Methadone Hydrochloride 10 mg/mL Concentrate, 1000 mL
Other active recalls for Methadone Hydrochloride (different manufacturers) — 1 · tap to view
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Opioid Agonist class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Methadone is used to relieve severe pain. Methadone also is used to treat opioid addiction (physical and psychological reliance on a chemical found in prescription and street drugs). Methadone is in a class of medications called opiate (narcotic) analgesics. Methadone works to treat pain by changing the way the brain and nervous system respond to pain. It works to treat people who were addicted to opiate drugs by producing similar effects and preventing withdrawal symptoms.
Read the full MedlinePlus article ↗- Methadone is reserved for severe, persistent pain that needs around-the-clock treatment and hasn't responded well to other options. It's a long-acting opioid, which means it works...
- Why is my doctor prescribing methadone instead of a regular painkiller?
- When methadone is used for opioid addiction — not pain — federal law requires it to be dispensed only through certified opioid treatment programs. These clinics follow strict safet...
- Why does methadone need to be dispensed at a special clinic for opioid treatment?
Patient education
Supplement & herbal interactions
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Ask a licensed pharmacist directly — free, answered by our team.
🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII XF417D3PSL
Anhydrous citric acid is a sour, crystalline powder derived from citric acid with water removed. In medicines, it acts as a buffer to control pH, adds tartness to improve taste, and helps tablets disintegrate.
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UNII BUC5I9595W
A natural flavoring derived from cherry fruit that gives the medicine its cherry taste. It helps mask bitter drug flavors and makes the medication more pleasant to take.
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UNII 9DBA0SBB0L
A synthetic red dye derived from coal tar used as a colorant in medicines and cosmetics. It gives tablets, capsules, and liquids their red or pink appearance for identification and visual appeal.
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UNII WZB9127XOA
A synthetic red dye used to color medications and make them easier to identify. It serves as a colorant in tablets, capsules, and liquid formulations.
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UNII PDC6A3C0OX
Glycerin is a clear, thick liquid derived from plant oils or fats. It acts as a humectant to retain moisture, a sweetener, and a solvent in medications.
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UNII 6DC9Q167V3
Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
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UNII SB8ZUX40TY
Saccharin sodium is an artificial sweetener made from saccharin salt. It's added to medicines to improve taste, especially in liquid formulations for children or bitter drugs.
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UNII OJ245FE5EU
Sodium benzoate is a salt derived from benzoic acid, a preservative. It's added to medicines to prevent growth of bacteria, fungi, and other microorganisms that could spoil the product.
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UNII 506T60A25R
Sorbitol is a natural sugar alcohol derived from glucose. It serves as a sweetener, humectant, and bulking agent in medications to improve taste and help maintain moisture in the product.
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UNII C151H8M554
A natural sugar derived from sugar cane or sugar beets. It's used as a sweetener, filler, and binder to improve taste, add bulk, and help hold tablet or capsule ingredients together.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
11 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $0.5316 | $531.60 / 1000 ml |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Methadone Hydrochloride 10 mg/mL 00054-3553-44 | Hikma | 30 ml | $0.554 | AA | Availability likely | — |
| Methadone Hydrochloride 10 mg/mL 00406-4123-03 | SpecGx | 1 bottle | $0.554 | AA | Availability likely | — |
| Methadone Hydrocloride dye-free, sugar-free, unflavored 10 mg/mL 00527-1927-36 | Lannett | 1 bottle | $0.554 | AA | Availability likely | — |
| Methadone Hydrochloride 10 mg/mL 00054-0391-68 | Hikma | 1000 ml | — | AA | FDA listed | — |
| Methadone Hydrochloride 10 mg/mLthis 00054-0392-68 | Hikma | 1000 ml | — | AA | FDA listed | — |
| Methadose 10 mg/mL 00406-0527-10 | SpecGx | 1000 ml | — | AA | FDA listed | — |
| Methadose Sugar-Free 10 mg/mL 00406-8725-10 | SpecGx | 1000 ml | — | AA | FDA listed | — |
| Methadone Hydrochloride 10 mg/mL 17856-0392-01 | ATLANTIC | 60 syringes | — | AA | FDA listed | — |
| Methadone Hydrocloride dye-free, sugar-free, unflavored 10 mg/mL 17856-1927-07 | Atlantic | 1 syringe | — | AA | FDA listed | — |
| Methadone Hydrocloride dye-free, sugar-free, unflavored 10 mg/mL 63629-2098-01 | Bryant | 30 ml | — | AA | FDA listed | — |
| Methadone Hydrochloride 10 mg/mL 66689-0694-30 | VistaPharm, | 30 ml | — | AA | Discontinued | — |
| Methadone Hydrochloride 10 mg/mL 66689-0695-30 | VistaPharm, | 30 ml | — | AA | FDA listed | — |
| Methadone Hydrocloride dye-free, sugar-free, unflavored 10 mg/mL 72162-1085-02 | Bryant | 30 ml | — | AA | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
🗺️ Medicaid utilization & spend
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 00054-0392-68 You're viewing this | 1000 mL in 1 BOTTLE (0054-0392-68) | 2010-03-16 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | ✓ Available |
Questions about this listing
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL, INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES 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 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 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. Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death [see Warnings and Precautions ( 5.2 )] . • Reserve concomitant prescribing of benzodiazepines or other CNS depressants in patients in methadone treatment to those for whom alternatives to benzodiazepines or other CNS depressants are inadequate. • Follow patients for signs and symptoms of respiratory depression and sedation.
If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing. Life-Threatening QT Prolongation QT interval prolongation and serious arrhythmia ( torsades de pointes ) have occurred during treatment with methadone [see Warnings and Precautions ( 5.3 )] . 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. Accidental Ingestion Accidental ingestion of methadone, especially by children, can result in fatal overdose of methadone [see Warnings and Precautions ( 5.4 )] . Misuse, Abuse, and Diversion of Opioids Methadone hydrochloride oral concentrate contains 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 ( 5.5 )] .
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The concomitant use of methadone 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 ( 5.7 ), 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 Dosage and Administration ( 2.1 )] . WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL, INTERACTIONS WITH DR…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Methadone hydrochloride oral concentrate contains methadone, an opioid agonist indicated for the: • 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 21 CFR, Title 42, Sec.
8 [see Dosage and Administration ( 2.1 )] . Methadone hydrochloride oral concentrate is an opioid agonist indicated for the: • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). ( 1 ) • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.
( 1 ) 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 21 CFR, Title 42, Sec. 8. ( 1 , 2.1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time methadone hydrochloride oral concentrate is initiated or renewed because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use. ( 2.3 ) • Initiation of Detoxification and Maintenance Treatment : A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. ( 2.4 ) • Maintenance Treatment : Clinical stability is most commonly achieved at doses between 80 to 120 mg/day.
( 2.5 ) • Do not rapidly reduce or abruptly discontinue methadone in a physically-dependent patient. ( 2.6 , 5.15 )
2.1Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction Code of Federal Regulations, Title 42, Sec. 8 : Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority.
Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program.
Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment • During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis. • During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)).
2.2Important Dosage and Administration Information Methadone is for oral administration only. The preparation must not be injected. Package in child-resistant containers and inform patients that methadone should be kept out of reach of children to prevent accidental ingestion.
Consider the following important factors that differentiate methadone from other opioids: • The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists. • There is high interpatient variability in absorption, metabolism, and relative analgesic potency.
Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing. Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.3Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated wit…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Oral Concentrate: • Methadone hydrochloride oral concentrate, USP (dye-free, sugar-free, unflavored) 10 mg per mL (equivalent to 8.95 mg of methadone) is supplied as a clear, colorless, unflavored solution. • Methadone hydrochloride oral concentrate, USP (cherry) 10 mg per mL (equivalent to 8.95 mg of methadone) is supplied as a clear, red, cherry-flavored solution. Oral concentrate: 10 mg/mL in bottles of 1,000 mL ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Methadone hydrochloride oral concentrate is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.1 )] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13 )] • Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadone [see Adverse Reactions ( 6 )] • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma ( 4 ) • Known or suspected paralytic ileus ( 4 ) • Known hypersensitivity to methadone ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Neonatal Opioid Withdrawal Syndrome : Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.6 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.8 ) • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration.
Discontinue methadone if serotonin syndrome is suspected. ( 5.9 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) • Severe Hypotension : Monitor during dose initiation and titration.
( 5.11 ) • Risks 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, 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 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 ( 2.4 )] . 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 ( 2.4 )] . • 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 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the r…
🤒 Adverse Reactions ▾
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 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. 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, 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.
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 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, sedation, nausea, vomiting, and sweating.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-8…
🔄 Drug Interactions ▾
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 recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions ( 5.1 )] .
Examples: Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids. 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 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 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 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 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 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 is necessary, consider increasing the methadone dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone do…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • Lactation : Monitor breastfed infants for increased drowsiness and breathing difficulties. ( 8.2 )
8.1Pregnancy Risk Summary The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy.
Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure in these studies appears to occur after the first trimester of pregnancy ( see Data ). Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )] . In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m 2 basis (HDD) and in mice at doses equivalent to the HDD.
Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD ( see Data ).
Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo-Fetal Risk : Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.
Dosage Adjustment During Pregnancy : Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with methadone. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see Dosage and Administration ( 2.9 ), Clinical Pharmacology ( 12.3 )] . Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary.
Fetal/Neonatal Adverse Reactions : Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with methadone. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth.
The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy.
Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure in these studies appears to occur after the first trimester of pregnancy ( see Data ). Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.6 )] . In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m 2 basis (HDD) and in mice at doses equivalent to the HDD.
Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD ( see Data ).
Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo-Fetal Risk : Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.
Dosage Adjustment During Pregnancy : Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with methadone. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see Dosage and Administration ( 2.9 ), Clinical Pharmacology ( 12.3 )] . Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary.
Fetal/Neonatal Adverse Reactions : Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with methadone. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth.
The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.6 )] . Labor or Delivery…
🧒 Pediatric Use ▾
8.4Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, start elderly patients at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Closely monitor elderly patients for signs of respiratory and central nervous system depression. Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
🆘 Overdosage ▾
10 OVERDOSAGE Clinical Presentation Acute overdosage with 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. Toxic leukoencephalopathy has been reported after opioid overdose, and can present hours, days, or weeks after apparent recovery from the initial intoxication.
Hearing loss has been reported after methadone overdose, in some cases permanent. Treatment of Overdose In the 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 techniques. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably established.
If the response to an opioid overdose reversal agent is suboptimal or not sustained, administer additional reversal agent as directed in the product’s prescribing information. In an individual physically dependent on opioids, the administration of the usual dose of an opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered.
If a decision is made treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.
The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.
12.2Pharmacodynamics Effects on the Central Nervous System Methadone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Methadone causes miosis, even in total darkness.
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Some NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.
Effects on the Gastrointestinal Tract and Other Smooth Muscle Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation.
Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.
Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Adverse Reaction Relationships There is a relationship between increasing methadone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.4 , 2.5 , 2.6 )] .
12.3Pharmacokinetics Absorption Following oral administration the bioavailability of methadone ranges between 36% to 100% and peak plasma conce…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.
The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Methadone Hydrochloride Oral Concentrate, USP (Dye-Free, Sugar-Free, Unflavored) 10 mg per mL is supplied as a clear, colorless, unflavored solution. NDC 0054-0391-68: Bottles of 1,000 mL Methadone Hydrochloride Oral Concentrate, USP (Cherry) 10 mg per mL is supplied as a clear, red, cherry-flavored solution. NDC 0054-0392-68: Bottles of 1,000 mL Store at 20° to 25°C (68° to 77°F); with excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in a tight container, as defined in the USP/NF.
Protect from light. Store methadone securely and dispose of properly [see Patient Counseling Information ( 17 )] .
📋 Description ▾
11 DESCRIPTION Methadone hydrochloride oral concentrate, USP contains methadone, an opioid agonist. Each mL for oral administration contains 10 mg methadone hydrochloride, USP. 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 mL of the unflavored liquid concentrate, for oral administration, contains 10 mg of methadone hydrochloride, USP.
The inactive ingredients are: citric acid, sodium benzoate and water. Each mL of the cherry flavored liquid concentrate, for oral administration, contains 10 mg of methadone hydrochloride, USP. The inactive ingredients are: citric acid, cherry pistachio flavor, D&C Red #33, FD&C Red #40, glycerin, propylene glycol, saccharin sodium, sodium benzoate, sorbitol solution, sucrose and water. methadone hydrochloride structural formula image
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Life-Threatening Respiratory Depression Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting methadone or when the dose is increased. 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 ( 5.1 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent.
Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, discuss the importance of having access to an opioid overdose reversal agent. Also discuss the importance of having access to an opioid overdose reversal agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter (some products), or as part of a community-based program) [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 )] .
There are important differences among the opioid overdose reversal agents. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.
Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene 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 an opioid overdose reversal agent is administered. Repeat administration may be necessary, particularly for overdose involving methadone [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), Overdosage ( 10 )] . Advise patients and caregivers: • how to treat with an opioid overdose reversal agent in the event of an opioid overdose. • to tell family and friends about their opioid overdose reversal agent, 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 opioid overdose reversal agent.
Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if methadone is used with benzodiazepines or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] .
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 and Precautions ( 5.3 )] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.4 )] . Instruct patients to take steps to store methadone securely.
Advise patients to dispose of unused methadone by flushing down the toilet. Abuse Potential Inform patients that methadone contains methadone, a Schedule II controlled subs…