Adverse reactions : תופעות לוואי

4.8      Undesirable effects

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 Table 3 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).

Table 3: Tabulated list of adverse reactions1

Frequency                  Adverse reaction
Blood and lymphatic system disorders
Uncommon:                  anaemia2
Psychiatric disorders
Common:                    abnormal dreams
Nervous system disorders
Common:                    headache, dizziness
Gastrointestinal disorders
Very common:               nausea
Common:                    diarrhoea, vomiting, abdominal pain, flatulence Uncommon:                  dyspepsia
Skin and subcutaneous tissue disorders
Common:                    rash
Uncommon:                  angioedema3, 4, pruritus, urticaria4
Musculoskeletal and connective tissue disorders
Uncommon:                  arthralgia
General disorders and administration site conditions
Common:                    fatigue
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 (see section 4.4).

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 (see section 4.4).

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 Descovy 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 Descovy 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 Descovy 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 (see section 4.4).

Paediatric population

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an open- label 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 (see section 5.1).

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 [eGFRCG]: 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 (see section 5.1).

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 (eGFRCG < 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 (see section 5.2).

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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

You can report any side effects to the Ministry of Health by clicking on the link "Report side effects due to medical treatment" that is located on the Ministry of Health homepage (www.health.gov.il) or by clicking on the link: https://sideeffects.health.gov.il.