Drug Interactions between emtricitabine / nelfinavir / tenofovir and Gianvi

MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of drospirenone, which is partially metabolized by the isoenzyme. In a drug interaction study conducted in 20 premenopausal females, administration of a combined oral contraceptive containing drospirenone 3 mg and ethinyl estradiol 0.02 mg with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) for 10 days increased drospirenone peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.97- and 2.68-fold, respectively, compared to administration of the contraceptive alone. When a single dose of the contraceptive was coadministered with atazanavir/cobicistat (300 mg/150 mg once daily) in 14 healthy study subjects, drospirenone Cmax was not altered but AUC increased by 2.30-fold. Administration of the contraceptive with another potent CYP450 3A4 inhibitor, boceprevir (800 mg three times daily for 7 days), increased Cmax and AUC of drospirenone by 57% and 99%, respectively. High exposure to drospirenone, a synthetic progestin and spironolactone analog, may potentiate the risk of hyperkalemia. When given at doses typically used for contraception, drospirenone has anti-mineralocorticoid activity comparable to a 25 mg dose of spironolactone.

MANAGEMENT: Caution and close clinical monitoring are recommended when drospirenone is prescribed with potent CYP450 3A4 inhibitors, particularly in patients requiring long-term concomitant use and those with other risk factors for hyperkalemia (e.g., renal insufficiency; coadministration with medications that can increase potassium such as aldosterone antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), potassium-sparing diuretics, potassium supplements, and heparin). Consider checking serum potassium levels during the first treatment cycle and periodically thereafter as indicated. Due to the risk for hyperkalemia, concomitant use with certain CYP450 3A4 inhibitors such as boceprevir or cobicistat-boosted atazanavir is considered contraindicated by the manufacturers.

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ADDITIONAL CONTRACEPTION RECOMMENDED: Nelfinavir may decrease the plasma concentrations of contraceptive hormones during chronic coadministration. The proposed mechanism is nelfinavir induction of the hepatic metabolism of sex hormones. In 12 study subjects, nelfinavir (750 mg every 8 hours for 7 days) decreased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of ethinyl estradiol (administered as ethinyl estradiol-norethindrone 0.035 mg-0.4 mg once a day for 15 days) by 28%, 47% and 62%, respectively, compared to administration of the oral contraceptive alone. The mean AUC and Cmin of norethindrone decreased by 18% and 46%, respectively.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with nelfinavir. Alternative or additional methods of birth control should be used during and for at least 4 weeks after nelfinavir therapy.
-If a combination oral contraceptive pill is used, a regimen containing at least 50 mcg of ethinyl estradiol per day or equivalent should be selected. Although breakthrough bleeding is not necessarily indicative of low ethinyl estradiol serum levels or increased risk of ovulation, some clinicians suggest that women who experience breakthrough bleeding during enzyme-inducing therapy may be prescribed an increased dose of ethinyl estradiol above 50 mcg daily by combining more than one formulation of contraceptive pill if necessary.
-For emergency contraception in patients who have used an hepatic enzyme inducer in the past 4 weeks, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. If this is not possible, some authorities recommend that the usual dose of levonorgestrel (1.5 mg) should be doubled to 3 mg and taken as a single dose as soon as possible (within 72 hours of unprotected sexual intercourse). However, there are no data on efficacy, compliance, or side effects of this regimen.
-No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. -Injectable progestin-only contraceptives are also thought to be unaffected by enzyme-inducing drugs.

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