Meperidine

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 opioid 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 opioid overdose reversal agents in the treatment of these reactions are 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, gabapentinoids (gabapentin or pregabalin), 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. Examples: Cyclobenzaprine, metaxalone 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.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with DEMEROL Injection because they may reduce analgesic effect of DEMEROL Injection or precipitate withdrawal symptoms. ( 7 )

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] . Available data with DEMEROL Injection are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics [see Clinical Considerations ] . Formal animal reproduction studies have not been conducted with meperidine.

Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1200 mg [see Data ] . The background risk of major birth defects and miscarriage for the indicated population is unknown. All ‎‎pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agents, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. DEMEROL Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.

Opioid analgesics, including DEMEROL Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent…