PMS-Gabapentin Drug Interactions

Overview: In vitro studies were performed to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism, using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) observed with isoform CYP2A6. No inhibition was observed with any of the other isoforms tested at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C_max at 3,600 mg/day). Gabapentin is not an inducer of cytochrome P₄₅₀ enzymes.
At plasma concentrations associated with doses up to 3600 mg/day (C_max 11.6 mcg/mL), the highest recommended daily dose, a metabolically-based interaction between gabapentin and a drug whose clearance is dependent upon the major cytochrome P450 enzymes is unlikely.
Gabapentin is not metabolized to a significant extent in humans and does not interfere with the metabolism of commonly administered antiepileptic drugs (see Drug-Drug Interactions: Antiepileptic agents as follows). Gabapentin also shows a low level of binding to plasma proteins (approximately 3%) and is eliminated solely by renal excretion as unchanged drug (see ACTIONS). Consequently, there have been few drug interactions described in which the pharmacokinetics of gabapentin or other co-administered drugs were affected to an appreciable extent.
Drug-Drug Interactions: The drug interaction data described in this subsection were obtained from studies involving healthy adults and adult patients with epilepsy: Antiepileptic Agents: There is no interaction between gabapentin and phenytoin, valproic acid, carbamazepine, or phenobarbital. Consequently, pms-GABAPENTIN may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or the other antiepileptic drugs.
Hydrocodone: Co-administration of single doses of gabapentin (125 mg to 500 mg; N = 48) and hydrocodone (10 mg; N = 50) decreased the C_max and AUC values of hydrocodone in a dose-dependent manner relative to administration of hydrocodone alone. The C_max and AUC values for hydrocodone were 2% and 4% lower, respectively, after administration of 125 mg gabapentin and 16% and 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increased gabapentin AUC values by 14%. The magnitude of interaction with higher doses of gabapentin is not known.
Morphine: A literature article reported that when a 60 mg controlled release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule in healthy volunteers (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine in this study. Because this was a single dose study, the magnitude of the interaction at steady state and at higher doses of gabapentin are not known.
Naproxen: In healthy adult volunteers (N = 18), the co-administration of single doses of naproxen sodium capsules (250 mg) and gabapentin (125 mg) increased the amount of gabapentin absorbed by 12% to 15%. Gabapentin did not affect naproxen pharmacokinetic parameters in this study. These doses are lower than the therapeutic doses for both drugs. Therefore, the magnitude of interaction at steady state and within the recommended dose ranges of either drug is not known.
Oral Contraceptives: Co-administration of gabapentin with the oral contraceptive norethindrone does not influence the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Antacids: Co-administration of gabapentin with an aluminum and magnesium-based antacid reduces gabapentin bioavailability by up to 20%. Although the clinical significance of this decrease is not known, co-administration of similar antacids and gabapentin is not recommended.
Cimetidine: A slight decrease in renal excretion of gabapentin observed when it is co-administered with cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine has not been evaluated.
Probenecid: Renal excretion of gabapentin is unaltered by probenecid.
Pharmacodynamic: Opioids, Benzodiazepines and Alcohol: Gabapentin appears to be additive in the impairment of cognitive and gross motor function caused by opioids, benzodiazepines and alcohol.
In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking gabapentin alone or in combination with other CNS depressants, including in patients with substance use disorders.
Drug-Food Interactions: pms-GABAPENTIN is given orally with or without food.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Interactions: For urinary protein determination the sulfosalicylic acid precipitation procedure is recommended, as false positive readings were reported with the Ames N-Multistix SG dipstick test, when gabapentin or placebo was added to other anticonvulsant drugs.