Methadone Hydrochloride 10 mg/mL Injection — NDC 0641-6266-01 (Billing 00641-6266-01)

WARNINGS Addiction, Abuse and Misuse Methadone Hydrochloride Injection contains methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Injection exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Injection.

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 Injection, and reassess all patients receiving Methadone Hydrochloride Injection 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 Injection for the proper management of pain in any given patient. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Methadone Hydrochloride Injection.

Strategies to reduce these risks include proper product storage and control practices for a C-II drug. 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. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.

Respiratory depression, if not immediately recognized and treated, may lead to respiratory depression and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO 2 ) 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 Injection, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Methadone Hydrochloride Injection are essential. Overestimating the Methadone Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Methadone Hydrochloride Injection should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as; asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma. In these patients even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose.

Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. 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 ). Life-Threatening QT Prolongation Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been obser… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse (see WARNINGS ) Life Threatening Respiratory Depression (see WARNINGS ) QT Prolongation (see WARNINGS ) Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) Interactions with CNS Depressants (see WARNINGS ) Serotonin Syndrome (see WARNINGS ) Adrenal Insufficiency (see WARNINGS ) Severe Hypotension (see WARNINGS ) Gastrointestinal Adverse Reactions (see WARNINGS ) Seizures (see WARNINGS ) Withdrawal (see WARNINGS ) Hypoglycemia (see WARNINGS ) The following adverse reactions associated with the use of methadone were identified in clinical studies or post-marketing 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 of methadone are advisable.

Other adverse reactions that have been reported in patients (including opioid addicts taking methadone for detoxification or maintenance) receiving methadone include the following: Body as a Whole : asthenia (weakness), edema, headache Cardiovascular: Arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, Torsade de Pointes, ventricular fibrillation, ventricular tachycardia. ECG abnormalities, prolonged QT interval, T-wave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope Digestive: Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic and Lymphatic: Reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis.

Metabolic and Nutritional: Hypokalemia, hypomagnesemia, weight gain Central Nervous System: Agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus) Respiratory: Pulmonary edema Skin and Appendages: Intramuscular and Subcutaneous: Local tissue reactions (pain, erythema, swelling), particularly with continuous subcutaneous infusion Intravenous: Pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses: Visual disturbances Urogenital: Antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency 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 Injection. Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time.

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration (see WARNINGS ). Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone (see WARNINGS ).

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 Injection 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 fatal overdose, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride Injection 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 ), 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 Injection until stable drug effects are achieved.

Monitor patients for respiratory depression and sedation at frequent intervals. If CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the Methadone Hydrochloride Injection 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 Injection and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone (see CLINICAL PHARMACOLOGY ), 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, CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase (see CLINICAL PHARMACOLOGY ), 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 Injection dosage until stable drug effects are achieved.

Monitor for signs of opioid withdrawal. If a CYP3A4, CTP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Injection 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 addictive 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: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and duration to the minimum required.

Follow patients closely for signs of respiratory depression and sedation (see WARNINGS , PRECAUTIONS ) 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… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Methadone given on a fixed-dose schedule may have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known potential risks of cardiac conduction abnormalities, respiratory depression, altered mental states and postural hypotension. Methadone Hydrochloride Injection should be used with caution in elderly and debilitated patients; patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease; and in patients with comorbid conditions or concomitant medications which may predispose to dysrhythmia.

Selection of patients for treatment with methadone should be governed by the same principles that apply to the use of other parenteral opioids (see INDICATIONS AND USAGE ). Physicians should individualize treatment in every case (see DOSAGE AND ADMINISTRATION ), taking into account the high degree of interpatient variability in response to and metabolism of methadone. Information for Patients Addiction, Abuse and Misuse Inform patients that the use of Methadone Hydrochloride Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death (see WARNINGS ).

Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Methadone Hydrochloride Injection or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS ). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Symptoms of Arrhythmia Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking methadone (see WARNINGS ).

Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Methadone Hydrochloride Injection are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider (see WARNINGS , PRECAUTIONS: Drug Interactions ). Hyperalgesia and Allodynia Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain (see WARNINGS : ADVERSE REACTIONS ).

Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications (see WARNINGS , PRECAUTIONS: Drug Interactions ).

MAOI Interaction Inform patients to avoid taking Methadone Hydrochloride Injection while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Methadone Hydrochloride Injection (see PRECAUTIONS: Drug Interactions) . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.

Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS ). Hypotension Inform patients that Methadone Hydrochloride Injection may cause orthostatic hypotension and syncope.

Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotens… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Controlled Substance Methadone Hydrochloride Injection contains methadone, a Schedule II controlled substance. Abuse Methadone Hydrochloride Injection contains methadone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction (see WARNINGS ). Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Methadone Hydrochloride Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death.

The risk is increased with concurrent abuse of Methadone Hydrochloride Injection with alcohol and/or other central nervous system depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Methadone Hydrochloride Injection abuse include those with a history of prolonged use of any opioid, including products containing methadone, those with a history of drug or alcohol abuse, or those who use Methadone Hydrochloride Injection in combination with other abused drugs. "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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Methadone Hydrochloride Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Methadone Hydrochloride Injection Abuse of Methadone Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent use of Methadone Hydrochloride Injection with alcohol and/or other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of… [Excerpted — this section continues on DailyMed.]

Controlled Substance Methadone Hydrochloride Injection contains methadone, a Schedule II controlled substance.