Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
HIV-1 infection: The most frequently reported adverse reactions considered possibly or probably related to emtricitabine and/or tenofovir disoproxil were nausea (12%) and diarrhoea (7%) in an open-label randomised clinical study in adults (GS-01-934, see section 5.1). The safety profile of emtricitabine and tenofovir disoproxil in this study was consistent with the previous experience with these agents when each was administered with other antiretroviral agents.

Pre-exposure prophylaxis: No new adverse reactions to Truvada were identified from two randomised placebo-controlled studies (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received Truvada once daily for pre-exposure prophylaxis. Patients were followed for a median of 71 weeks and 87 weeks, respectively. The most frequent adverse reaction reported in the Truvada group in the iPrEx study was headache (1%).

Tabulated summary of adverse reactions

The adverse reactions considered at least possibly related to treatment with the components of Truvada from clinical study and post-marketing experience in HIV-1 infected patients are listed in Table 3, 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 3: Tabulated summary of adverse reactions associated with the individual components of Truvada based on clinical study and post-marketing experience

Frequency                    Emtricitabine                        Tenofovir disoproxil Blood and lymphatic system disorders:
Common:                      neutropenia
Uncommon:                    anaemia2
Immune system disorders:
Common:                      allergic reaction
Metabolism and nutrition disorders:
Very common:                                                      hypophosphataemia1 hyperglycaemia,
Common: hypertriglyceridaemia
Uncommon:                                                         hypokalaemia1 Rare:                                                             lactic acidosis Psychiatric disorders:
Common:                      insomnia, abnormal dreams
Nervous system disorders:
Very common:                 headache                             dizziness Common:                      dizziness                            headache 

Frequency                          Emtricitabine                                  Tenofovir disoproxil Gastrointestinal disorders:
Very common:                       diarrhoea, nausea                              diarrhoea, vomiting, nausea elevated amylase including elevated pancreatic amylase, elevated serum             abdominal pain, abdominal Common: lipase, vomiting, abdominal pain,              distension, flatulence dyspepsia
Uncommon:                                                                         pancreatitis Hepatobiliary disorders: elevated serum aspartate aminotransferase (AST) and/or
Common:                            elevated serum alanine                         increased transaminases aminotransferase (ALT),
hyperbilirubinaemia
Rare:                                                                             hepatic steatosis, hepatitis Skin and subcutaneous tissue disorders:
Very common:                                                                      rash vesiculobullous rash,
pustular rash, maculopapular rash,
Common:                       rash, pruritus, urticaria, skin discolouration (increased pigmentation)2
Uncommon:                     angioedema3
Rare:                                                                             angioedema Musculoskeletal and connective tissue disorders:
Very common:                  elevated creatine kinase
Common                                                                            bone mineral density decreased Uncommon:                                                                         rhabdomyolysis1, muscular weakness1 osteomalacia (manifested as bone pain
Rare:                                                                             and infrequently contributing to fractures)1,3, myopathy1
Renal and urinary disorders: increased creatinine, proteinuria,
Uncommon:                                                                         proximal renal tubulopathy including Fanconi syndrome renal failure (acute and chronic), acute tubular necrosis, nephritis (including
Rare: acute interstitial nephritis)3,
nephrogenic diabetes insipidus
General disorders and administration site conditions:
Very common:                                                                      asthenia Common:                     pain, asthenia
1 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.
2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was
 administered to paediatric patients.
3 This adverse reaction was identified through post-marketing surveillance 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: As Truvada may cause renal damage monitoring of renal function is recommended (see section 4.4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some HIV-1 infected 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).

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).

Paediatric population

Truvada is not recommended in this population (see section 4.2).
Other special populations

Individuals with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any adults with renal impairment receiving Truvada (see sections 4.2, 4.4 and 5.2). The use of Truvada is not recommended in individuals under the age of 18 years with renal impairment (see sections 4.2 and 4.4).

HIV/HBV or HCV co-infected patients: The adverse reaction profile of emtricitabine and tenofovir disoproxil in a limited number of HIV-infected patients in study GS-01-934 who were co-infected with HBV (n = 13) or HCV (n = 26) 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 HBV infected patients, 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 will direct you to the online form for reporting side effects or by clicking on the link: https://sideeffects.health.gov.il.