DEMEROL Drug Interactions

(Meperidine Hydrochloride Injection, USP)

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with DEMEROL Injection.

Table 1: Clinically Significant Drug Interactions with DEMEROL Injection

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors, and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension [see Warnings and Precautions (5.6)]‎.

Intervention:

Do not use DEMEROL Injection in patients taking MAOIs or within 14 days of stopping such treatment.

Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.

Examples:

Phenelzine, tranylcypromine, linezolid

Inhibitors of CYP3A4 and CYP2B6

Clinical Impact:

The concomitant use of DEMEROL Injection and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of DEMEROL Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL Injection is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.

Intervention:

If concomitant use is necessary, consider dosage reduction of DEMEROL Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the DEMEROL Injection dosage until stable drug effects are achieved.

Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconizole), protease inhibitors (e.g., ritonavir)

CYP3A4 and CYP2B6 Inducers

Clinical Impact:

The concomitant use of DEMEROL Injection and CYP3A4 inducers or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the DEMEROL Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Injection dosage reduction and monitor for signs of respiratory depression.

Examples:

Rifampin, carbamazepine, phenytoin

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 [see Warnings and Precautions (5.3)].

Intervention:

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. Monitor patients closely for signs of respiratory depression and sedation.

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

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 (5.8)].

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DEMEROL Injection if serotonin syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of DEMEROL Injection and/or precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

Butorphanol, nalbuphine, pentazocine, buprenorphine.

Muscle Relaxants

Clinical Impact:

Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DEMEROL Injection and/or the muscle relaxant as necessary.

Diuretics

Clinical Impact:

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

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when DEMEROL Injection is used concomitantly with anticholinergic drugs.

Acyclovir

Clinical Impact:

The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.

Intervention:

If concomitant use of acyclovir and DEMEROL Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

Cimetidine

Clinical Impact:

The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects

Intervention:

If concomitant use cimetidine and DEMEROL Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

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Drug Interactions

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with DEMEROL Injection.

Table 1: Clinically Significant Drug Interactions with DEMEROL Injection

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors, and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension [see Warnings and Precautions (5.6)]‎.

Intervention:

Do not use DEMEROL Injection in patients taking MAOIs or within 14 days of stopping such treatment.

Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.

Examples:

Phenelzine, tranylcypromine, linezolid

Inhibitors of CYP3A4 and CYP2B6

Clinical Impact:

The concomitant use of DEMEROL Injection and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of DEMEROL Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL Injection is achieved [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.

Intervention:

If concomitant use is necessary, consider dosage reduction of DEMEROL Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the DEMEROL Injection dosage until stable drug effects are achieved.

Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconizole), protease inhibitors (e.g., ritonavir)

CYP3A4 and CYP2B6 Inducers

Clinical Impact:

The concomitant use of DEMEROL Injection and CYP3A4 inducers or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the DEMEROL Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Injection dosage reduction and monitor for signs of respiratory depression.

Examples:

Rifampin, carbamazepine, phenytoin

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 [see Warnings and Precautions (5.3)].

Intervention:

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. Monitor patients closely for signs of respiratory depression and sedation.

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

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 (5.8)].

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DEMEROL Injection if serotonin syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of DEMEROL Injection and/or precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

Butorphanol, nalbuphine, pentazocine, buprenorphine.

Muscle Relaxants

Clinical Impact:

Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DEMEROL Injection and/or the muscle relaxant as necessary.

Diuretics

Clinical Impact:

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

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when DEMEROL Injection is used concomitantly with anticholinergic drugs.

Acyclovir

Clinical Impact:

The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.

Intervention:

If concomitant use of acyclovir and DEMEROL Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

Cimetidine

Clinical Impact:

The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects

Intervention:

If concomitant use cimetidine and DEMEROL Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

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