Methadone Hydrochloride 40 mg Tablet, 100-count — NDC 66689-898-40 (Billing 66689-0898-40)

5 WARNINGS AND PRECAUTIONS N e o natal Op i o i d Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.6 ) L i f e - T h r e at e nin g Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.8 ) S e ro t o ni n Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration.

Discontinue methadone hydrochloride tablets for oral suspension if serotonin syndrome is suspected. ( 5.9 ) A d r e na l Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) S e v e r e Hypotension: Monitor during dose initiation and titration.

( 5.11 ) Ri s k s of Use in 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. ( 5.12 )

5.1Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. 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 overdose reversal agents, 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 tablets for oral suspension, 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. Monitor patients closely for respiratory depression, when initiating therapy with methadone hydrochloride tablets for oral suspension 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 [see Patient Counseling Information ( 17 )] .

To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential [see Dosage and Administration ( 2.5 )] . Overestimating the methadone dosage when initiating treatment can result in fatal overdose with the first dose. 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. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Follow induction directions closely to avoid inadvertent overdose [see Dosage and Administration ( 2.5 )] .

Proper dosing and titration are essential and methadone should be overseen only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )] . Op… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS The following serious adverse reactions and/or conditions are described, or described in greater detail, in other sections: Respiratory Depression [see Warnings and Precautions ( 5.1 )] Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ( 5.2 )] QT Prolongation [see Warnings and Precautions ( 5.3 )] 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 )] Hypoglycemia [see Warnings and Precautions ( 5.17 )] 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 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 included lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seemed to be more prominent in ambulatory patients and in those who are not suffering severe pain. 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, congenital oculomotor disorders (nystagmus, strabismus) 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.

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. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in methadone hydrochloride tablets for oral suspension.

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )]. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions ( 5.17 )]. Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.13 )].

Most Common Adverse Reactions Are : lightheadedness, dizziness… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS 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 : 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 [ see Warnings and Precautions ( 5.2 )] . If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions ( 5.1 ) ].

Examples : Benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. 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 for oral suspension 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 for oral suspension is achieved.

These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed 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 for oral suspension 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 for oral suspension 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 for oral suspension 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… [Excerpted — this section continues on DailyMed.]

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance Methadone hydrochloride tablets for oral suspension contain methadone, a Schedule II controlled substance.

9.2Abuse Methadone hydrochloride tablets for oral suspension contain methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. Methadone hydrochloride tablets for oral suspension can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.5 )] . Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: 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 persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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.

Methadone hydrochloride tablets for oral suspension, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity and frequency as required by state and federal law, is strongly advised. 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.

Risks Specific to Methadone Hydrochloride Tablets for Oral Suspension: Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. Methadone hydrochloride tablets for oral suspension are intended 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. Methadone hydrochloride tablets for oral suspension, 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, and institutions by formal agreements with the program sponsor).

9.3Dependence 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 (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 significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocin… [Excerpted — this section continues on DailyMed.]

9.1Controlled Substance Methadone hydrochloride tablets for oral suspension contain methadone, a Schedule II controlled substance.