4.4 Special warnings and precautions for use
Fuzeon must be taken as part of a combination regimen. Please also refer to the respective summary of product characteristics of the other antiretroviral medicinal products used in the combination. As with other antiretrovirals, enfuvirtide should optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section 5.1).

Patients should be informed that Fuzeon is not a cure for HIV-1 infection. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Animal studies have shown that enfuvirtide may impair some immune functions (see section 5.3). In clinical trials, an increased rate of some bacterial infections, most notably a higher rate of pneumonia, was seen in patients treated with Fuzeon; however, an increased risk of bacterial pneumonia related to the use of Fuzeon has not been confirmed by subsequent epidemiological data.

Hypersensitivity reactions have occasionally been associated with therapy with enfuvirtide and in rare cases hypersensitivity reactions have recurred on rechallenge. Events included rash, fever, nausea and vomiting, chills, rigors, low blood pressure and elevated serum liver transaminases in various combinations, and possibly primary immune complex reaction, respiratory distress and glomerulonephritis. Patients developing signs/symptoms of a systemic hypersensitivity reaction should discontinue enfuvirtide treatment and should seek medical eva luation immediately. Therapy with enfuvirtide should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction considered related to enfuvirtide. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified.

Liver disease: The safety and efficacy of enfuvirtide has not been specifically studied in patients with significant underlying liver disorders. Patients with chronic hepatitis B and C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. Few patients included in the phase III trials were co-infected with hepatitis B/C. In these the addition of Fuzeon did not increase the incidence of hepatic events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Administration of Fuzeon to non-HIV-1 infected individuals may induce anti-enfuvirtide antibodies that cross-react with HIV gp41. This may result in a false positive HIV test with the anti-HIV ELISA test.

There is no experience in patients with reduced hepatic function. Data is limited in patients with moderate to severe renal impairment, and in patients maintained on dialysis. Fuzeon should be used with caution in these populations (see sections 4.2 and 5.2).

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically