Adverse reactions : תופעות לוואי

4.8       Undesirable effects
Summary of the safety profile
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The most frequently reported adverse reactions related to Viramune therapy, across all clinical studies, were rash, allergic reactions, hepatitis, abnormal liver function tests, nausea, vomiting, diarrhoea, abdominal pain, fatigue, fever, headache, and myalgia.

The postmarketing experience has shown that the most serious adverse reactions are Stevens-Johnson syndrome/ toxic epidermal necrolysis, serious hepatitis/hepatic failure and drug reaction with eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction. The first 18 weeks of treatment is a critical period which requires close monitoring (see section 4.4).


Tabulated summary of adverse reactions
The following adverse reactions which may be causally related to the administration of Viramune have been reported. The frequencies estimated are based on pooled clinical study data for adverse reactions considered related to Viramune treatment.

Frequency is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Blood and lymphatic system disorders
Common                granulocytopenia
Uncommon              anaemia

Immune system disorders
Common              hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria) Uncommon            anaphylactic reaction
Rare:               drug reaction with eosinophilia and systemic symptoms, 

Nervous system disorders
Common               headache
Gastrointestinal disorders
Common                 nausea, vomiting, abdominal pain, diarrhoea.

Hepatobiliary disorders
Common                hepatitis (including severe and life-threatening hepatotoxicity) (1.9%) Uncommon              jaundice
Rare                  hepatitis fulminant (which may be fatal)


Skin and subcutaneous tissue disorders
Very common rash (12.5%)
Uncommon      Stevens-Johnson syndrome/toxic epidermal necrolysis (which may be fatal) (0.2%) , angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon              arthralgia, myalgia.

General disorders and administration site conditions
Common                pyrexia, fatigue
Investigations
Common             liver function test abnormal (alanine aminotransferase increased; transaminases increased; aspartate aminotransferase increased; gamma-glutamyltransferase increased; hepatic enzyme increased; hypertransaminasaemia)

Uncommon           blood phosphorus decreased; blood pressure increased 
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Description of selected adverse reactions
In study 1100.1090, from which the majority of related adverse events (n=28) were received, patients on placebo had a higher incidence of events of granulocytopenia (3.3%) than patients on nevirapine (2.5%).

Anaphylactic reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical studies. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to nevirapine in randomised controlled clinical studies (n= 2,718).

Decreased blood phosphorus and increased blood pressure were observed in clinical studies with co- administration of tenofovir/emtricitabine.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

The following adverse reactions have also been reported when nevirapine has been used in combination with other anti-retroviral agents: pancreatitis, peripheral neuropathy and thrombocytopaenia. These adverse reactions are commonly associated with other antiretroviral agents and may be expected to occur when nevirapine is used in combination with other agents; however it is unlikely that these adverse reactions are due to nevirapine treatment. Hepatic-renal failure syndromes have been reported rarely.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (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).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Skin and subcutaneous tissues
The most common clinical toxicity of nevirapine is rash, with Viramune attributable rash occurring in 12.5% of patients in combination regimens in controlled studies.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Hypersensitivity (anaphylactic reaction, angioedema and urticaria) have been reported. Rashes occur alone or in the context of drug reaction with eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lympadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction.

Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS, TEN and drug reaction with eosinophilia and systemic symptoms have been reported. The majority of severe rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with one patient requiring surgical intervention (see section 4.4).

Hepato-biliary

The most frequently observed laboratory test abnormalities are elevations in liver function tests (LFTs), including ALAT, ASAT, GGT, total bilirubin and alkaline phosphatase. Asymptomatic elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of hepatitis (severe and life-threatening hepatoxicity, including fatal fulminant hepatitis) have been reported in patients treated with nevirapine. The best predictor of a serious hepatic event was elevated baseline liver function tests. The first 18 weeks of treatment is a critical period which requires close monitoring (see section 4.4).

Paediatric population
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Based on clinical study experience of 361 paediatric patients the majority of which received combination treatment with ZDV or/and ddI , the most frequently reported adverse events related to nevirapine were similar to those observed in adults. Granulocytopenia was more frequently observed in children. In an open-label clinical study (ACTG 180) granulocytopenia assessed as medicinal product related occurred in 5/37 (13.5%) of patients.
In ACTG 245, a double-blind placebo controlled study, the frequency of serious medicinal product-related granulocytopenia was 5/305 (1.6%). Isolated cases of Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome have been reported in this population.

Reporting of suspected adverse reactions
You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of Drug Treatment' on the Ministry of Health home page (www.health.gov.il) which links to an online form for reporting side effects. You can also use this link: https://sideeffects.health.gov.il