Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 30 November 2017
Indication(s)
Related Content
Advisory information
contraindications
4 CONTRAINDICATIONS Patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (4.1, 5.1) Use with drugs highly dependent on CYP 3A for clearance or are potent CYP 3A inducers (4.2, 5.3, 7) 4.1 Hepatic Impairment APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Warnings and Precautions (5.1) ]. 4.2 Drug Interactions Co-administration of APTIVUS/ritonavir with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers are contraindicated (see Table 1). These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. For information regarding clinical recommendations [ see Drug Interactions (7.2) ]. Table 1 Drugs that are Contraindicated with APTIVUS Co-Administered with Ritonavir Drug Class Drugs within Class that are Contraindicated with APTIVUS Co-administered with Ritonavir Clinical Comments: Alpha 1-adrenoreceptor antagonist Alfuzosin Potentially increased alfuzosin concentrations can result in hypotension. Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics. Antimycobacterials Rifampin May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors or other co-administered antiretroviral agents. Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent Cisapride Potential for cardiac arrhythmias. Herbal products St. John's wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors. HMG CoA reductase inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis. Antipsychotics Pimozide Lurasidone Potential for cardiac arrhythmias. Potential for serious and/or life-threatening reactions. PDE-5 inhibitors Sildenafil (Revatio) [for treatment of pulmonary arterial hypertension] A safe and effective dose has not been established when used with APTIVUS/ritonavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Sedatives/hypnotics Oral midazolam, triazolam Prolonged or increased sedation or respiratory depression. Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications.
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are described, in greater detail, in other sections: Hepatic Impairment and Toxicity [ see Warnings and Precautions (5.1) ] Intracranial Hemorrhage [ see Warnings and Precautions (5.2) ] Rash [ see Warnings and Precautions (5.6) ] Due to the need for co-administration of APTIVUS with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In adults the most frequent adverse reactions (incidence >4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain (6.1) 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. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials in Adults APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks [ see Clinical Studies (14) ]. In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated patients and 10.8% for the comparator arm patients. Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 - 4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below. Table 2 Adverse Reactions Reported in Randomized, Controlled Clinical Trials (1182.12 and 1182.48) Based on Treatment-Emergent Clinical Adverse Reactions of Moderate to Severe Intensity (Grades 2 - 4) in at least 2% of Treatment-Experienced Subjects in either Treatment Groupa (48-week Analyses) Percentage of patients (rate per 100 patient-exposure years) APTIVUS/ritonavir (500/200 mg BID) + OBRc (n=749; 757.4 patient-exposure years) Comparator PI/ritonavirb + OBR (n=737; 503.9 patient-exposure years) a Excludes laboratory abnormalities that were Adverse Events b Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID c Optimized Background Regimen Blood and Lymphatic Disorders Anemia 3.3% (3.4) 2.3% (3.4) Neutropenia 2.0% (2.0) 1.0% (1.4) Gastrointestinal Disorders Diarrhea 15.0% (16.5) 13.4% (21.6) Nausea 8.5% (9.0) 6.4% (9.7) Vomiting 5.9% (6.0) 4.1% (6.1) Abdominal pain 4.4% (4.5) 3.4% (5.1) Abdominal pain upper 1.5% (1.5) 2.3% (3.4) General Disorders Pyrexia 7.5% (7.7) 5.4% (8.2) Fatigue 5.7% (5.9) 5.6% (8.4) Investigations Weight decreased 3.1% (3.1) 2.2% (3.2) ALT increased 2.0% (2.0) 0.5% (0.8) GGT increased 2.0% (2.0) 0.4% (0.6) Metabolism and Nutrition Disorders Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0) Hyperlipidemia 2.5% (2.6) 0.8% (1.2) Dehydration 2.1% (2.1) 1.1% (1.6) Musculoskeletal and Connective Tissue Disorders Myalgia 2.3% (2.3) 1.8% (2.6) Nervous System Disorders Headache 5.2% (5.3) 4.2% (6.3) Peripheral neuropathy 1.5% (1.5) 2.0% (3.0) Psychiatric Disorders Insomnia 1.7% (1.7) 3.7% (5.5) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 2.1% (2.1) 1.0% (1.4) Skin and Subcutaneous Tissue Disorders Rash 3.1% (3.1) 3.8% (5.7) Less Common Adverse Reactions Other adverse reactions reported in <2% of adult patients (n=1474) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system: Blood and Lymphatic System Disorders : thrombocytopenia Gastrointestinal Disorders : abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis General Disorders : influenza-like illness, malaise Hepatobiliary Disorders : hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis Immune System Disorders : hypersensitivity Investigations : hepatic enzymes increased, liver function test abnormal, lipase increased Metabolism and Nutrition Disorders : anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity Musculoskeletal and Connective Tissue Disorders : muscle cramp Nervous System Disorders : dizziness, intracranial hemorrhage, somnolence Psychiatric Disorders : sleep disorder Renal and Urinary Disorders : renal insufficiency Skin and Subcutaneous System Disorders : exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus Laboratory Abnormalities Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below. Table 3 Treatment-Emergent Laboratory Abnormalities Reported in ≥2% of Adult Patients (48-week Analyses) Randomized, Controlled Clinical Trials 1182.12 and 1182.48 Percentage of Patients (rate per 100 patient-exposure years) Limit APTIVUS/ritonavir (500/200 mg BID) + OBR (n=738) Comparator PI/ritonavir + OBR* (n=724) *Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID Hematology WBC count decrease Grade 3 <2.0 x 103/μL 5.4% (5.6) 4.8% (7.7) Grade 4 <1.0 x 103/μL 0.3% (0.3) 1.1% (1.7) Chemistry Amylase Grade 3 >2.5 x ULN 5.7% (5.9) 6.4% (10.4) Grade 4 >5 x ULN 0.3% (0.3) 0.7% (1.1) ALT Grade 2 >2.5-5 x ULN 14.9% (16.5) 7.5% (12.4) Grade 3 >5-10 x ULN 5.6% (5.7) 1.7% (2.6) Grade 4 >10 x ULN 4.1% (4.1) 0.4% (0.7) AST Grade 2 >2.5-5 x ULN 9.9% (10.5) 8.0% (13.3) Grade 3 >5-10 x ULN 4.5% (4.6) 1.4% (2.2) Grade 4 >10 x ULN 1.6% (1.6) 0.4% (0.6) ALT and/or AST Grade 2-4 >2.5 x ULN 26.0% (31.5) 13.7% (23.8) Cholesterol Grade 2 >300 – 400 mg/dL 15.6% (17.7) 6.4% (10.5) Grade 3 >400 – 500 mg/dL 3.3% (3.3) 0.3% (0.4) Grade 4 >500 mg/dL 0.9% (1.0) 0.1% (0.2) Triglycerides Grade 2 400 – 750 mg/dL 35.9% (49.9) 26.8% (51.0) Grade 3 >750 – 1200 mg/dL 16.9% (19.4) 8.7% (14.6) Grade 4 >1200 mg/dL 8.0% (8.4) 4.3% (7.0) In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 32.1% at week 96 with APTIVUS/ritonavir. The risk of developing transaminase elevations is greater during the first year of therapy. 6.2 Clinical Trials in Pediatric Patients APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs. The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults. The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%). Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of >1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction.
Usage information
Dosing and administration
2 DOSAGE AND ADMINISTRATION APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals APTIVUS co-administered with ritonavir tablets must only be taken with meals [see Clinical Pharmacology (12.3) ] APTIVUS may be administered as either capsules or oral solution to either pediatric or adult patients. Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information. Adults: 500 mg APTIVUS, co-administered with 200 mg ritonavir, twice daily (2.1) Pediatric patients (age 2 to 18 years): Dosing is based on body weight or body surface area not to exceed adult dose (2.2) APTIVUS taken with ritonavir capsules or solution can be taken with or without meals (2) APTIVUS taken with ritonavir tablets must be taken with meals (2) Store unopened bottles of APTIVUS capsules in the refrigerator (16) Do not freeze or refrigerate APTIVUS oral solution (16) 2.1 Adults The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily. 2.2 Pediatric Patients (age 2 to 18 years) Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose. Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose. Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed. The recommended pediatric dose of APTIVUS is 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed a maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir (or APTIVUS 290 mg/m2 co-administered with 115 mg/m2 ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors [ see Adverse Reactions (6.2), Use in Specific Populations (8.4), and Clinical Studies (14.2) ]. Body surface area can be calculated as follows: aptivus-formula
Use in special populations
8 USE IN SPECIFIC POPULATIONS The risk-benefit has not been established in pediatric patients <2 years of age (8.4) 8.1 Pregnancy Teratogenic Effects, Pregnancy Category C. Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats. No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 μM·h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 μM/340 μM·h and 8.4 μM/120 μM·h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to APTIVUS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263. 8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breast-feed if they are receiving APTIVUS. 8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years [ see Adverse Reactions (6.2) and Clinical Studies (14.2) ]. The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults [ see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ]. The risk-benefit has not been established in pediatric patients <2 years of age. 8.5 Geriatric Use Clinical studies of APTIVUS/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild (Child-Pugh Class A) hepatic impairment because tipranavir concentrations may be increased [ see Clinical Pharmacology (12.3) ]. APTIVUS/ritonavir is contraindicated in patients with moderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepatic impairment [ see Contraindications (4.1) ].
Pregnancy and lactation
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breast-feed if they are receiving APTIVUS.
Interactions
More information
Category | Value |
---|---|
Authorisation number | NDA022292 |
Agency product number | ZZT404XD09 |
Orphan designation | No |
Product NDC | 0597-0003,0597-0002 |
Date Last Revised | 21-09-2016 |
Type | HUMAN PRESCRIPTION DRUG |
RXCUI | 577212 |
Storage and handling | Storage APTIVUS capsules should be stored in a refrigerator 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days after first opening the bottle. APTIVUS oral solution should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze . The solution must be used within 60 days after first opening the bottle. Store in a safe place out of the reach of children. |
Marketing authorisation holder | Boehringer Ingelheim Pharmaceuticals, Inc. |
Warnings | WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE Hepatotoxicity: Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity [ see Warnings and Precautions (5.1) ]. Intracranial Hemorrhage: Both fatal and non-fatal intracranial hemorrhage have been reported [ see Warnings and Precautions (5.2) ]. WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE See full prescribing information for complete boxed warning. Clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection. (5.1) Fatal and non-fatal intracranial hemorrhage (5.2) |