METHADONE Drug Interactions: What You Need to Know
Boost Your Natural Energy & Metabolism
Mitolyn — 6 exotic plants to unlock your body's fat-burning power. 90-day guarantee.
Drug Interactions (FDA Label)
INTERACTIONS Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of Methadone Hydrochloride Tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride Tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone. Intervention: If concomitant use is necessary, consider dosage reduction of Methadone Hydrochloride Tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, consider increasing the Methadone Hydrochloride Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 Clinical Impact: The concomitant use of Methadone Hydrochloride Tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death. Intervention: If concomitant use is necessary, consider increasing the Methadone Hydrochloride Tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples : Rifampin, carbamazepine, phenytoin, St. John's Wort, Phenobarbital Benzodiazepines and Other Central Nervous System (CNS)
Depressants Clinical
Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: For Patients Being Treated for Pain Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. If concomitant use is warranted, consider prescribing or recommending an opioid overdose reversal agent [see Dosage and Administration (2.3) and Warnings and Precautions (5.2, 5.3, 5.)].
For Patients Being
Treated for Opioid Addiction Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments. If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.1, 5.2, 5.7)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin) other opioids, alcohol.
Potentially Arrhythmogenic Agents Clinical
Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia). Intervention: Evaluate patients closely for cardiac conduction changes. Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, 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 ( 5.9 )]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment.
Discontinue Methadone Hydrochloride
Tablets 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase
Inhibitors (MAOIs)
Clinical
Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.9 )] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.3 )]. Intervention: The use of Methadone Hydrochloride Tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed
Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Methadone Hydrochloride Tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Methadone Hydrochloride Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.3) and Warnings and Precautions (5.3, 5.4)]. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs Clinical
Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Methadone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
Paradoxical
Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of Methadone Hydrochloride Tablets and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Effects of Methadone Hydrochloride Tablets on Antiretroviral 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 Hydrochloride Tablets on Antidepressants Desipramine: Blood levels of desipramine have increased with concurrent methadone administration. Anti-Retroviral Agents : May result in decreased efficacy or, in certain cases, increased toxicity. ( 7 )
Potentially Arrhythmogenic
Agents : Pharmacodynamic interactions may occur. Regularly evaluate patients closely for cardiac conduction changes. ( 7 )
Mixed
Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Methadone Hydrochloride Tablets because they may reduce analgesic effect of Methadone Hydrochloride Tablets or precipitate withdrawal symptoms. ( 5.1 6, 7 )
Monoamine Oxidase
Inhibitors (MAOIs ) : Can potentiate the effects of methadone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )
Contraindications
Methadone Hydrochloride Tablets are contraindicated in patients with:
- Significant respiratory depression [see Warnings and Precautions ( 5.2 )].
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.10 )].
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 )].
- Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions ( 6 )].
- Significant respiratory depression ( 4 )
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( 4 )
- Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 )
- Hypersensitivity to methadone ( 4 )
Related 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. ( 5.9 )
- Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration.
Discontinue Methadone Hydrochloride Oral
Solution if serotonin syndrome is suspected. ( 5.10 )
- 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. ( 5.11 )
- Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.12 )
- Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use in patients with circulatory shock. ( 5.13 )
- 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. ( 5.14 )
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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . 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 recommending or prescribing an opioid overdose reversal agent <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 )]</span> . 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 overdose reversal agents, depending on the patient’s clinical status <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span>. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 , 2.5 )]</span> . 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .
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 recommending or prescribing 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 recommending or prescribing 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 (e.g., alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], 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 ( 7 )] . 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 recommending or 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 ( 7 ), Patient Counseling Information ( 17 )] .
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 recommending or 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 ( 7 )] .
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 <span class="opacity-50 text-xs">[see Use in Special Populations ( 8.1 )]</span> . 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 program offered 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .
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 <span class="opacity-50 text-xs">[see Dependence ( 9.3 )]</span> . 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) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.9 )]</span> .
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, 5HT 3 receptor 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 ), Drug Interactions ( 7 )]</span> . 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors)
Methadone Hydrochloride Oral
Solution may reduce respiratory drive, and the resultant CO 2 retention 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.