Aptivus

Aptivus must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with Aptivus (especially as regards the contraindications, warnings and undesirable effects sections).

Aptivus should be prescribed by physicians who are experienced in the treatment of HIV-1 infection. 4 for precautionary measures in adolescents). 3 Body surface area (BSA) can be calculated as follows: Mosteller Formula: 𝐵𝑆𝐴 (𝑚²) = √𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚) × 𝑊𝑡 (𝑘𝑔) 3600 Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy profile of the combination.

1) close monitoring of virologic response and tolerance is particularly warranted in this patient group. Missed dose Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time.

If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time. 2). 4). Liver impairment Tipranavir is metabolised by the hepatic system.

Liver impairment could therefore result in an increase of tipranavir exposure and a worsening of its safety profile. Therefore, Aptivus should be used with caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child- Pugh Class A).

2). 2). Paediatric population The safety and efficacy of Aptivus capsules in children has not been established below 12 years of age. 2 but no recommendation on a posology can be made. Also, appropriate dose adjustments for children under 12 years cannot be achieved with Aptivus capsules.

Aptivus capsules should not be used in paediatric patients less than 12 years of age as there are no clinical data supporting the use of capsules in this paediatric subset. Method of administration Oral use. 2). Aptivus soft capsules must be swallowed whole and must not be opened or chewed.

Summary of the safety profile Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include hepatic impairment and liver toxicity.

4). Aptivus co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the tipranavir with ritonavir arm compared to the comparator arm.

4). Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Aptivus should therefore be used with caution in patients co-infected with hepatitis B or C.

Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring. Tabulated summary of adverse reactions Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n = 1 397) and are listed below by system organ class and frequency according to the following categories: 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) 25 Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post- marketing experience: Blood and lymphatic system disorders uncommon neutropenia, anaemia, thrombocytopenia Immune system disorders uncommon hypersensitivity Metabolism and nutrition disorders common hypertriglyceridaemia, hyperlipidaemia uncommon anorexia, decreased appetite, weight decreased, hyperamylasaemia, hypercholesterolaemia, diabetes mellitus, hyperglycaemia rare dehydration Psychiatric disorders uncommon insomnia, sleep disorder Nervous system disorders common headache uncommon dizziness, neuropathy peripheral, somnolence rare intracranial haemorrhage* Respiratory, thoracic and mediastinal disorders uncommon dyspnoea Gastrointestinal disorders very common diarrhoea, nausea common vomiting, flatulence, abdominal pain, abdominal distension, dyspepsia uncommon gastrooesophageal reflux disease, pancreatitis rare lipase increased Hepatobiliary disorders uncommon hepatic enzyme increased (ALAT, ASAT), cytolytic hepatitis, liver function test abnormal (ALAT, ASAT), hepatitis toxic rare hepatic failure (including fatal outcome), hepatitis, hepatic steatosis, hyperbilirubinaemia Skin and subcutaneous tissue disorders common rash uncommon pruritus, exanthem Musculoskeletal and connective tissue disorders uncommon myalgia, muscle spasms Renal and urinary disorders uncommon renal failure General disorders and administration site conditions common fatigue uncommon pyrexia, influenza like illness, malaise * see section Description of selected adverse reactions “Bleeding” for source of information Description of selected adverse reactions The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with ritonavir administration.

2). Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly. Aptivus is not a cure for HIV-1 infection or AIDS.

Patients receiving Aptivus or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection. Liver disease Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic insufficiency.

Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. 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 reaction.

Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination therapy and should be monitored according to standard practice.

Aptivus with ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease. Aptivus co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities.

These have generally occurred in patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised when administering Aptivus to patients with liver enzyme abnormalities or with a history of hepatitis.

1. Patients with moderate or severe (Child-Pugh B or C) hepatic impairment. 5). 5). Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

5). Also the use of the alpha-1 adrenoceptor antagonist alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. 5). 5).