Genvoya (cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide) Disease Interactions

Hepatotoxicity including lactic acidosis, severe hepatomegaly with steatosis, fulminant hepatitis, and hepatic failure has rarely been associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) alone or in combination with other antiretroviral agents. Therapy with NRTIs should be administered cautiously in patients with preexisting liver disease, a history of alcohol abuse, or hepatitis. Therapy should be suspended if clinical or laboratory findings suggestive of lactic acidosis or pronouced hepatotoxicity occur.

Tenofovir is primarily eliminated by the kidney via glomerular filtration and active tubular secretion. Renal impairment, including acute renal failure and Fanconi syndrome, has been reported with tenofovir use. Close monitoring of renal function and lengthening the dosing interval are recommended for patients with creatinine clearance less than 50 mL/min. Creatinine clearance should be calculated in all patients before starting tenofovir treatment and during treatment when clinically appropriate. Routine monitoring of serum creatinine and phosphorus is recommended for patients at risk of or with a history of renal dysfunction. Safety and effectiveness have not been evaluated in patients with renal insufficiency using dose adjustments; therefore, the benefit of tenofovir treatment should be weighed against the risk of renal toxicity. Tenofovir should be avoided in patients who are currently using or have recently used nephrotoxic drugs.

Cobicistat has shown to decrease creatinine clearance without affecting actual renal glomerular function and no dose adjustment is required in patients with renal impairment, including those with severe renal impairment. However, this effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating cobicistat when there is presence of renal impairment or in patients receiving other drugs that need to be monitored with estimated creatinine clearance. Patients who experience a confirmed increase of serum creatinine of 0.4 mg/dL from baseline should be closely monitored for renal safety.

Emtricitabine is removed by hemodialysis. Following an emtricitabine dose administered 1.5 hours before the hemodialysis session, approximately 30% of the dose was removed over three hours of hemodialysis (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Emtricitabine should be administered after hemodialysis.

Emtricitabine is primarily eliminated by the kidney. Compared to patients with normal renal function (CrCl above 80 mL/min), peak plasma concentration (Cmax) and systemic exposure (AUC) of emtricitabine increased by 45% and 113%, respectively, in patients with moderate renal dysfunction (CrCl 30 to 49 mL/min), and 27% and 186%, respectively, in patients with severe renal dysfunction (CrCl below 30 mL/min). Systemic exposure was increased even further in patients with end-stage renal disease managed on dialysis. These patients had an approximately 3.5-fold increase in emtricitabine AUC compared to patients with normal renal function. Renal clearance of emtricitabine decreased by 68% and 86%, respectively, in patients with moderate and severe renal dysfunction. Dosage adjustment of emtricitabine is recommended for patients with CrCl below 50 mL/min, including patients on dialysis, in accordance with the manufacturer's product labeling. Clinical response to treatment and renal function should be closely monitored.

Osteomalacia and reduced bone mineral density have been reported in animal toxicology studies involving tenofovir exposures 6- to 12-fold those observed in humans. The mechanism of bone toxicity has not been established, and it is not known if long-term use of tenofovir disoproxil fumarate will cause bone abnormalities in humans.

There are no data concerning the use of tenofovir disoproxil fumarate in patients with hepatic impairment. Tenofovir and tenofovir disoproxil are not metabolized by liver enzymes. However, since tenofovir is not entirely eliminated by the kidney (70% to 80%), tenofovir pharmacokinetics may be altered in patients with impaired hepatic function.