Interactions : אינטראקציות

7    DRUG INTERACTIONS
Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6

Clinical     Methadone undergoes hepatic N-demethylation by several Impact:      cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of
Methadone and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or
CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects,
and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of Methadone is achieved.
These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above.
After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or
CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical
Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of Methadone until stable drug effects are achieved.
Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is
              discontinued, follow patients for signs of opioid withdrawal and consider increasing the Methadone dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole- antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir),
fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical      The concomitant use of Methadone and CYP3A4, CYP2B6,
Impact:       CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)],
resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone.
These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression,
sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the Methadone dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6,
CYP2C19, or CYP2C9 inducer is discontinued, consider
Methadone dosage reduction and monitor 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      Due to additive pharmacologic effect, the concomitant use of Impact:       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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Warnings and Precautions (5.1, 5.3, 5.7)].
For Patients Being Treated for Opioid Addiction Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others,
gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.
Before co-prescribing benzodiazepines for anxiety or insomnia,
ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments.
If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder[see Warnings and Precautions (5.1, 5.3, 5.7)].

Examples:     Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical      Pharmacodynamic interactions may occur with concomitant use Impact:       of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia,
hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Serotonergic Drugs
Clinical      The concomitant use of opioids with other drugs that affect the Impact:       serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.9)].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue Methadone 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      MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.9)] or opioid
Impact: toxicity (e.g., respiratory depression, coma) [see Warnings and
Precautions (5.3)].
Intervention: The use of Methadone is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical      May reduce the analgesic effect of Methadone and/or
Impact:       precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical      Methadone may enhance the neuromuscular blocking action of Impact:       skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of
Methadone and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see
Warnings and Precautions (5.3, 5.7)]
Examples:    Cyclobenzaprine, metaxalone
Diuretics
Clinical      Opioids can reduce the efficacy of diuretics by inducing the Impact:       release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical      The concomitant use of anticholinergic drugs may increase risk Impact:       of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Methadone is used concomitantly with anticholinergic drugs.

Paradoxical Effects of Antiretroviral Agents on Methadone
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 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 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 on Antidepressants:
Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.