Methadone Hydrochloride

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF METHADONE HYDROCHLORIDE ORAL SOLUTION

BOXED WARNING SECTION

Risk of Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with methadone solutions of different concentrations, when prescribing, dispensing, and administering Methadone Hydrochloride Oral Solution, 5 mg per 5 mL or 10 mg per 5 mL. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients and caregivers on how to measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices [see Dosage and Administration (2.1 ), Warnings and Precautions (5.1)]. Addiction, Abuse, and Misuse Because the use of Methadone Hydrochloride Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Methadone Hydrochloride Oral Solution, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Methadone Hydrochloride Oral Solution are essential [see Warnings and Precautions (5.3 )] . Accidental Ingestion Accidental ingestion of even one dose of Methadone Hydrochloride Oral Solution, especially by children, can result in a fatal overdose of methadone [see Warnings and Precautions (5.3) ] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Methadone Hydrochloride Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4) , Drug Interactions (7) ] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.6)] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.7)]. Life-threatening QT Prolongation QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. 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 with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of Methadone Hydrochloride Oral Solution [see Warnings and Precautions (5.5)]. Cytochrome P450 Interaction The concomitant use of Methadone Hydrochloride Oral Solution with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels [see Warnings and Precautions (5.8) , Drug interactions (7)]. 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 ), Dosage and Administration (2.1)].

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Methadone Hydrochloride Oral Solution is indicated for the: Management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2)], reserve Methadone Hydrochloride Oral Solution for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. Methadone Hydrochloride Oral Solution is not indicated as an as-needed (prn) analgesic. Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. ​ Limitations of Use: Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 CFR 8.12 [see Dosage and Administration (2.1) ] .

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Each 5 mL of clear or nearly clear orange colored Methadone Hydrochloride Oral Solution USP contains methadone hydrochloride USP 5 mg or 10 mg. The concentration of the 5 mg per 5 mL solution is 1 mg/mL and the concentration of the 10 mg per 5 mL solution is 2 mg/mL.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Methadone Hydrochloride Oral Solution is contraindicated in patients with: Significant respiratory depression [ see Warnings and Precautions (5.4 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)] Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions (6)]

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2 )] Life Threatening Respiratory Depression [see Warnings and Precautions (5.4 )] QT Prolongation [see Warnings and Precautions (5.5 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.6) ] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.8)] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9)] Serotonin Syndrome [see Warnings and Precautions (5.10 )] Adrenal Insufficiency [see Warnings and Precautions (5.11 )] Severe Hypotension [see Warnings and Precautions (5.12 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14 )] Seizures [see Warnings and Precautions (5.15 )] Withdrawal [see Warnings and Precautions (5.16 )] 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, congenital oculomotor disorders (nystagmus, strabismus) 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 Oral Solution. 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 use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)]. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions (5.19)].

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

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 Oral Solution 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 Oral Solution 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 Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, consider increasing the Methadone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. 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 Oral Solution 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 Pharmacokinetics 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 Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Oral Solution dose reduction and evaluate patients at frequent intervals 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, can increase the risk of hypotension, 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. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. 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. 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 (5.2 , 5.4 , 5.8 )] . 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: Evaluate 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, mineralocorticoid 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 (5.10) ]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Methadone Hydrochloride Oral Solution 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 (5.10) ] or opioid toxicity (e.g , respiratory depression, coma) [see Warnings and Precautions (5.4) ]. Intervention: The use of Methadone Hydrochloride Oral Solution 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 Oral Solution 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: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Methadone Hydrochloride Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate 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 dr...

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

9 DRUG ABUSE AND DEPENDENCE

DRUG ABUSE AND DEPENDENCE SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

Clinical Presentation : Acute overdosage of methadone can be manifested by respiratory depression somnolence progressing to stupor or coma, skeletal-muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2 )] . In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Methadone overdosage is associated with rhabdomyolysis. Seek medical attention, especially if abuse/misuse results in prolonged immobilization. Acute toxic leukoencephalopathy has been reported after methadone overdose, often weeks after apparent recovery from the initial intoxication. Hearing loss has been reported after methadone overdose, in some cases permanent. Treatment of Overdose : In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of reversal would be expected to be less than the duration of action of methadone in Methadone Hydrochloride Oral Solution, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, administer additional antagonist as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experience will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

DESCRIPTION SECTION

Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Methadone hydrochloride USP is a white powder that is water-soluble. Its molecular formula is C 21 H 27 NO• HCl and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5. It has the following structural formula: Each 5 mL of Methadone Hydrochloride Oral Solution contains 5 mg or 10 mg of methadone hydrochloride USP and the following inactive ingredients: alcohol (8%), benzoic acid, citric acid, FD&C Red #40, FD&C Yellow #6, flavoring (lemon), glycerin, sorbitol, and water.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Methadone is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. Methadone may be targeted for theft and diversion by criminals [see Warnings and Precautions (5.2) ]. Store at 20° to 25ºC (68º to 77°F), with excursions permitted between 15° to 30°C (59° to 86° F). [See USP Controlled Room Temperature.] Store Methadone Hydrochloride Oral Solution securely and dispose of properly [see Patient Counseling Information (17) ]. Methadone Hydrochloride Oral Solution USP 5 mg per 5 mL (1 mg/mL) is supplied as a clear or nearly clear, orange-colored, citrus-flavored solution. Unit dose cups: 30 cups (3 x 10) NDC 60687-818-86 DO NOT USE IF SEAL IS BROKEN DEA order form required.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal : Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Methadone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Methadone Hydrochloride Oral Solution unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.2 , 5.3 ), Drug Abuse and Dependence (9.2 )] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Methadone Hydrochloride Oral Solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Medication Errors : Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication. Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure Methadone Hydrochloride Oral Solution [see Warnings and Precautions (5.1 )] . Advise patients and caregivers that Methadone Hydrochloride Oral Solution, is available in two concentrations: 5 mg per 5 mL and 10 mg per 5 mL. Inform patients and caregivers about which concentration they have been prescribed and provide detailed instruction on how to measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution, and to always use a graduated oral syringe or measuring cup when administering Methadone Hydrochloride Oral Solution, to ensure that the dose is measured and administered accurately. If the prescribed concentration is changed, instruct patients and caregivers on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse ; Inform patients that the use of Methadone Hydrochloride Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.2 )] . Instruct patients not to share Methadone Hydrochloride Oral Solution with others and to take steps to protect Methadone Hydrochloride Oral Solution from theft or misuse. 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 Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages. 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 Warnings and Precautions (5.4)]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose : Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Methadone Hydrochloride Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.3 ), Warnings and Precautions (5.4 )] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [ see Overdosage (10) ] . If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Accidental Ingestion : Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.4 )] . 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 Hydrochloride Oral Solution [see Warnings and Precautions (5.5 )] . Interactions with Benzodiazepines and Other CNS Depressants : Inform patients and caregivers that potentially fatal additive effects may occur if Methadone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.8.), Drug Interactions (7)]. Hyperalgesia and Allodynia : Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9) and Adverse Reactions (6) ] . Serotonin Syndrome : Inform patients that Methadone Hydrochloride Oral Solution could cause a rare but potentially life-threatening condition 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 and Precautions (5.10 ), Drug Interactions (7 )] . MAOI Interaction : Inform patients to avoid taking Methadone Hydrochloride Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Methadone Hydrochloride Oral Solution [see Warnings and Precautions (5.10) , Drug Interactions (7) ] . Important Administration Instructions : Instruct patients how to properly take Methadone Hydrochloride Oral Solution, including the following: Use methadone exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Dosage and Administration (2 ), Warnings and Precautions (5.4)]. Instruct patients and caregivers on how to accurately measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution. Strongly advise patients and caregivers to always use a graduated oral dosing syringe/measuring cup with metric units of measurements (i.e., mL) to correctly measure the prescribed amount of medication. Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure Methadone Hydrochloride Oral Solution [see Dosage and Administration (2) ] . Advise patients and caregivers not to adjust the dose of Methadone Hydrochloride Oral Solution without consulting with a physician or other healthcare professional. Important Discontinuation Instructions: In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Methadone Hydrochloride Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.6 )] ...

Medication Guide

SPL MEDGUIDE SECTION

Methadone Hydrochloride (meth’ a done hye” droe klor’ ide) Oral Solution USP, CII Rx only Methadone Hydrochloride Oral Solution is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them. A long-acting opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse than can lead to death. Not to be taken on an “as needed” basis. Also used to manage drug addiction. Important information about Methadone Hydrochloride Oral Solution: Get emergency help or call 911 right away if you take too much Methadone Hydrochloride Oral Solution (overdose). When you first start taking Methadone Hydrochloride Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking Methadone Hydrochloride Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your Methadone Hydrochloride Oral Solution. They could die from taking it. Selling or giving away Methadone Hydrochloride Oral Solution is against the law. Store Methadone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take Methadone Hydrochloride Oral Solution if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. Before taking Methadone Hydrochloride Oral Solution, tell your healthcare provider if you have a history of: head injury, seizures pancreas or gallbladder problems liver, kidney, thyroid problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems problems urinating heart rhythm problems (Long QT syndrome) Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take Methadone Hydrochloride Oral Solution, do not take more of Methadone Hydrochloride Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Methadone Hydrochloride Oral Solution. pregnant or planning to become pregnant. Use of Methadone Hydrochloride Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. Talk to your doctor if you are pregnant or plan to be pregnant. breastfeeding. Methadone Hydrochloride Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Methadone Hydrochloride Oral Solution with certain other medicines may cause serious side effects. When taking Methadone Hydrochloride Oral Solution: Do not change your dose. Take Methadone Hydrochloride Oral Solution exactly as prescribed by your healthcare provider. Always use a calibrated measuring device for Methadone Hydrochloride Oral Solution to correctly measure your dose. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Take your prescribed dose every 8 to 12 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. If you take Methadone Hydrochloride Oral Solution for opioid addiction and miss a dose, take your next dose the following day as scheduled. Do not take extra doses. Taking more than the prescribed dose may cause you to overdose because Methadone Hydrochloride Oral Solution builds up in your body over time. Call your healthcare provider if the dose you are taking does not control your pain. Do not stop taking Methadone Hydrochloride Oral Solution without talking to your healthcare provider. Dispose of expired, unwanted, or unused Methadone Hydrochloride Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking Methadone Hydrochloride Oral Solution DO NOT: Drive or operate heavy machinery, until you know how Methadone Hydrochloride Oral Solution affects you. Methadone can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Methadone Hydrochloride Oral Solution may cause you to overdose and die. The possible side effects of Methadone Hydrochloride Oral Solution are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Methadone Hydrochloride Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Distributed by: For more information about the drug product, please call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 For more information about the packaging or labeling, call American Health Packaging at 1-800-707-4621 This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: American Health Packaging Columbus, OH 43217 8481886/1024F

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Methadone Hydrochloride Oral Solution USP CII Contains 8% alcohol Rx Only FOR ORAL USE ONLY - NOT TO BE INJECTED FOR INSTITUTIONAL USE ONLY PHARMACIST: Dispense with attached Medication Guide DEA Order Form Required. Store at 20° to 25° (68° to 77°F); with excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Keep in secure area and protect from diversion. 8481886/0224F

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rx Only NDC 60687- 818 -40 Methadone Hydrochloride CII Oral Solution USP 5 mg/5 mL Alcohol 8% Delivers 5 mL FOR ORAL USE ONLY See package insert for full prescribing information and storage. For Institutional Use Only. American Health Packaging Columbus, OH 43217 0481886/0224