Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
In clinical studies of treatment-naïve patients receiving Biktarvy, the most frequently reported adverse reactions in the double-blind phase (Week 144) were headache (5%), diarrhoea (5%) and nausea (4%).

Tabulated list of adverse reactions

The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with Biktarvy and from post-marketing experience. The adverse reactions in Table 2 are listed by system organ class and frequency. Frequencies are defined as follows: common (≥ 1/100 to < 1/10) uncommon (≥ 1/1 000 to < 1/100) and rare (≥1/10 000 to <1/1 000).

Table 2: Tabulated list of adverse reactions1

Frequency             Adverse reaction
Blood and lymphatic system disorders
Uncommon:             anaemia2
Psychiatric disorders
Common:               depression, abnormal dreams suicidal ideation, suicide attempt (particularly in patients with a pre-existing Uncommon: history of depression or psychiatric illness), anxiety, sleep disorders Nervous system disorders
Common:               headache, dizziness
Gastrointestinal disorders
Common:               diarrhoea, nausea
Uncommon:             vomiting, abdominal pain, dyspepsia, flatulence Hepatobiliary disorders
Uncommon:             hyperbilirubinaemia
Skin and subcutaneous tissue disorders
Uncommon:             angioedema3,4, rash, pruritus, urticaria4

Frequency            Adverse reaction
Rare:                Stevens-Johnson syndrome5
Musculoskeletal and connective tissue disorders
Uncommon:            arthralgia
General disorders and administration site conditions
Common:              fatigue
1    With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adverse reactions were identified from Biktarvy clinical studies. The frequencies were derived from the double-blind phase (Week 144) of Phase 3 Biktarvy 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 Biktarvy. The frequency has been calculated using 3/X, where X represent the cumulative number of subjects exposed to Biktarvy 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 (see section 4.4).

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 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 Biktarvy, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively. There were no discontinuations due to renal adverse reactions through Week 144 in patients administered Biktarvy 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 Biktarvy 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 Biktarvy (1%) had grade 3 bilirubin increases that were not considered related to study drug. There were no discontinuations due to hepatic adverse reactions through Week 144 in Biktarvy clinical studies.


Other special populations

Patients co-infected with hepatitis B
In 16 HIV/HBV co-infected adults administered Biktarvy (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 Biktarvy was similar to that in patients with HIV-1 monoinfection (see section 5.1).

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 Biktarvy. In these patients, no differences in the safety profile of Biktarvy 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 Biktarvy for 48 weeks. No additional adverse reactions were identified in patients with end stage renal disease on chronic haemodialysis in this study (see sections 4.4 and 5.2).

Pregnancy
Biktarvy was evaluated in a clinical study of 33 HIV-1 infected virologically suppressed (HIV-1 RNA < 50 copies/mL) pregnant adults administered 50 mg/200 mg/25 mg Biktarvy once daily from the second or third trimester through postpartum. There were no new safety findings compared to the known safety profile of Biktarvy in HIV-1 infected adults.

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) which redirects to the online form for reporting side effects or by clicking on the link: https://sideeffects.health.gov.il.