ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT INVIRASE 200 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One capsule of Invirase contains saquinavir mesylate corresponding to 200 mg saquinavir. For excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Invirase is indicated for the treatment of HIV-1 infected adult patients. Invirase should only be given in combination with ritonavir and other antiretroviral medicinal products (see section 4.2). 4.2 Posology and method of administration Therapy with Invirase should be initiated by a physician experienced in the management of HIV infection. Adults and adolescents over the age of 16 years In combination with ritonavir The recommended dose of Invirase is 1000 mg (5 x 200 mg capsules) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. Invirase capsules should be swallowed whole and taken at the same time as ritonavir within 2 hours following a meal (see section 5.2). In combination with other protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors Dose reduction may be required when Invirase/ritonavir is administered with some other HIV protease inhibitors (e.g. nelfinavir, indinavir and delavirdine), since these drugs may increase saquinavir plasma levels (see section 4.5). Renal and hepatic impairment No dosage adjustment is necessary for patients with mild to moderate renal or mild hepatic impairment. Caution should be exercised in patients with severe renal or moderate hepatic impairment. Invirase/ritonavir is contraindicated in patients with severe hepatic impairment. (see sections 4.3 and 4.4) Paediatric and elderly patients There is only limited information on the safety and efficacy of saquinavir in HIV infected patients younger than 16 years and in adults over 60 years. Due to the significantly lower saquinavir plasma levels in children compared to adults, Invirase should not be used as the sole PI in children (see section 4.4). For further information on special patient groups, refer to section 4.4, and for pharmacokinetic interactions see sections 4.5. and 5.2. 2 4.3 Contraindications Invirase/ritonavir is contraindicated in patients with hypersensitivity to saquinavir, ritonavir or any of the excipients contained in the capsules. Invirase/ritonavir should not be given together with other drugs which may interact and result in potentially life threatening side effects. Drugs which should not be given with Invirase/ritonavir include terfenadine, astemizole, pimozide, cisapride, amiodarone, propafenone and flecainide (potential for life threatening cardiac arrhythmia), midazolam, triazolam (potential for prolonged or increased sedation, respiratory depression), simvastatin, lovastatin (increased risk of myopathy including rhabdomyolysis) and ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine) (potential for acute ergot toxicity) (see section 4.5). Invirase/ritonavir is contraindicated in patients with severe hepatic impairment (see section 4.4). 4.4 Special warnings and special precautions for use Considerations when initiating Invirase therapy: Invirase should not be given as the sole protease inhibitor. Invirase should only be given in combination with ritonavir (see section 4.2). Patients should be informed that saquinavir is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. Patients should also be advised that they might experience undesirable effects associated with co- administered medications. Liver disease: The safety and efficacy of saquinavir has not been established in patients with significant underlying liver disorders. Invirase/ritonavir is contraindicated in patients with severe hepatic impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. In cases of mild hepatic impairment no initial dosage adjustment is necessary at the recommended dose. The use of Invirase in combination with ritonavir in patients with moderate hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur. There have been reports of exacerbation of chronic liver dysfunction, including portal hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver abnormalities. Renal impairment: Renal clearance is only a minor elimination pathway, the principal route of metabolism and excretion for saquinavir being via the liver. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied and caution should be exercised when prescribing saquinavir in this population. Patients with chronic diarrhoea or malabsorption: Only limited information on the safety and efficacy of saquinavir is available for patients suffering from chronic diarrhoea or malabsorption. It is unknown whether patients with such conditions could receive subtherapeutic drug levels. Young and elderly patients: The safety and efficacy of saquinavir in HIV-infected patients younger than 16 years have not been established. Limited information is available in children treated with Fortovase and none for children treated with Invirase as the sole protease inhibitor. Due to the 3 significantly lower saquinavir plasma levels in children compared with adults, neither Invirase nor Fortovase should be used as the sole protease inhibitor in children. When Fortovase (50 mg/kg bid) is co-administered with nelfinavir or ritonavir in children, saquinavir exposures are greatly increased and, when combined with ritonavir, may provide saquinavir exposures up to 2-fold greater than those achieved with Fortovase 1200 mg tid in adults. Only limited experience is available in patients older than 60 years. Lactose intolerance: Invirase 200 mg capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Use during pregnancy and lactation: See section 4.6. Patients with haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Diabetes mellitus and hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these patients, the hyperglycaemia was severe and in some cases was also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia. Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8.). Interaction with ritonavir: The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 100 mg ritonavir bid. Higher doses of ritonavir have been shown to be associated with an increased incidence of adverse events. Co-administration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease. Interaction with HMG-CoA reductase inhibitors: Caution must be exercised if Invirase/ritonavir is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this situation a reduced dose of atorvastatin should