5.4 Accidental Exposure Accidental ingestion of methadone hydrochloride, especially in children, can result in a fatal overdose of methadone. Methadone hydrochloride should be kept out of reach of children to prevent accidental ingestion. 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 and when methadone hydrochloride is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)] . 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 for respiratory depression, particularly when initiating therapy and titrating with methadone hydrochloride, as in these patients, even usual therapeutic doses of methadone hydrochloride may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)] . Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if methadone hydrochloride is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of methadone hydrochloride 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 hydrochloride therapy is to be initiated in a patient taking a CNS depressant, start with a lower methadone hydrochloride 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 hydrochloride 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 (7.2)] . Monitor these patients for signs of hypotension after initiating or titrating the dose of methadone hydrochloride. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking methadone hydrochloride 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 hydrochloride. Methadone hydrochloride 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 hydrochloride in patients with impaired consciousness or coma. 5.10 Use in Patients with Gastrointestinal Conditions Methadone hydrochloride is contraindicated in patients with paralytic ileus. Avoid the use of methadone hydrochloride in patients with other gastrointestinal obstruction. The methadone in methadone hydrochloride 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 The methadone in methadone hydrochloride 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 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 hydrochloride. In these patients, partial agonists or mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4)] . When discontinuing methadone hydrochloride, gradually taper the dose [see Dosage and Administration (2.3)] . Do not abruptly discontinue methadone hydrochloride. 5.13 Driving and Operating Machinery Methadone hydrochloride 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 and know how they will react to the medication.