EMEA public statement on Viramune (nevirapine): severe and life-threatening cutaneous and hepatic reactions
The European Medicines Evaluation Agency’s (EMEA) scientific committee, the Committee for Proprietary Medicinal Products (CPMP), has recently been made aware of additional reports of serious cutaneous and hepatic reactions, sometimes fatal, associated with Viramune  (nevirapine). This has led to a re-assessment the benefit risk profile of nevirapine.
This assessment confirmed that severe and life-threatening cutaneous (including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis) and hepatic reactions are the major clinical toxicity of nevirapine. The first 8 weeks of therapy are a critical period which therefore require a close monitoring of the patients to disclose the potential appearance of severe and life-threatening skin reactions or serious hepatitis/hepatic failure. Some of the severe cutaneous reactions were associated with risk factors such as not following the dose escalation regimen or delaying seeking medical attention when the symptoms appeared. Furthermore, most of the cases of hepatitis were reported to be within the first 8 weeks of treatment, some of them were associated with hypersensitivity reactions (such as fever, rash, arthralgia, myalgia, hypereosinophilia or acute renal failure). Following a review of the above information, the EMEA wishes to draw attention to the following:
- Concerning cutaneous reactions, the initial dosing of nevirapine of 200 mg daily and for patients 2 months up to 8 years 4 mg/kg once daily during the 14 days lead-in period must be STRICTLY adhered to.
- Patients should be intensively monitored during the first 8 weeks of treatment. Nevirapine must be permanently discontinued in patients developing a serious cutaneous reaction i.e. Stevens-Johnson syndrome, a toxic epidermal necrolysis or a severe rash accompanied by hypersensitivity reactions (characterised by rash, constitutional symptoms such as fever, myalgia and lymphadenopathy, and visceral involvement such as hepatitis, cosinophilia, granulocytopenia and renal dysfunction).
- Concerning hepatic reactions, a close liver monitoring of patients must be performed especially during the first 8 weeks of therapy (see below). Nevirapine should be stopped and never readministered in patients with ASAT or ALAT greater the 2ULN associated with hypersensitivity reactions (characterised by rash, constitutional symptoms such as fever, myalgia and lymphadenopathy, and visceral involvement such as hepatitis, cosinophilia, granulocytopenia and renal dysfunction) or hepatitis.
As an urgent measure, the prescribing and patient information has been modified through a rapid procedure at the request of the marketing authorisation holder. The EMEA thought it necessary to provide this new information to the public. The complete revised product information is available in the European Public Assessment Report of Viramune published on the EMEA Website.
Monitoring of hepatic function must be performed every two weeks during the first 2 months of treatment, at the 3rd month and then on a 3-6 monthly basis. It is also recommended that monitoring of the liver function should also be performed if the patient experiences signs or symptoms suggestive of a hepatitis and/or hypersensitivity reactions.
For further information contact: Dr Isabelle Moulon, Deputy Head of Regulatory Affairs and Pharmacovigilance, Unit of Evaluation of Medicines for Human Use Tel: +44 (0) 207 418 8443 Fax: +44 (0) 207 418 8668.
|Activity of aminotransferases||Clinical symptoms of hypersensitivity (such as fever, rash, arthralgia, myalgia, hypereosinophilia, acute renal failure)||Recommendations|
|ASAT or ALAT >5ULN||No||The treatment should be stopped immediately. When liver function test return to baseline values, it may be possible to reintroduce nevirapine on a case by case basis at the starting dose of 200 mg/day for 14 days followed by 400 mg/day. If significant liver function abnormalities rapidly recur, nevirapine must be permanently discontinued.|
|ASLT or ALAT >2ULN||No||Nevirapine can be continued provided that the patient is closely monitored|
|Yes (or signs or laboratory findings of hepatitis)||Nevirapine should be stopped AND NOT READMINISTERED|
|Unknown||Yes||Liver function testing should be performed|
This statement, including the complete revised product information for nevirapine, highlighting the changes is available in pdf format from the EMEA website.
The risks of these adverse events with nevirapine were previously known . However, particularly given that some of the serious cutaneous reactions were associated with not following the strict dose escalation regimen, or delaying seeking medical assistance, the focus on more careful monitoring, particularly during the first months of treatment is welcomed. Closer monitoring indeed is something that would probably add benefit to combinations with other agents.
The additional clinic visits required may also provide a valuable opportuity to provide simple adherence support for patients in their new treatment.
- Viramune is a non-nucleoside inhibitor of the reverse transcriptase of the HIV virus and indicated for antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV-1) infected patients with advanced or progressive immunodeficiency. The European Commission granted marketing authorisation for the European Union tro Boehringer Ingelheim International GmbH on 5 February 1988 for the medicinal product Viramune 200 mg tablets and on 18 June 1999 Viramune 50 mg/5 ml oral suspension, which contains the active substance nevirapine. Viramune 200 mg tablets is marketed in all EU Member States and Viramune 50 mg/5 ml oral suspension is marketed in Austria, France, Germany, The Netherlands and United Kingdom.