Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir and Parlodel

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.

Switch to consumer interaction data

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

Switch to consumer interaction data

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

Switch to consumer interaction data