Methadone Hydrochloride

Check Drug InteractionsCheck known drug interactions.

Methadone Hydrochloride Prescribing Information

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 Life-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 (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

[see Overdosage ]

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone hydrochloride oral concentrate, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Monitor patients closely for respiratory depression, when initiating therapy with methadone hydrochloride oral concentrate 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 ]

To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential

[see Dosage and Administration ]

. 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 ]
.
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 ]

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

[see Dosage and Administration ]

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. 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, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with methadone hydrochloride oral concentrate. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose

[see Dosage and Administration ]

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with methadone hydrochloride oral concentrate itself

[see Overdosage ]

Inform patients and caregivers of their options for obtaining 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). Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered

[see Patient Counseling Information ]

)].

Proper dosing and titration are essential and methadone hydrochloride oral concentrate 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 hydrochloride oral concentrate 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.

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 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS
Depressants with Methadone

Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation and delays or omits the methadone dose if appropriate.

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 a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in methadone treatment for opioid use disorder

[see Warnings and Precautions ]

In addition, take measures to confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines

[see Drug Interactions ( 7

)].

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 Life-Threatening QT
Prolongation

Cases of QT interval prolongation and serious arrhythmia (

torsades de pointes

) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in

in vivo

laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in

in vitro

studies.

Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.

Evaluate patients developing QT prolongation while on methadone hydrochloride oral concentrate treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism.

Only initiate therapy with methadone hydrochloride oral concentrate in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.

)].

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 concentrate.

Accidental Ingestion

Accidental ingestion of methadone hydrochloride oral concentrate, especially by children, can result in fatal overdose of methadone

[see Warnings and Precautions (

5.4 Accidental Ingestion

Accidental ingestion of even one dose of methadone hydrochloride oral concentrate, especially by children, can result in respiratory depression and death due to an overdose. Keep methadone hydrochloride oral concentrate out of reach of children to prevent accidental ingestion

[see Warnings and Precautions ]

)].

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 Misuse, Abuse, and
Diversion of Opioids

Methadone hydrochloride oral concentrate contains methadone, an opioid agonist and a Schedule II controlled substance. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by and people with opioid use disorders and are subject to criminal diversion.

Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The concomitant use of methadone hydrochloride oral concentrate 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 Risks of Concomitant
Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or
Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

Concomitant use of methadone hydrochloride oral concentrate with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of methadone hydrochloride oral concentrate is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone hydrochloride oral concentrate-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of methadone hydrochloride oral concentrate when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation

[see Drug Interactions ]

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with methadone hydrochloride oral concentrate may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using methadone hydrochloride oral concentrate with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the methadone hydrochloride oral concentrate dosage as needed

[see Drug Interactions ]

), 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 ]

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 ]

Examples:

Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 ]

, 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 ]

, 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 ]

, 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 dosage reduction and monitor for signs of respiratory depression and sedation.

Examples:

Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital

Potentially Arrhythmogenic Agents

Clinical Impact:

Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).

Intervention:

Monitor patients closely 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, mineralocortocoid 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 ]

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride oral concentrate 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 or opioid toxicity (e.g., respiratory depression, coma)

[see Warnings and Precautions ]

Intervention:

The use of methadone hydrochloride oral concentrate is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

Patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists.

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:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride oral concentrate and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration , Warnings and Precautions ]

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention:

Monitor 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 drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride oral concentrate is used concomitantly with anticholinergic drugs.

Paradoxical Effects of Anti-Retroviral Agents on Methadone

Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone hydrochloride oral concentrate and could precipitate a withdrawal syndrome. Monitor patients receiving methadone hydrochloride oral concentrate

and

any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone hydrochloride oral concentrate dose accordingly.

Effects of Methadone on Anti-Retroviral Agents

Didanosine and Stavudine

Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.

Zidovudine

Experimental evidence demonstrated that methadone increased the AUC of zidovudine which could result in toxic effects.

Effects of Methadone on Antidepressants

Desipramine

Plasma levels of desipramine have increased with concurrent methadone administration.

Potentially Arrhythmogenic Agents
: Monitor patients closely for cardiac conduction changes.
Interactions with CNS Depressants
: Consider dose reduction of one or both drugs because of additive effects.
Mixed Agonist/Antagonist and Partial Agonist Opioids
: Avoid concomitant use with methadone hydrochloride oral concentrate because it may precipitate withdrawal symptoms.

)].

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 Conditions 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)).

)].

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 Conditions for Distribution and Use of
Methadone Products for the Treatment of Opioid Addiction

Code of Federal Regulations, Title 42, Sec 8

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)).

)]

Methadone hydrochloride oral concentrate is contraindicated in patients with:

Significant respiratory depression
[see Warnings and Precautions (
5.1 Life-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 (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status
[see Overdosage ]
.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone hydrochloride oral concentrate, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Monitor patients closely for respiratory depression, when initiating therapy with methadone hydrochloride oral concentrate 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 ]
.
To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential
[see Dosage and Administration ]
. 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 ]
.
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 ]
.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration ]
.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. 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, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with methadone hydrochloride oral concentrate. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose
[see Dosage and Administration ]
.
Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with methadone hydrochloride oral concentrate itself
[see Overdosage ]
.
Inform patients and caregivers of their options for obtaining 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). Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
[see Patient Counseling Information ]
.
)]
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
[see Warnings and Precautions (
5.8 Life-Threatening Respiratory
Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic,
or Debilitated Patients
The use of methadone hydrochloride oral concentrate in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease

Methadone hydrochloride oral concentrate-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of methadone hydrochloride oral concentrate
[see Warnings and Precautions ]
.
Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
[see Warnings and Precautions ]
.
Monitor such patients closely, particularly when initiating and titrating methadone hydrochloride oral concentrate and when methadone hydrochloride oral concentrate is given concomitantly with other drugs that depress respiration
[see Warnings and Precautions ]
.
)]
Known or suspected gastrointestinal obstruction, including paralytic ileus
[see Warnings and Precautions (
5.13 Risks of Use in Patients with
Gastrointestinal Conditions
Methadone hydrochloride oral concentrate is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in methadone hydrochloride oral concentrate may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
)]
Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadone hydrochloride oral concentrate
[see 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 ]
Interactions with Benzodiazepines and other CNS Depressants
[see Warnings and Precautions ]
QT Prolongation
[see Warnings and Precautions ]
Serotonin Syndrome
[see Warnings and Precautions ]
Adrenal Insufficiency
[see Warnings and Precautions ]
Severe Hypotension
[see Warnings and Precautions ]
Gastrointestinal Adverse Reactions
[see Warnings and Precautions ]
Seizures
[see Warnings and Precautions ]
Withdrawal
[see Warnings and Precautions ]
Hypoglycemia
[see
Warnings and Precautions
]
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 hydrochloride oral concentrate.
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 ]
.
Hypoglycemia
: Cases of hypoglycemia have been reported in patients taking methadone
[see
Warnings and Precautions
].
Most Common Adverse Reactions Are
: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.
To report SUSPECTED ADVERSE REACTIONS, contact VistaPharm, LLC, at 1-888-655-1505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
)]

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 Life-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 (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status
[see Overdosage ]
.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone hydrochloride oral concentrate, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Monitor patients closely for respiratory depression, when initiating therapy with methadone hydrochloride oral concentrate 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 ]
.
To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential
[see Dosage and Administration ]
. 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 ]
.
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 ]
.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration ]
.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. 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, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with methadone hydrochloride oral concentrate. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose
[see Dosage and Administration ]
.
Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with methadone hydrochloride oral concentrate itself
[see Overdosage ]
.
Inform patients and caregivers of their options for obtaining 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). Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
[see Patient Counseling Information ]
.
)]
Interactions with Benzodiazepines and other CNS Depressants
[see Warnings and Precautions (
5.2 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS
Depressants with Methadone
Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol.
Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation and delays or omits the methadone dose if appropriate.

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 a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with concomitant use.
If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in methadone treatment for opioid use disorder
[see Warnings and Precautions ]
.
In addition, take measures to confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines
[see Drug Interactions ]
. This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue methadone hydrochloride oral concentrate if serotonin syndrome is suspected.
)]
Adrenal Insufficiency
[see Warnings and Precautions (
5.10 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
)]
Severe Hypotension
[see Warnings and Precautions (
5.11 Severe Hypotension
Methadone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain normal blood pressure is compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)
[see Drug Interactions ]
. Monitor these patients for signs of hypotension after initiating or titrating the dosage of methadone hydrochloride oral concentrate. In patients with circulatory shock, methadone hydrochloride oral concentrate may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of methadone hydrochloride oral concentrate in patients with circulatory shock.
)]
Gastrointestinal Adverse Reactions
[see Warnings and Precautions (
5.13 Risks of Use in Patients with
Gastrointestinal Conditions
Methadone hydrochloride oral concentrate is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in methadone hydrochloride oral concentrate may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
)]
Seizures
[see Warnings and Precautions (
5.14 Increased Risks of Seizure in Patients with Seizure Disorders
Methadone may increase frequency of seizures in patients with seizure disorders and increase the risks of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during methadone hydrochloride oral concentrate therapy.
)]
Withdrawal
[see Warnings and Precautions (
5.15 Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including methadone hydrochloride oral concentrate. In these patients, mixed agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms
[see Drug Interactions ]
.
When discontinuing methadone hydrochloride oral concentrate, gradually taper the dosage
[see Dosage and Administration ]
. Do not abruptly discontinue methadone hydrochloride oral concentrate
[see Drug Abuse and Dependence ]
.
)]
Hypoglycemia
[see
Warnings and Precautions (
5.17 Hypoglycemia
Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization. In many cases, patients had predisposing risk factors (e.g., diabetes). The relationship between methadone and hypoglycemia is not fully understood but may be dose dependent. If hypoglycemia is suspected, monitor blood glucose levels, and manage the patient as clinically appropriate.
)
]

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 hydrochloride oral concentrate.

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 Pharmacodynamics

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, and transient elevations in serum amylase.

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 ]

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 ]

)]

Hypoglycemia

: Cases of hypoglycemia have been reported in patients taking methadone

[see

Warnings and Precautions (

5.17 Hypoglycemia

Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization. In many cases, patients had predisposing risk factors (e.g., diabetes). The relationship between methadone and hypoglycemia is not fully understood but may be dose dependent. If hypoglycemia is suspected, monitor blood glucose levels, and manage the patient as clinically appropriate.

)

Report Adverse Event

Methadone Hydrochloride

Methadone Hydrochloride Prescribing Information

Methadone Hydrochloride PubMed™ News