Methadone Hydrochloride

Methadone Hydrochloride Oral Solution is indicated for the:

• •
  Management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.
•  
  Limitations of Use:
  • •
    Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration

    [see Warnings and Precautions (
    5.1 Risk of Accidental Overdose and Death due to Medication Errors

    Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with methadone solutions of different concentrations, when prescribing, dispensing, and administering Methadone Hydrochloride Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.

    Instruct patients and caregivers on how to measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution

    and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices.

    )]
    and persist over the course of therapy, reserve opioid analgesics, including Methadone Hydrochloride Oral Solution, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
  • •
    Methadone Hydrochloride Oral Solution is not indicated as an as-needed (prn) analgesic.
• •Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).
• •Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.
•  
  Limitations of Use:
  • •Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 CFR 8.12
    [see Dosage and Administration
    (

    2.1 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 21CFR 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 21CFR 1306.07(b)).

    )]
    .

• •Consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) based on the patient’s risk factors for overdose (
  2.3 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

  [see Warnings and Precautions (

  5.3

  ), Overdosage (

  10

  )]

  .

  For Patients Being Treated for Pain

  • Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

    [see Warnings and Precautions (
    5.2
    ,
    5.3
    ,
    5.4
    )]

    .

  For Patients Being Treated for Opioid Addiction

  • Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing or recommending an overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Methadone Hydrochloride Oral Solution. Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene may also be administered for a known or suspected overdose with Methadone Hydrochloride Oral Solution itself

    [see Overdosage (
    10

    )]
    .

  For patients being treated with methadone (regardless of indication), also consider prescribing or recommending such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program)

  [see Warnings and Precautions (

  5.4

  )]

  .

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.
  ,
  5.2 Addiction, Abuse and Misuse

  Methadone Hydrochloride Oral Solution contains methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse

  .

  As long-acting opioids such as Methadone Hydrochloride Oral Solution have pharmacological effects over an extended period of time, there is a greater risk for overdose and death

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Oral Solution and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

  The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience (

  6

  )]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Oral Solution, and reassess all patients receiving Methadone Hydrochloride Oral Solution for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Methadone Hydrochloride Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Methadone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse.

  Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.3

  )]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Methadone Hydrochloride Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  ,
  5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone Hydrochloride Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, and other opioids).

  For Patients Being Treated for Pain

  Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

  Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

  [see Drug Interactions ]

  .

  If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.4

  )]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions , Patient Counseling Information ]

  .

  For Patients Being Treated for Opioid Addiction

  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 an opioid overdose reversal agent, as is recommended for all patients in methadone treatment for opioid use disorder

  [see Warnings and Precautions (

  5.4

  )]

  .

  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 ]

  .
  ,
  5.8 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitor or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

  Concomitant use of Methadone Hydrochloride Oral Solution 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 dosage of Methadone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Oral Solution-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone Hydrochloride Oral Solution when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Oral Solution-treated patients, and evaluate 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 CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone Hydrochloride Oral Solution 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 Solution with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, assess patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone Hydrochloride Oral Solution dosage as needed

  [see Drug Interactions ]

  .
  ).

• •Methadone Hydrochloride Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
  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 21CFR 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 21CFR 1306.07(b)).
  )
• •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Methadone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (
  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 21CFR 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 21CFR 1306.07(b)).
  ,
  5 WARNINGS AND PRECAUTIONS

  • •Opioid Induced Hyperalgesia (OIH) and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • •Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Methadone Hydrochloride Oral Solution if serotonin syndrome is suspected.
  • •Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, Debilitated Patients: Regularly evaluate, particularly during initiation and titration.
  • •Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • •Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use in patients with circulatory shock.
  • •Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Regularly evaluate for sedation and respiratory depression. Avoid use of methadone in patients with impaired consciousness or coma.

  5.1 Risk of Accidental Overdose and Death due to Medication Errors

  Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with methadone solutions of different concentrations, when prescribing, dispensing, and administering Methadone Hydrochloride Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.

  Instruct patients and caregivers on how to measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution

  and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices.

  5.2 Addiction, Abuse and Misuse

  Methadone Hydrochloride Oral Solution contains methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse

  .

  As long-acting opioids such as Methadone Hydrochloride Oral Solution have pharmacological effects over an extended period of time, there is a greater risk for overdose and death

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Oral Solution and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

  The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience (

  6

  )]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Oral Solution, and reassess all patients receiving Methadone Hydrochloride Oral Solution for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Methadone Hydrochloride Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Methadone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse.

  Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.3

  )]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Methadone Hydrochloride Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  5.3 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

  [see Overdosage ].

  Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of done Methadone Hydrochloride Oral Solution, 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 analgesic effect, especially during the initial dosing period.

  Regularly evaluate patients for respiratory depression when initiating therapy with Methadone Hydrochloride Oral Solution and following dose increases.

  To reduce the risk of respiratory depression, proper dosing and titration of Methadone Hydrochloride Oral Solution are essential

  [see Dosage and Administration ]

  . Overestimating the Methadone Hydrochloride Oral Solution dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

  Accidental ingestion of even one dose of Methadone Hydrochloride Oral Solution, especially by children, can result in respiratory depression and death due to overdose 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 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.

  For Patients Being Treated for Pain

  Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorders, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.2

  ,

  5.4

  ), Overdosage (

  10

  )]

  .

  For Patients Being Treated for Opioid Addiction

  Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing or recommending an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with Methadone Hydrochloride Oral Solution. Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with Methadone Hydrochloride Oral Solution itself

  [see Overdosage (

  10

  )]

  .

  For patients being treated with methadone (regardless of indication), also consider prescribing or recommending such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. 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 respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered.

  5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone Hydrochloride Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, and other opioids).

  For Patients Being Treated for Pain

  Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

  Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

  [see Drug Interactions ]

  .

  If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.4

  )]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions , Patient Counseling Information ]

  .

  For Patients Being Treated for Opioid Addiction

  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 an opioid overdose reversal agent, as is recommended for all patients in methadone treatment for opioid use disorder

  [see Warnings and Precautions (

  5.4

  )]

  .

  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 ]

  .

  5.5 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 treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism.

  Only initiate Methadone Hydrochloride Oral Solution therapy for pain 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.

  5.6 Neonatal Opioid Withdrawal Syndrome

  Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of use of opioids for an extended period of time during pregnancy. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly

  [see Use in Special Populations ]

  .

  The balance between the risks of NOWS and the benefits of maternal Methadone Hydrochloride Oral Solution use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.

  • •For management of pain, prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options.

  Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

  5.7 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

  To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

  • •Complete a REMS-compliant education programoffered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
  • •Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG)can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG
  • •Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
  • •Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

  To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800‑503‑0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

  5.8 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitor or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

  Concomitant use of Methadone Hydrochloride Oral Solution 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 dosage of Methadone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Oral Solution-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone Hydrochloride Oral Solution when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Oral Solution-treated patients, and evaluate 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 CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone Hydrochloride Oral Solution 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 Solution with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, assess patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone Hydrochloride Oral Solution dosage as needed

  [see Drug Interactions ]

  .

  5.9 Opioid Induced Hyperalgesia and Allodynia

  Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

  [see Dependence ]

  . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

  Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety)

  [see Dosage and Administration , Warnings and Precautions ]

  .

  5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

  Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of methadone with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5HT₃receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)

  [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 Solution if serotonin syndrome is suspected.

  5.11 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, and Debilitated Patients

  The use of Methadone Hydrochloride Oral Solution 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 Solution-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 Solution

  [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 ]

  .

  Regularly evaluate patients, particularly when initiating and titrating Methadone Hydrochloride Oral Solution and when Methadone Hydrochloride Oral Solution is given concomitantly with other drugs that depress respiration

  [see Warnings and Precautions , Drug Interactions ]

  . Alternatively, consider the use of non-opioid analgesics in these patients.

  5.12 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.

  5.13 Severe Hypotension

  Methadone Hydrochloride Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics)

  [see Drug Interactions ].

  Regularly evaluate these patients for signs of hypotension after initiating or titrating the dose of Methadone Hydrochloride Oral Solution. In patients with circulatory shock, Methadone Hydrochloride Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Methadone Hydrochloride Oral Solution in patients with circulatory shock.

  5.14 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

  In patients who may be susceptible to the intracranial effects of CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors) Methadone Hydrochloride Oral Solution may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Methadone Hydrochloride Oral Solution.

  Opioids may also obscure the clinical course in a patient with a head injury.

  Avoid the use of Methadone Hydrochloride Oral Solution in patients with impaired consciousness or coma.

  5.15 Risks of Gastrointestinal Complications

  Methadone Hydrochloride Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

  The methadone in Methadone Hydrochloride Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including pancreatitis, for worsening symptoms.

  Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate.

  5.16 Increased Risk of Seizures in Patients with Seizure Disorders

  The methadone in Methadone Hydrochloride Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Methadone Hydrochloride Oral Solution therapy.

  5.17 Withdrawal

  Do not abruptly discontinue Methadone Hydrochloride Oral Solution in a patient physically dependent on opioids. When discontinuing Methadone Hydrochloride Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

  [see Dosage and Administration , Drug Abuse and Dependence ]

  .

  Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Methadone Hydrochloride Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms

  [see Drug Interactions ]

  .

  5.18 Risks of Driving and Operating Machinery

  Methadone Hydrochloride Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of methadone and know how they will react to the medication

  [see Patient Counseling Information ]

  .

  5.19 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.

  5.20 Laboratory Test Interactions

  False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.
  )
• •Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (
  5.2 Addiction, Abuse and Misuse

  Methadone Hydrochloride Oral Solution contains methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse

  .

  As long-acting opioids such as Methadone Hydrochloride Oral Solution have pharmacological effects over an extended period of time, there is a greater risk for overdose and death

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Oral Solution and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

  The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience (

  6

  )]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Oral Solution, and reassess all patients receiving Methadone Hydrochloride Oral Solution for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Methadone Hydrochloride Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Methadone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse.

  Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.3

  )]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Methadone Hydrochloride Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  )
• •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and making dose adjustments (
  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 21CFR 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 21CFR 1306.07(b)).
  ,
  5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone Hydrochloride Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, and other opioids).

  For Patients Being Treated for Pain

  Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

  Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

  [see Drug Interactions ]

  .

  If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (

  2.3

  ), Warnings and Precautions (

  5.4

  )]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions , Patient Counseling Information ]

  .

  For Patients Being Treated for Opioid Addiction

  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 an opioid overdose reversal agent, as is recommended for all patients in methadone treatment for opioid use disorder

  [see Warnings and Precautions (

  5.4

  )]

  .

  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 ]

  .
  )
• •To convert to methadone hydrochloride from another opioid, use available conversion factors to obtain estimated dose. (
  2.4 Methadone Hydrochloride Oral Solution for Management of Pain

  Important Dosage and Administration Instructions

  Ensure accuracy when prescribing, dispensing, and administering Methadone Hydrochloride Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other methadone solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.

  Instruct patients and caregivers on how to accurately measure and take or administer the correct dose of Methadone Hydrochloride Oral Solution.

  Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication.

  Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure Methadone Hydrochloride Oral Solution.

  Methadone Hydrochloride Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Consider the following important factors that differentiate methadone from other opioid analgesics:

  • •There is high interpatient variability in absorption, metabolism, and relative analgesic potency of methadone. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
  • •The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours.
  • •With repeated dosing, the potency of methadone increases due to systemic accumulation.
  • •Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions ]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Methadone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions ]

  .

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions ]

  .

  Conversion from Other Oral Opioids to Methadone Hydrochloride Oral Solution

  When Methadone Hydrochloride Oral Solution therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

  Deaths have occurred in opioid-tolerant patients during conversion to methadone.

  The potency of methadone relative to other opioid analgesics is nonlinear and increases with increasing dose. Table 1 provides an estimated conversion factor for use when converting patients from another opioid to methadone. Because of the high inter-patient variability in absorption, metabolism, and relative potency, it is critical to avoid overestimating the methadone dose which can lead to fatal respiratory depression. It is safer to underestimate a patient’s 24-hour methadone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour methadone dosage and manage an adverse reaction due to an overdose.

  Consider the following when using the information in Table 1:

  • •This is not a table of equianalgesic doses.
  • •The conversion factors in this table are only for the conversion from another oral opioid analgesic to Methadone Hydrochloride Oral Solution.
  • •The table cannot be used to convert from Methadone Hydrochloride Oral Solution to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.

  Table 1: Conversion Factors to Methadone Hydrochloride Oral Solution

  Total Daily Baseline Oral Morphine Equivalent Dose	Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose
  < 100 mg	20% to 30%
  100 to 300 mg	10% to 20%
  300 to 600 mg	8% to 12%
  600 mg to 1000 mg	5% to 10%
  > 1000 mg	< 5 %

  To calculate the estimated methadone dose using Table 1:

  • •For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
  • •For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
  • •For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.

  Always round the dose down, if necessary, to the appropriate Methadone Hydrochloride Oral Solution strength(s) available.

  Example Conversion from a Single Opioid to Methadone Hydrochloride Oral Solution:

  Step 1

  : Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

  • 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine
  • Step 2
    : Calculate the approximate equivalent dose of Methadone Hydrochloride Oral Solution based on the total daily dose of Morphine using Table 1.
  • 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadone Hydrochloride Oral Solution daily
  • Step 3
    : Calculate the approximate starting dose of Methadone Hydrochloride Oral Solution to be given every 12 hours. Round down, if necessary, to the appropriate Methadone Hydrochloride Oral Solution strengths available.
  • 15 mg daily / 2 = 7.5 mg Methadone Hydrochloride Oral Solution every 12 hours
  • Then 7.5 mg is rounded down to 5 mg Methadone Hydrochloride Oral Solution every 12 hours

  Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Methadone Hydrochloride Oral Solution.

  Conversion from Parenteral Methadone to Methadone Hydrochloride Oral Solution:

  Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).
  )
• •Titrate slowly with dose increases no more frequent than every 3 to 5 days. (
  2.5 Titration and Maintenance of Therapy

  Individually titrate Methadone Hydrochloride Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Methadone Hydrochloride Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

  Patients who experience breakthrough pain may require a dose increase of Methadone Hydrochloride Oral Solution, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Methadone Hydrochloride Oral Solution dosage.

  Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T_1/2) from 8 to 59 hours in different studies

  [see Clinical Pharmacology ]

  ), titrate Methadone Hydrochloride Oral Solution slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

  If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage

  [see Warnings and Precautions ]

  . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
  )
• •Periodically reassess patients receiving methadone hydrochloride to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (
  2.5 Titration and Maintenance of Therapy

  Individually titrate Methadone Hydrochloride Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Methadone Hydrochloride Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

  Patients who experience breakthrough pain may require a dose increase of Methadone Hydrochloride Oral Solution, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Methadone Hydrochloride Oral Solution dosage.

  Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T_1/2) from 8 to 59 hours in different studies

  [see Clinical Pharmacology ]

  ), titrate Methadone Hydrochloride Oral Solution slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

  If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage

  [see Warnings and Precautions ]

  . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
  )
• •Do not rapidly reduce or abruptly discontinue methadone in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.6 Safe Reduction or Discontinuation of Methadone Hydrochloride Oral Solution

  Do not rapidly reduce or abruptly discontinue Methadone Hydrochloride Oral Solution in patients who may be physically dependent on opioids.

  Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

  When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Methadone Hydrochloride Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including Methadone Hydrochloride Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

  There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Methadone Hydrochloride Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

  It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

  When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

  [see Warnings and Precautions , Drug Abuse and Dependence ]

  .
  ,
  5.17 Withdrawal

  Do not abruptly discontinue Methadone Hydrochloride Oral Solution in a patient physically dependent on opioids. When discontinuing Methadone Hydrochloride Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

  [see Dosage and Administration , Drug Abuse and Dependence ]

  .

  Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Methadone Hydrochloride Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms

  [see Drug Interactions ]

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  )

• •A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. (
  2.7 Induction/Initial Dosing for Detoxification and Maintenance 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 8.12, including limitations on unsupervised administration.

  Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of Methadone Hydrochloride Oral Solution will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

  To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of Methadone Hydrochloride Oral Solution if withdrawal symptoms have not been suppressed or if symptoms reappear.

  The total daily dose of Methadone Hydrochloride Oral Solution on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

  Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

  During the induction phase of methadone maintenance treatment, patients are being withdrawn from opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms of opioid withdrawal including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated.

  Short-Term Detoxification

  For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of Methadone Hydrochloride Oral Solution. Decrease the dose of Methadone Hydrochloride Oral Solution on a daily basis or at 2-day intervals, keeping the amount of Methadone Hydrochloride Oral Solution sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.
  )

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

• •
  Lactation
  : Monitor breastfed infants for increased drowsiness and breathing difficulties. (
  8.2 Lactation

  Risk Summary

  Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. There have been rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk (

  see Data

  ). Monitor infants exposed to methadone through breastmilk for excess sedation and respiratory depression. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

  Data

  In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose.

  In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day, which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone.
  )