Emtricitabine, Tenofovir alafenamide and Bictegravir

Bictegravir is both a P-gp and a BCRP substrate. The clinical relevance of this feature is not established. Therefore, caution is recommended when bictegravir is combined with medicinal products known to inhibit P-gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone, glecaprevir/pibrentasvir).

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of Biktarvy with medicinal products that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption.

Medicinal products that induce P-gp activity (e.g. rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Biktarvy and development of resistance.

Co-administration of Biktarvy with other medicinal products that inhibit P-gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

Co-administration of bictegravir with medicinal products that potently inhibit both CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations of bictegravir, therefore co-administration is not recommended.

No dose adjustment of emtricitabine/tenofovir alafenamide/bictegravir is required in adult patients with end stage renal disease (estimated creatinine clearance <15 mL/minute) who are receiving chronic haemodialysis. However, emtricitabine/tenofovir alafenamide/bictegravir should generally be avoided and only be used in these patients if the potential benefits are considered to outweigh the potential risks. On days of haemodialysis, administer the daily dose of emtricitabine/tenofovir alafenamide/bictegravir after completion of haemodialysis treatment.

In a study of emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adults with end stage renal disease (estimated CrCl <15 mL/min) on chronic haemodialysis, efficacy was maintained through 96 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Efficacy was also maintained in the extension phase of the study in which 10 patients switched to emtricitabine/tenofovir alafenamide/bictegravir for 48 weeks. Although no additional adverse reactions were identified, the implications of increased emtricitabine exposure remain uncertain.

Emtricitabine/tenofovir alafenamide/bictegravir should not be co-administered simultaneously with magnesium/aluminium-containing antacids or iron supplements under fasted conditions.

Emtricitabine/tenofovir alafenamide/bictegravir should be administered at least 2 hours before, or with food 2 hours after antacids containing magnesium and/or aluminium.

Emtricitabine/tenofovir alafenamide/bictegravir should be administered at least 2 hours before iron supplements, or taken together with food.

The safety and efficacy of emtricitabine/tenofovir alafenamide/bictegravir in patients with significant underlying liver disorders have not been established.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

There are limited safety and efficacy data for emtricitabine/tenofovir alafenamide/bictegravir in patients co-infected with HIV-1 and hepatitis C virus (HCV).

Emtricitabine/tenofovir alafenamide/bictegravir contains tenofovir alafenamide, which is active against hepatitis B virus (HBV).

Discontinuation of emtricitabine/tenofovir alafenamide/bictegravir therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue emtricitabine/tenofovir alafenamide/bictegravir should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

There are no or limited data (less than 300 pregnancy outcomes) from the use of bictegravir or tenofovir alafenamide in pregnant women. A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development. Studies of bictegravir and tenofovir alafenamide, administered separately, in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development.

Emtricitabine/tenofovir alafenamide/bictegravir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether bictegravir or tenofovir alafenamide is excreted in human milk. Emtricitabine is excreted in human milk. In animal studies, bictegravir was detected in the plasma of nursing rat pups likely due to the presence of bictegravir in milk, without effects on nursing pups. In animal studies it has been shown that tenofovir is excreted in milk.

There is insufficient information on the effects of all the components of the emtricitabine/tenofovir alafenamide/bictegravir combination in newborns/infants, therefore it should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV-infected women do not breast-feed their infants under any circumstances.

Fertility

No human data on the effect of emtricitabine/tenofovir alafenamide/bictegravir on fertility are available. Animal studies indicate no effects of bictegravir, emtricitabine or tenofovir alafenamide on mating or fertility.

Patients should be informed that dizziness has been reported during treatment with the components of emtricitabine/tenofovir alafenamide/bictegravir.

Summary of the safety profile

The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with emtricitabine/tenofovir alafenamide/bictegravir combination and from post-marketing experience. In clinical studies of treatment-naïve patients receiving emtricitabine/tenofovir alafenamide/bictegravir, the most frequently reported adverse reactions in the double-blind phase (Week 144) were headache (5%), diarrhoea (5%) and nausea (4%).

Tabulated summary of adverse reactions

The adverse reactions in the following table are listed by system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100).

Tabulated list of adverse reactions¹:

¹ With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adverse reactions were identified from emtricitabine/tenofovir alafenamide/bictegravir clinical studies. The frequencies were derived from the double-blind phase (Week 144) of Phase 3 emtricitabine/tenofovir alafenamide/bictegravir clinical studies in treatment-naïve patients (GS-US-380-1489 and GS-US-380-1490).
² This adverse reaction was not observed in the clinical studies of emtricitabine + tenofovir alafenamide-containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.
³ This adverse reaction was identified through post-marketing surveillance for emtricitabine-containing products.
⁴ This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products.
⁵ This adverse reaction was identified through post-marketing surveillance for emtricitabine/tenofovir alafenamide/bictegravir. The frequency has been calculated using 3/X, where X represent the cumulative number of subjects exposed to emtricitabine/tenofovir alafenamide/bictegravir in clinical trials (N=3963).

Description of selected adverse reactions

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.

Changes in serum creatinine

Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine, however these changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 144. In Studies GS-US-380-1489 and GS-US-380-1490, median (Q1, Q3) serum creatinine increased by 0.11 (0.03, 0.19) mg/dL (9.7 [2.7, 16.8] µmol/L), 0.11 (0.04, 0.19) mg/dL (9.7 [3.5, 16.8] µmol/L), and 0.12 (0.06, 0.21) mg/dL (10.6 [5.3, 18.6] μmol/L) from baseline to Week 144 in the emtricitabine/tenofovir alafenamide/bictegravir, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively. There were no discontinuations due to renal adverse events through Week 144 in patients administered emtricitabine/tenofovir alafenamide/bictegravir in clinical studies.

Changes in bilirubin

In Studies GS-US-380-1489 and GS-US-380-1490, total bilirubin increases were observed in 17% of treatment-naïve patients administered emtricitabine/tenofovir alafenamide/bictegravir through Week 144. Increases were primarily Grade 1 (12%) and Grade 2 (4%) (≥1.0 to 2.5 x Upper Limit of Normal [ULN]), and were not associated with hepatic adverse reactions or other liver related laboratory abnormalities. Five patients administered emtricitabine/tenofovir alafenamide/bictegravir (1%) had grade 3 bilirubin increases that were not considered related to study drug. There were no discontinuations due to hepatic adverse events through Week 144 in emtricitabine/tenofovir alafenamide/bictegravir clinical studies.

Other special populations

Patients co-infected with hepatitis B

In 16 HIV/HBV co-infected adults administered emtricitabine/tenofovir alafenamide/bictegravir (8 HIV/HBV treatment-naïve adults in Study GS-US-380-1490; 8 HIV/HBV suppressed adults in Study GS-US-380-1878), the safety profile of emtricitabine/tenofovir alafenamide/bictegravir was similar to that in patients with HIV-1 monoinfection.

Elderly

Studies GS-US-380-1844, GS-US-380-1878 and the dedicated Study GS-US-380-4449 in patients ≥65 years old (evaluation of 86 HIV-1 infected, virologically-suppressed subjects ≥65 years old) included 111 patients aged ≥65 years who received emtricitabine/tenofovir alafenamide/bictegravir. In these patients, no differences in the safety profile of emtricitabine/tenofovir alafenamide/bictegravir were observed.

Patients with renal impairment

The safety of emtricitabine + tenofovir alafenamide was evaluated in a single arm, open-label clinical study (GS-US-292-1825), in which 55 virologically-suppressed HIV-1 infected patients with end stage renal disease (eGFRCG <15 mL/min) on chronic haemodialysis received emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet for 96 weeks. In an extension phase of Study GS-US-292-1825, 10 patients switched to emtricitabine/tenofovir alafenamide/bictegravir for 48 weeks. No additional adverse reactions were identified in patients with end stage renal disease on chronic haemodialysis in this study.