Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The combination of emtricitabine, rilpivirine and tenofovir disoproxil has been studied as the component products in treatment-naïve patients (Phase III studies C209 and C215). The single-tablet regimen (STR), Eviplera, has been studied in virologically suppressed patients who switched from a regimen containing a ritonavir-boosted PI (Phase III study GS-US-264-0106) or from efavirenz/emtricitabine/tenofovir disoproxil (Phase IIb study GS-US-264-0111). In treatment-naïve patients, the most frequently reported adverse reactions considered possibly or probably related to rilpivirine hydrochloride and emtricitabine/tenofovir disoproxil were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhoea (5%) and insomnia (5%) (pooled data from the Phase III clinical studies C209 and C215, see section 5.1). In virologically suppressed patients switching to Eviplera, the most frequently reported adverse reactions considered possibly or probably related to Eviplera were fatigue (3%), diarrhoea (3%), nausea (2%) and insomnia (2%) (48 week data from the Phase III study GS-US-264-0106). The safety profile of emtricitabine and tenofovir disoproxil in these studies was consistent with the previous experience with these agents when each was administered with other antiretroviral agents.

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 Eviplera (see section 4.4).

Discontinuation of Eviplera 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

The adverse reactions considered at least possibly related to treatment with the components of Eviplera from clinical study and post-marketing experience are listed in Table 2, below, by body system organ class and frequency. 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 to Eviplera based on clinical study and post-marketing experience with Eviplera and its individual components 
Frequency           Adverse reaction
Blood and lymphatic system disorders neutropenia1, decreased white blood cell count2, decreased haemoglobin2, decreased Common: platelet count2
Uncommon:           anaemia1, 4
Immune system disorders
Common:             allergic reaction1
Uncommon:           immune reactivation syndrome
Metabolism and nutrition disorders increased total cholesterol (fasted)2, increased LDL-cholesterol (fasted)2, Very common: hypophosphataemia3, 5
Common:             hypertriglyceridaemia1, 2, hyperglycaemia1, decreased appetite2 Uncommon:           hypokalaemia3, 5
Rare:               lactic acidosis3
Psychiatric disorders
Very common:        insomnia1, 2
Common:             depression2, depressed mood2, sleep disorders2, abnormal dreams1, 2 Nervous system disorders
Very common:        headache1, 2, 3, dizziness1, 2, 3
Common:             somnolence2
Gastrointestinal disorders
Very common:        increased pancreatic amylase2, vomiting1, 2, 3, diarrhoea1, 3, nausea1, 2, 3 elevated amylase including elevated pancreatic amylase1, elevated serum lipase1, 2, Common:             abdominal pain1, 2, 3, abdominal discomfort2, abdominal distension3, dyspepsia1, flatulence3, dry mouth2
Uncommon:           pancreatitis3
Hepatobiliary disorders
Very common:        increased transaminases (AST and/or ALT)1, 2, 3
Common:             increased bilirubin1, 2
Rare:               hepatitis3, hepatic steatosis3
Skin and subcutaneous tissue disorders
Very common:        rash1, 2, 3 vesiculobullous rash1, pustular rash1, urticaria1, skin discolouration (increased Common: pigmentation)1, 4, maculopapular rash1, pruritus1
Uncommon:           angioedema1, 3, 6, severe skin reactions with systemic symptoms7 Musculoskeletal and connective tissue disorders
Very common:        elevated creatine kinase1
Common:             bone mineral density decreased3
Uncommon:           rhabdomyolysis3, 5, muscular weakness3, 5 osteomalacia (manifested as bone pain and infrequently contributing to fractures)3, 5, 8, Rare: myopathy3, 5
Renal and urinary disorders proximal renal tubulopathy including Fanconi syndrome3, increased creatinine3, Uncommon: proteinuria3 renal failure (acute and chronic)3, acute tubular necrosis3, nephritis (including acute Rare: interstitial nephritis)3, 8, nephrogenic diabetes insipidus3



Frequency          Adverse reaction
General disorders and administration site conditions
Very common:       asthenia1, 3
Common:            pain1, fatigue2
1     Adverse reaction identified for emtricitabine.
2     Adverse reaction identified for rilpivirine hydrochloride.
3     Adverse reaction identified for tenofovir disoproxil.
4     Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients (see section 4.8, Paediatric population).
5     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.
6     This was a rare adverse reaction for tenofovir disoproxil. It was also identified as an adverse reaction for emtricitabine through post-marketing surveillance but was not observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies of emtricitabine. The frequency category of uncommon was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in these clinical studies (n = 1,563).
7     This adverse reaction was identified through post-marketing surveillance for Eviplera (fixed-dose combination) but not observed in randomised controlled clinical studies for Eviplera. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to Eviplera or all of its components in randomised controlled clinical studies (n = 1,261). See section 4.8, Description of selected adverse reactions.
8     This adverse reaction was identified through post-marketing surveillance for tenofovir disoproxil but not observed in randomised controlled clinical studies or the expanded access program for tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical studies and the expanded access program (n = 7,319).

Laboratory abnormalities

Lipids
At 96 weeks in the pooled Phase III C209 and C215 studies of treatment-naïve patients, in the rilpivirine arm the mean change from baseline in total cholesterol (fasted) was 5 mg/dL, in high-density lipoprotein (HDL)-cholesterol (fasted) 4 mg/dL, in low density lipoprotein (LDL)-cholesterol (fasted) 1 mg/dL, and in triglycerides (fasted) -7 mg/dL. At 48 weeks in Phase III study GS-US-264-0106 of virologically suppressed patients switching to Eviplera from a regimen containing a ritonavir-boosted PI, the mean change from baseline in total cholesterol (fasted) was -24 mg/dL, in HDL-cholesterol (fasted) -2 mg/dL, in LDL-cholesterol (fasted) -16 mg/dL, and in triglycerides (fasted) -64 mg/dL.

Description of selected adverse reactions

Renal impairment
As Eviplera may cause renal damage, monitoring of renal function is recommended (see sections 4.4 and 4.8, Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in CrCl 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).

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).

Severe skin reactions
Severe skin reactions with systemic symptoms have been reported during post-marketing experience with Eviplera, including rashes accompanied by fever, blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia (see section 4.4).

Paediatric population

Insufficient safety data are available for children under the age of 18 years. Eviplera is not recommended in this population (see section 4.2).

When emtricitabine (one of the components of Eviplera) was administered to paediatric patients, the following adverse reactions were observed more frequently in addition to the adverse reactions reported in adults: anaemia was common (9.5%) and skin discolouration (increased pigmentation) was very common (31.8%) in paediatric patients (see section 4.8, Tabulated summary of adverse reactions).

Other special populations

Elderly
Eviplera has not been studied in patients over the age of 65 years. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with Eviplera (see section 4.4).

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 Eviplera (see sections 4.2, 4.4 and 5.2).

HIV/HBV or HCV co-infected patients
The adverse reaction profile of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without co-infection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population.

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form : https://sideeffects.health.gov.il/