Autoimmune disorders (such as Graves' disease), have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Osteonecrosis:

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.

No clinically significant pharmacokinetic interactions are expected between enfuvirtide and concomitantly given medicinal products metabolised by CYP450 enzymes.

Influence of enfuvirtide on metabolism of concomitant medicinal products: In an in-vivo human metabolism study enfuvirtide, at the recommended dose of 90 mg twice daily, did not inhibit the metabolism of substrates by CYP3A4 (dapsone), CYP2D6 (debrisoquine), CYP1A2 (caffeine), CYP2C19 (mephenytoin), and CYP2E1 (chlorzoxazone).

Influence of concomitant medicinal products on enfuvirtide metabolism: In separate pharmacokinetic interaction studies, co-administration of ritonavir (potent CYP3A4 inhibitor) or saquinavir in combination with a booster dose of ritonavir or rifampicin (potent CYP34A inducer) did not result in clinically significant changes of the pharmacokinetics of enfuvirtide.

4.6 Fertility, pregnancy and lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women. Animal studies do not indicate harmful effects with respect to foetal development. Enfuvirtide should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding: It is not known whether enfuvirtide is secreted in human milk. Mothers should be instructed not to breast-feed if they are receiving enfuvirtide because of the potential for HIV transmission and any possible undesirable effects in breast-fed infants.

4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. There is no evidence that enfuvirtide may alter the patient's ability to drive and use machines, however, the adverse event profile of enfuvirtide should be taken into account (see section 4.8).

4.8 Undesirable effects
a. Summary of the safety profile

Safety data mainly refer to 48-week data from studies TORO 1 and TORO 2 combined (see section 5.1). Safety results are expressed as the number of patients with an adverse reaction per 100 patient-years of exposure (except for injection site reactions).

The most frequently reported events were injection site reactions, diarrhoea and nausea. The addition of Fuzeon to background antiretroviral therapy generally did not increase the freque