Emtricitabine and Tenofovir alafenamide

No dose adjustment of emtricitabine/tenofovir alafenamide is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥30 mL/min. Emtricitabine/tenofovir alafenamide should be discontinued in patients with estimated CrCl that declines below 30 mL/min during treatment.

No dose adjustment of emtricitabine/tenofovir alafenamide is required in adults with end stage renal disease (estimated CrCl <15 mL/min) on chronic haemodialysis; however, emtricitabine/tenofovir alafenamide should generally be avoided but may be used in these patients if the potential benefits are considered to outweigh the potential risks. On days of haemodialysis, emtricitabine/tenofovir alafenamide should be administered 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 48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Although there were no new safety issues identified, the implications of increased emtricitabine exposure remain uncertain.

Emtricitabine/tenofovir alafenamide should be avoided in patients with estimated CrCl ≥15 mL/min and <30 mL/min, or <15 mL/min who are not on chronic haemodialysis, as the safety of emtricitabine/tenofovir alafenamide has not been established in these populations.

No data are available to make dose recommendations in children less than 18 years with end stage renal disease.

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. Therefore, the same problems may be seen if emtricitabine/tenofovir alafenamide is administered with a third nucleoside analogue.

The safety and efficacy of emtricitabine/tenofovir alafenamide 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.

The safety and efficacy of emtricitabine/tenofovir alafenamide in patients co-infected with HIV-1 and hepatitis C virus (HCV) have not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of emtricitabine/tenofovir alafenamide 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 should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emtricitabine/tenofovir alafenamide should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation.

There are no adequate and well-controlled studies of emtricitabine/tenofovir alafenamide or its components in pregnant women. There are no or limited data (less than 300 pregnancy outcomes) from the use of tenofovir alafenamide in pregnant women. However, 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 tenofovir alafenamide in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development.

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

It is not known whether tenofovir alafenamide is excreted in human milk. Emtricitabine is excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk.

There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants. Therefore, emtricitabine/tenofovir alafenamide 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

There are no data on fertility from the use of emtricitabine/tenofovir alafenamide in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters.

Emtricitabine/tenofovir alafenamide may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with emtricitabine/tenofovir alafenamide.

Summary of the safety profile

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which HIV-1 infected patients received medicinal products containing emtricitabine and tenofovir alafenamide and from post-marketing experience. In clinical studies of treatment-naïve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as the fixed-dose combination tablet elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide (as fumarate) 10 mg (E/C/F/TAF) through 144 weeks, the most frequently reported adverse reactions were diarrhoea (7%), nausea (11%), and headache (6%).

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 and urticaria (see footnotes 2,3 and 4), all adverse reactions were identified from clinical studies of F/TAF containing products. The frequencies were derived from Phase 3 E/C/F/TAF clinical studies in 866 treatment-naïve adult patients through 144 weeks of treatment (GS-US-292-0104 and GS-US-292-0111).
² This adverse reaction was not observed in the clinical studies of F/TAF-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.

Description of selected adverse reactions

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 lipid laboratory tests

In studies in treatment-naïve patients, increases from baseline were observed in both the tenofovir alafenamide fumarate and tenofovir disoproxil fumarate containing treatment groups for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)cholesterol, and triglycerides at Week 144. The median increase from baseline for those parameters was greater in the E/C/F/TAF group compared with the elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) group at Week 144 (p<0.001 for the difference between treatment groups for fasting total cholesterol, direct LDL and HDL-cholesterol, and triglycerides). The median (Q1, Q3) change from baseline in total cholesterol to HDL-cholesterol ratio at Week 144 was 0.2 (-0.3, 0.7) in the E/C/F/TAF group and 0.1 (-0.4, 0.6) in the E/C/F/TDF group (p=0.006 for the difference between treatment groups).

In a study of virologically suppressed patients switching from emtricitabine/tenofovir disoproxil fumarate to emtricitabine/tenofovir alafenamide while maintaining the third antiretroviral agent (Study GS-US-311-1089), increases from baseline were observed in the fasting lipid parameters total cholesterol, direct LDL cholesterol and triglycerides in the emtricitabine/tenofovir alafenamide arm compared with little change in the emtricitabine/tenofovir disproxil fumarate arm (p≤0.009 for the difference between groups in changes from baseline). There was little change from baseline in median fasting values for HDL cholesterol and glucose, or in the fasting total cholesterol to HDL cholesterol ratio in either treatment arm at Week 96. None of the changes was considered clinically relevant.

In a study of virologically suppressed adult patients switching from abacavir/lamivudine to emtricitabine/tenofovir alafenamide while maintaining the third antiretroviral agent (Study GS-US-311-1717), there were minimal changes in lipid parameters.

Metabolic parameters

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

Paediatric population

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an openlabel clinical study (GS-US-292-0106) in which HIV-1 infected, treatment-naïve paediatric patients aged 12 to <18 years received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile of emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat in 50 adolescent patients was similar to that in adults.

Other special populations

Patients with renal impairment

The safety of emtricitabine and tenofovir alafenamide was evaluated through 144 weeks in an open-label clinical study (GS-US-292-0112) in which 248 HIV-1 infected patients who were either treatment-naïve (n=6) or virologically suppressed (n=242) with mild to moderate renal impairment (estimated glomerular filtration rate by Cockcroft-Gault method [eGFR_CG]: 30-69 mL/min) received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile in patients with mild to moderate renal impairment was similar to that in patients with normal renal function.

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks 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 (eGFR_CG <15 mL/min) on chronic haemodialysis received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. There were no new safety issues identified in patients with end stage renal disease on chronic haemodialysis receiving emtricitabine and tenofovir alafenamide, in combination with elvitegravir and cobicistat as a fixed-dose combination tablet.

Patients co-infected with HIV and HBV

The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide [E/C/F/TAF]) was evaluated in 72 HIV/HBV co-infected patients receiving treatment for HIV in an open-label clinical study (GS-US-292-1249), through Week 48, in which patients were switched from another antiretroviral regimen (which included tenofovir disoproxil fumarate [TDF] in 69 of 72 patients) to E/C/F/TAF. Based on these limited data, the safety profile of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet, in patients with HIV/HBV co-infection, was similar to that in patients with HIV-1 monoinfection.