Drug Interactions between Addyi and Sublocade

CONTRAINDICATED: Grapefruit juice may increase the plasma concentrations of flibanserin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In 26 healthy female subjects, administration of a single 100 mg dose of flibanserin with 240 mL grapefruit juice increased flibanserin peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.1- and 1.4-fold, respectively, compared to administration of flibanserin alone. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

ADJUST DOSING INTERVAL: Coadministration of flibanserin with alcohol may potentiate the risk of severe hypotension, syncope, and central nervous system depression. In a dedicated alcohol interaction study, hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenberg position) occurred in 4 (17%) of 23 subjects given flibanserin 100 mg with 0.4 g/kg alcohol (equivalent to two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person) consumed over 10 minutes in the morning. In these four subjects, systolic blood pressure reductions ranged from 28 to 54 mmHg and diastolic blood pressure reductions ranged from 24 to 46 mmHg. In addition, 6 (25%) of 24 subjects coadministered flibanserin with 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. Systolic and diastolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg and 0 to 27 mmHg, respectively, with one requiring therapeutic intervention. No adverse events requiring therapeutic intervention were observed when flibanserin or alcohol was administered alone. Somnolence was reported in 67%, 74%, and 92% of subjects who received flibanserin alone, flibanserin with 0.4 g/kg ethanol, and flibanserin with 0.8 g/kg ethanol, respectively. Subsequent data from postmarketing trials showed that the risk of severe hypotension and syncope was reduced when women who consumed up to two alcoholic drinks waited at least two hours before taking flibanserin.

MANAGEMENT: Concomitant use of flibanserin with moderate or potent CYP450 3A4 inhibitors such as grapefruit juice is considered contraindicated. The patient should be advised to avoid the consumption of grapefruit and grapefruit juice during treatment, and to take flibanserin at bedtime to minimize the risk of hypotension, syncope, accidental injury, and central nervous system depression. In addition, patients should consume no more than 1 to 2 alcoholic drinks and discontinue drinking alcohol at least two hours before taking flibanserin at bedtime; otherwise, they should skip the flibanserin dose that evening. Alcohol should not be consumed until at least the morning after taking flibanserin at bedtime. A standard alcoholic drink contains 14 g of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).

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GENERALLY AVOID: Concomitant use of buprenorphine with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may increase the risk of buprenorphine overdose, severe respiratory depression, coma, and death. Reported cases have primarily occurred in the setting of buprenorphine maintenance treatment for opiate addiction, and many, but not all, involved abuse or misuse of buprenorphine including intravenous self-injection. The mechanism of interaction probably involves some degree of additive pharmacologic effects. Preclinical studies also suggest that benzodiazepines can alter the usual ceiling effect on buprenorphine-induced respiratory depression and render the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Coadministration of buprenorphine with some CNS depressants such as alcohol, benzodiazepines, and phenothiazines may also increase the risk of hypotension.

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Extreme caution is advised when prescribing buprenorphine to patients who are addicted to opioids and also abusing benzodiazepines or alcohol. Due to potential risk of overdose and death, dependence on sedative-hypnotics such as benzodiazepines or alcohol is considered a relative contraindication for office-based buprenorphine treatment of opioid addiction. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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