Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients either as the fixed-dose combination tablet Atripla (study AI266073) or as the component products (study GS-01-934). Adverse reactions were generally consistent with those seen in previous studies of the individual components. The most frequently reported adverse reactions considered possibly or probably related to Atripla among patients treated up to 48 weeks in study AI266073 were psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported.

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 also been reported. Monitoring of renal function is recommended for patients receiving Atripla (see section 4.4).

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

The administration of Atripla with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 5.2).

Tabulated list of adverse reactions

The adverse reactions from clinical study and post-marketing experience with Atripla and the individual components of Atripla in antiretroviral combination therapy are listed in Table 2 below by body system organ class, frequency and the component(s) of Atripla to which the adverse reactions are attributable. 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).

Adverse reactions associated with the use of Atripla: Treatment-emergent adverse reactions considered possibly or probably related to Atripla reported in study AI266073 (over 48 weeks; n = 203), which have not been associated with one of the individual components of Atripla, include: 
Common:         -    anorexia

Uncommon:       -    dry mouth
-    incoherent speech
-    increased appetite
-    libido decreased
-    myalgia
Table 2: Adverse reactions associated with Atripla listed by the component(s) of Atripla to which the adverse reactions are attributable

Atripla
Efavirenz              Emtricitabine        Tenofovir disoproxil
Blood and lymphatic system disorders:
Common                                            neutropenia
Uncommon                                          anaemia1
Immune system disorders:
Common                                            allergic reaction
Uncommon                 hypersensitivity
Metabolism and nutrition disorders:
Very common                                                               hypophosphataemia2 Common                   hypertriglyceridaemia3   hyperglycaemia,
hypertriglyceridaemia
Uncommon                hypercholesterolaemia3                            hypokalaemia2 Rare                                                                      lactic acidosis 

Atripla
Efavirenz                 Emtricitabine         Tenofovir disoproxil
Psychiatric disorders:
Common                    depression (severe in       abnormal dreams, 1.6%)3, anxiety3,           insomnia abnormal dreams3,
insomnia3
Uncommon                  suicide attempt3, suicide ideation3, psychosis3,
mania3, paranoia3,
hallucination3, euphoric mood3, affect lability3,
confusional state3,
aggression3, catatonia3
Rare                      completed suicide3,4,
delusion3,4, neurosis3,4
Nervous system disorders:
Very common                                           headache                 dizziness Common                    cerebellar coordination     dizziness                headache and balance disturbances3,
somnolence (2.0%)3,
headache (5.7%)3,
disturbance in attention
(3.6%)3, dizziness
(8.5%)3
Uncommon                  convulsions3, amnesia3,
thinking abnormal3,
ataxia3, coordination abnormal3, agitation3,
tremor
Eye disorders:
Uncommon                  vision blurred
Ear and labyrinth disorders:
Uncommon                  tinnitus, vertigo
Vascular disorders:
Uncommon                  flushing
Gastrointestinal disorders:
Very common                                           diarrhoea, nausea        diarrhoea, vomiting, nausea
Common                    diarrhoea, vomiting,        elevated amylase         abdominal pain, abdominal pain, nausea      including elevated       abdominal distension, pancreatic amylase,      flatulence elevated serum lipase,
vomiting, abdominal pain, dyspepsia
Uncommon                 pancreatitis                                          pancreatitis Hepatobiliary disorders:
Common                   elevated aspartate           elevated serum AST       increased transaminases aminotransferase (AST),      and/or elevated serum elevated alanine             ALT,
aminotransferase (ALT),      hyperbilirubinaemia elevated gamma- glutamyltransferase
(GGT)
Uncommon                 hepatitis acute
Rare                     hepatic failure3,4                                    hepatic steatosis, hepatitis


Atripla
Efavirenz                        Emtricitabine              Tenofovir disoproxil Skin and subcutaneous tissue disorders:
Very common              rash (moderate-severe,                                           rash 11.6%, all grades, 18%)3
Common                   pruritus                          vesiculobullous rash, pustular rash,
maculopapular rash,
rash, pruritus, urticaria,
skin discolouration
(increased pigmentation)1
Uncommon                Stevens-Johnson                    angioedema4 syndrome, erythema multiforme3, severe rash
(< 1%)
Rare                    photoallergic dermatitis                                          angioedema Musculoskeletal and connective tissue disorders:
Very common                                                elevated creatine kinase Uncommon                                                                                  rhabdomyolysis2, muscular weakness2
Rare                                                                                      osteomalacia (manifested as bone pain and infrequently contributing to fractures)2,4,
myopathy2
Renal and urinary disorders:
Uncommon                                                                                  increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome
Rare                                                                                      renal failure (acute and chronic), acute tubular necrosis, nephritis
(including acute interstitial nephritis)4,
nephrogenic diabetes insipidus
Reproductive system and breast disorders:
Uncommon                gynaecomastia
General disorders and administration site conditions:
Very common                                                                               asthenia Common                  fatigue                      pain, asthenia
1    Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.
2    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.
3    See section 4.8 Description of selected adverse reactions for more details.
4    This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients treated with efavirenz in clinical trials (n = 3,969) or exposed to emtricitabine in randomised controlled clinical trials (n = 1,563) or exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access programme (n = 7,319).

Description of selected adverse reactions

Rash: In clinical trials of efavirenz, rashes were usually mild-to-moderate maculopapular skin eruptions that occurred within the first two weeks of initiating therapy with efavirenz. In most patients rash resolved with continuing therapy with efavirenz within one month. Atripla can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Atripla is restarted.
Psychiatric symptoms: Patients with a history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions listed in the efavirenz column of Table 2.

Nervous system symptoms: Nervous system symptoms are common with efavirenz, one of the components of Atripla. In clinical controlled studies of efavirenz, nervous system symptoms of moderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2% of patients discontinued therapy due to such symptoms. They usually begin during the first one or two days of efavirenz therapy and generally resolve after the first two to four weeks. They may occur more frequently when Atripla is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms (see section 4.2).

Hepatic failure with efavirenz: Hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, as reported post-marketing, were sometimes characterised by a fulminant course, progressing in some cases to transplantation or death.

Renal impairment: As Atripla 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 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 severe hepatic impairment (CPT, Class C) (see section 4.3), 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 populations
Elderly: Atripla has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased hepatic or renal function, therefore caution should be exercised when treating elderly patients with Atripla (see section 4.2).

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


HIV/HBV or HCV co-infected patients: Only a limited number of patients were co-infected with HBV (n = 13) or HCV (n = 26) in study GS-01-934. The adverse reaction profile of efavirenz, emtricitabine 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 may occur 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.

You can also report any side effects directly to the registration holder via email: (DrugSafety.Israel@gilead.com).