Drug Interactions between bromocriptine and cobicistat / darunavir / emtricitabine / tenofovir alafenamide

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of bromocriptine. Orally administered bromocriptine is extensively metabolized in the gastrointestinal tract and liver by CYP450 3A4, with approximately 93% of the absorbed dose undergoing first-pass metabolism and only the remaining 7% reaching systemic circulation. As such, inhibitors of CYP450 3A4 may markedly reduce the metabolic clearance of bromocriptine. The interaction has been studied with erythromycin, a moderate CYP450 3A4 inhibitor. When a single 5 mg oral dose of bromocriptine was given following a 4-day treatment of erythromycin estolate 250 mg four times a day in five male volunteers, mean bromocriptine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.6- and 3.7-fold, respectively, compared to administration of bromocriptine alone. High bromocriptine plasma levels may increase the frequency and/or severity of adverse effects such as nausea, headache, dizziness, somnolence (e.g., episodes of sudden sleep onset), hypotension, syncope, and impulse control problems or compulsive behaviors (e.g., gambling or sexual urges; uncontrolled spending).

MANAGEMENT: Caution and close monitoring for development of adverse effects are advisable during coadministration of bromocriptine with moderate CYP450 3A4 inhibitors. Bromocriptine dosage may need to be reduced to avoid toxicity. The prescribing information for Cycloset, a bromocriptine product indicated for use in adults with type 2 diabetes mellitus to improve glycemic control, recommends limiting the dose to 1.6 mg daily during concomitant use of a moderate CYP450 3A4 inhibitor.

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of bromocriptine. Orally administered bromocriptine is extensively metabolized in the gastrointestinal tract and liver by CYP450 3A4, with approximately 93% of the absorbed dose undergoing first-pass metabolism and only the remaining 7% reaching systemic circulation. As such, inhibitors of CYP450 3A4 may markedly reduce the metabolic clearance of bromocriptine. The interaction has been studied with erythromycin, a moderate CYP450 3A4 inhibitor. When a single 5 mg oral dose of bromocriptine was given following a 4-day treatment of erythromycin estolate 250 mg four times a day in five male volunteers, mean bromocriptine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.6- and 3.7-fold, respectively, compared to administration of bromocriptine alone. An even greater magnitude of interaction should be expected with more potent inhibitors. High bromocriptine plasma levels may increase the frequency and/or severity of adverse effects such as nausea, headache, dizziness, somnolence (e.g., episodes of sudden sleep onset), hypotension, syncope, and impulse control problems or compulsive behaviors (e.g., gambling or sexual urges; uncontrolled spending).

MANAGEMENT: Concomitant use of bromocriptine with potent CYP450 3A4 inhibitors should be avoided when possible. In patients who have been treated with a potent CYP450 3A4 inhibitor, an adequate washout of the inhibitor (approximately 3 to 5 elimination half-lives) is recommended prior to initiation of bromocriptine. If coadministration with a potent CYP450 3A4 inhibitor is required, bromocriptine dosage should be reduced to avoid toxicity. Caution and close monitoring for development of adverse effects are advisable, and the bromocriptine dosage further adjusted if necessary.

MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. Data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir) or is nephrotoxic.

MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.