Inhibitors of CYP3A4
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Clinical Impact:
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The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see Warnings and Precautions (
5.7
)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.
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Intervention:
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If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
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Examples:
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice
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CYP3A4 Inducers
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Clinical Impact:
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The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology (
12.3
)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions (5.7)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology (
12.3
)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
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Intervention:
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If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage as needed.
If a CYP3A4 inducer is discontinued, consider Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals.
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Examples:
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Rifampin, carbamazepine, phenytoin
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Inhibitors of CYP2D6
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Clinical Impact:
|
Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see Clinical Pharmacology (
12.3
)].
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology (
12.3
)].
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Intervention:
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If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and monitor patients closely at frequent intervals.
If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules as needed.
After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and monitor the patient for signs and symptoms of respiratory depression or sedation.
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Examples:
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paroxetine, fluoxetine, bupropion, quinidine
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Benzodiazepines and Other Central Nervous System (CNS) Depressants
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Clinical Impact:
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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.
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Intervention:
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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 (
5.4
)].
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Examples:
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
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Serotonergic Drugs
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Clinical Impact:
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
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Intervention:
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if serotonin syndrome is suspected.
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Examples:
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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Monoamine Oxidase Inhibitors (MAOIs)
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Clinical Impact:
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (
5.10
)].
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Intervention:
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Do not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydromorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
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Examples:
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phenelzine, tranylcypromine, linezolid
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Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
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Clinical Impact:
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May reduce the analgesic effect of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and/or precipitate withdrawal symptoms.
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Intervention:
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Avoid concomitant use.
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Examples:
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butorphanol, nalbuphine, pentazocine, buprenorphine
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Muscle Relaxants
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Clinical Impact:
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Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
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Intervention:
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and/or the muscle relaxant as necessary.
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Diuretics
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Clinical Impact:
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
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Intervention:
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
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Anticholinergic Drugs
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Clinical Impact:
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
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Intervention:
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Monitor patients for signs of urinary retention or reduced gastric motility when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used concomitantly with anticholinergic drugs.
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