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 with Gendevra and from post-marketing experience. The most frequently reported adverse reactions in clinical studies through 144 weeks were nausea (11%), diarrhoea (7%), and headache (6%).

Tabulated summary of adverse reactions

The adverse reactions in Table 2 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 2: Tabulated list of adverse reactions

Frequency                  Adverse reaction
Blood and lymphatic system disorders
Uncommon:                  anaemia1
Psychiatric disorders
Common:                    abnormal dreams suicidal ideation and suicide attempt (in patients with a pre-existing history of Uncommon: depression or psychiatric illness), depression2
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
General disorders and administration site conditions
Common:                    fatigue
1    This adverse reaction was not observed in the Phase 3 clinical studies for Gendevra but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.
2    This adverse reaction was not observed in the Phase 3 clinical studies for Gendevra but identified from clinical studies for elvitegravir 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

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
Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In clinical studies of Gendevra, increases in serum creatinine occurred by Week 2 of treatment and remained stable through 144 weeks. In treatment-naïve patients, a mean change from baseline of 0.04 ± 0.12 mg/dL (3.5 ± 10.6 μmol/L) was observed after 144 weeks of treatment. Mean increases from baseline in the Gendevra group were smaller than in the elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) group at Week 144 (difference −0.04, p < 0.001).

Changes in lipid laboratory tests
In studies in treatment-naïve patients, increases from baseline were observed in both 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 Gendevra group compared with the 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 Gendevra group and 0.1 (-0.4, 0.6) in the E/C/F/TDF group (p = 0.006 for the difference between treatment groups).

Paediatric population

The safety of Gendevra was evaluated through 48 weeks in HIV-1 infected adolescent patients aged 12 to < 18 years weighing ≥ 35 kg, (n = 100), and in children aged 7 to < 12 years weighing > 25 kg (n = 52). The safety profile in paediatric patients who received treatment with Gendevra was similar to that in adults. After 48 weeks of treatment with Genvoya, reductions in BMD of the spine and of the TBLH ≥ 4% have been reported in 2.1% (1/47) and 0.0% of adolescents and in 12.2% (6/49) and 3.9% (2/51) of children aged 7 to < 12 years weighing at least 25 kg.


Other special populations
Patients with renal impairment
The safety of Gendevra in 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) was evaluated through 144 weeks in an open-label clinical study (GS-US-292-0112). The safety profile of Gendevra 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 Gendevra in 55 virologically suppressed HIV-1 infected patients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis was evaluated through 48 weeks in a single arm, open-label clinical study (GS-US-292-1825). There were no new safety issues identified in patients with end stage renal disease on chronic haemodialysis receiving Gendevra (see section 5.2).

Patients co-infected with HIV and HBV
The safety of Gendevra 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 in 69 of 72 patients) to Gendevra. Based on these limited data, the safety profile of Gendevra in patients with HIV/HBV co-infection was similar to that in patients with HIV-1 monoinfection.

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.