Important Safety Information

Important Safety Information for APTIVUS

• APTIVUS/r has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation.
• APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).
• All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/r, and frequently throughout the duration of treatment.
• Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminase are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In the RESIST trials, Grade 3 and 4 increases in hepatic transaminase were observed in 10.3 percent (10.9/100 PEY) of patients receiving APTIVUS/r through week 48. In a study of treatment-naïve patients, 20.3 percent (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/r through week 48.
• APTIVUS/r is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
• The drug-drug interaction potential of APTIVUS/r when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/r use.
• APTIVUS/r is contraindicated with alfuzosin, amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, sildenafil (for the treatment of pulmonary arterial hypertension), midazolam (oral) and triazolam due to the potential for serious and/or life-threatening events or loss of efficacy.
• Concurrent administration of APTIVUS/ritonavir with salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol.
• A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of APTIVUS/r and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing’s syndrome and adrenal suppression. APTIVUS/r should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk.
• Caution should be used when prescribing sildenafil, tadalafil, and vardenafil for the treatment of erectile dysfunction to patients receiving APTIVUS/r because concentrations of these drugs may increase.
• For the treatment of PAH, only tadalafil has been studied in combination with APTIVUS/r, and dosing must be modified as described in the APTIVUS full prescribing information.
• Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations.
• Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentrations.
• Use caution when prescribing APTIVUS/r in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E.
• Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
• Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in patients receiving APTIVUS/r. In some, rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10 percent of females and in 8 percent of males receiving APTIVUS/r through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5 percent. In an uncontrolled compassionate use program (n=3,920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21 percent. Most of these patients had mild rash and 5 percent had moderate rash. Overall, 3 percent interrupted APTIVUS treatment due to rash and the discontinuation rate for rash was 0.9 percent. Discontinue and initiate appropriate treatment if severe skin rash develops.
• APTIVUS should be used with caution in patients with a known sulfonamide allergy.
• New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS/r.
• Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. A causal relationship has not been established.
• Treatment with APTIVUS/r has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during APTIVUS/r therapy.
• Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in APTIVUS/r-treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.
• APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
• Please refer to the complete ritonavir prescribing information for a description of ritonavir contraindications and additional information on precautionary measures.
• APTIVUS must be taken with meals when co-administered with the ritonavir tablet formulation.
• In adults, the most frequent adverse reactions (incidence greater than 4 percent) were diarrhea, nausea, fever, vomiting, fatigue, headache, and abdominal pain. In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric patients than in adults.
• The use of APTIVUS/r in treatment-naïve patients is not recommended.
• APTIVUS should not be used in children under 2 years of age.