Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions considered possibly or probably related to Stribild in clinical studies through 144 weeks in treatment-naïve adult patients were nausea (16%) and diarrhoea (12%).

The most frequently reported adverse reactions to Stribild in clinical studies through 48 weeks in virologically-suppressed adult patients were nausea (3% to 5%) and fatigue (6%).

In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Stribild (see section 4.4).

Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

Tabulated summary of adverse reactions

Adverse reactions to Stribild from Phase 3 clinical studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals, are listed in Table 2, below, by body system organ class and highest frequency observed. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated summary of adverse reactions associated with Stribild based on experience from Phase 3 studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals

Frequency               Adverse reaction
Blood and lymphatic system disorders:
Common:                 neutropenia1
Uncommon:               anaemia1,2
Immune system disorders:
Common:                 allergic reaction1
Metabolism and nutrition disorders:
Very common:            hypophosphataemia1,3
Common:                 hyperglycaemia1, hypertriglyceridaemia1, decreased appetite Uncommon:               hypokalaemia1,3
Rare:                   lactic acidosis1
Frequency                      Adverse reaction
Psychiatric disorders:
Common:                  insomnia, abnormal dreams suicidal ideation and suicide attempt (in patients with a pre-existing Uncommon: history of depression or psychiatric illness), depression
Nervous system disorders:
Very common:             headache, dizziness
Gastrointestinal disorders:
Very common:             diarrhoea, vomiting, nausea elevated amylase including elevated pancreatic amylase1, elevated serum Common:                  lipase1, abdominal pain, dyspepsia, constipation, abdominal distension1, flatulence
Uncommon:                pancreatitis1
Hepatobiliary disorders:
Common:                  increased transaminases1, hyperbilirubinaemia1 Rare:                    hepatic steatosis1, hepatitis1
Skin and subcutaneous tissue disorders:
Very common:             rash vesiculobullous rash1, pustular rash1, maculopapular rash1, pruritus1, Common: urticaria1, skin discolouration (increased pigmentation)1,2
Uncommon:                angioedema1
Musculoskeletal and connective tissue disorders:
Very common:             elevated creatine kinase1
Common:                        bone mineral density decreased
Uncommon:               rhabdomyolysis1,3, muscular weakness1,3 osteomalacia (manifested as bone pain and infrequently contributing to Rare: fractures)1,3,5, myopathy1,3
Renal and urinary disorders:
Common:                 increased blood creatinine4 renal failure4, proximal renal tubulopathy including Fanconi syndrome Uncommon: acquired4, proteinuria acute tubular necrosis1, nephritis (including acute interstitial nephritis)1,5, Rare: nephrogenic diabetes insipidus1
General disorders and administration site conditions:
Very common:            asthenia1
Common:                 pain1, fatigue
1     This adverse reaction was not observed in the Phase 3 clinical studies for Stribild but identified from clinical studies or post-marketing experience for emtricitabine or tenofovir disoproxil when used with other antiretrovirals.
2     Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.
3     This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.
4     See section 4.8, Description of selected adverse reactions for more details.
5     This adverse reaction was identified through post-marketing surveillance for emtricitabine or tenofovir disoproxil but not observed in randomised, controlled clinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies or the tenofovir disoproxil expanded access program for tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical studies (n = 1,563) or tenofovir disoproxil in randomised controlled clinical studies and the expanded access program (n = 7,319).

Description of selected adverse reactions

Renal impairment
Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation.
However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic 

medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

In the clinical studies of Stribild over 144 weeks, 13 (1.9%) subjects in the Stribild group (n = 701) and 8 (2.3%) subjects in the ATV/r+FTC/tenofovir disoproxil group (n = 355) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 7 in the Stribild group and 1 in the ATV/r+FTC/tenofovir disoproxil group occurred during the first 48 weeks. The types of renal adverse reactions seen with Stribild were consistent with previous experience with tenofovir disoproxil. Four (0.6%) of the subjects who received Stribild developed laboratory findings consistent with proximal tubulopathy leading to discontinuation of Stribild during the first 48 weeks. No additional proximal renal tubular dysfunction cases were reported from Week 48 to Week 144. Two of the four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL/min) at baseline. The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved without clinical consequence upon discontinuation of Stribild, but did not completely resolve in all subjects.
Three (0.8%) subjects who received ATV/r+FTC/tenofovir disoproxil developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of ATV/r+FTC/tenofovir disoproxil after Week 96 (see section 4.4).

The cobicistat component of Stribild has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies GS-US-236-0102 and GS-US-236-0103, decreases in estimated creatinine clearance occurred early in treatment with Stribild, after which they stabilised. The mean change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -14.0 ± 16.6 mL/min for Stribild, -1.9 ± 17.9 mL/min for EFV/FTC/tenofovir disoproxil, and -9.8 ± 19.4 mL/min for ATV/r+FTC/tenofovir disoproxil.

Lactic acidosis
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

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).

Other special population(s)

Patients with renal impairment
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any patient with renal impairment treated with Stribild (see sections 4.2, 4.4 and 5.2).


Exacerbations of hepatitis after discontinuation of treatment
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have occurred after discontinuation of treatment (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) which redirects to the online form for reporting side effects or by clicking on the link: https://sideeffects.health.gov.il.