Aptivus

1 INDICATIONS AND USAGE APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adults and pediatric patients weighing 36 kg or higher who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI) . This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy. The following points should be considered when initiating therapy with APTIVUS/ritonavir: The use of APTIVUS/ritonavir in treatment-naïve patients is not recommended . The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response . Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir . The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir . Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment . Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment . The drug-drug interaction potential of APTIVUS/ritonavir when co-administered with other drugs must be considered prior to and during APTIVUS/ritonavir use . Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding . There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.

APTIVUS, a protease inhibitor, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult and pediatric patients weighing 36 kg or higher who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor Do not use APTIVUS/ritonavir in treatment-naïve patients

Adults: 500 mg APTIVUS, co-administered with 200 mg ritonavir, twice daily Pediatric patients (weighing 36 kg or higher): 500 mg APTIVUS, co-administered with 200 mg ritonavir twice daily. APTIVUS taken with ritonavir tablets must be taken with meals APTIVUS capsules must be swallowed whole and must not be opened or chewed Children should be assessed for their ability to swallow capsules before prescribing APTIVUS capsules. Store unopened bottles of APTIVUS capsules in the refrigerator.

2.1Dosage and Administration Overview

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 . Children should be assessed for their ability to swallow capsules before prescribing APTIVUS capsules . APTIVUS co-administered with ritonavir tablets must only be taken with meals . APTIVUS is supplied as capsules. APTIVUS capsules must be swallowed whole and must not be opened or chewed.

Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information.

2.2Recommended Dosage in Adults and Pediatric Patients

Weighing 36 kg or Higher The recommended dosage in adults and pediatric patients weighing 36 kg or higher is 500 mg (two 250 mg capsules) of APTIVUS co-administered with 200 mg of ritonavir, twice daily.

Co-administration with Ritonavir: APTIVUS must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer APTIVUS with ritonavir and food may result in a loss of efficacy of tipranavir. Hepatic Impairment: Discontinue for signs and symptoms of clinical hepatitis or asymptomatic increases in ALT/AST >10 times ULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitant increases in total bilirubin. Monitor liver function tests prior to therapy and frequently thereafter. Intracranial Hemorrhage/Platelet Aggregation and Coagulation: Use with caution in patients at risk for increased bleeding or who are receiving medications that increase the risk of bleeding. ( 5.3 , 5.5 ) The concomitant use of APTIVUS/ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.4 , 7.2 ) Rash: Discontinue and initiate appropriate treatment if severe skin reaction occurs or is suspected. Use with caution in patients with a known sulfonamide allergy. Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia, immune reconstitution syndrome, redistribution/accumulation of body fat, and elevated lipids. Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.

5.1Importance of Co-administration with Ritonavir

APTIVUS must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer APTIVUS with ritonavir and food may result in a loss of efficacy of tipranavir. Please refer to the ritonavir prescribing information for additional information on precautionary measures.

5.2Hepatic Impairment and Toxicity Clinical

hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS co-administered with 200 mg of ritonavir. These have generally occurred in subjects with advanced HIV-1 disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established.

Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. 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/ritonavir, and frequently throughout the duration of treatment. If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. If asymptomatic elevations in AST or ALT between 5 – 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued.

Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced subjects, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48. In a study of treatment-naïve subjects, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir 500 mg/200 mg through week 48.

Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased .

5.3Intracranial Hemorrhage APTIVUS,

co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these subjects had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in subjects in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.

5.4Risk of Serious Adverse Reactions Due

to Drug Interactions Initiation of APTIVUS/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving APTIVUS/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of APTIVUS/ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of APTIVUS/ritonavir.

Loss of therapeutic effect of APTIVUS/ritonavir and possible development of resistance. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . Consider the potential for drug interactions prior to and during APTIVUS/ritonavir therapy; review concomitant medications during APTIVUS/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications .

5.5Effects on Platelet Aggregation and Coagulation APTIVUS/ritonavir

should be used with caution 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. In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects . However, analyses of stored plasma from adult and pediatric subjects treated with APTIVUS capsules plus low-dose ritonavir showed no effect of APTIVUS/ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times. In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in subjects receiving APTIVUS/ritonavir.

5.6Rash Rash,

including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in subjects receiving APTIVUS/ritonavir. In some cases rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled adult clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavir 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%. In an uncontrolled compassionate use program (n=3920), 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%. Overall, most of the pediatric subjects had mild rash and 5 (5%) had moderate rash.

Overall 3% of pediatric subjects interrupted APTIVUS treatment due to rash and the discontinuation rate for rash in pediatric subjects was 0.9%. Discontinue and initiate appropriate treatment if severe skin rash develops.

5.7Sulfa Allergy

APTIVUS should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and APTIVUS is unknown.

5.8Diabetes Mellitus/Hyperglycemia New

onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.

In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

5.9Immune Reconstitution Syndrome Immune

reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.10Fat Redistribution Redistribution/accumulation of

body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.11Elevated Lipids Treatment with

APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides . Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate; taking into account any potential drug-drug interactions .

5.12Patients with Hemophilia There

have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued.

A causal relationship between protease inhibitors and these events has not been established.

5.13Resistance/Cross Resistance Because the

potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in APTIVUS/ritonavir treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.

4 CONTRAINDICATIONS APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment . APTIVUS/ritonavir is contraindicated when co-administered with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers . 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 Potential for cardiac arrhythmias.

Lurasidone 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. Patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment ( 4 , 5.2 ) Use with drugs highly dependent on CYP3A for clearance or are potent CYP3A inducers ( 4 , 5.4 , 7 )

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTIVUS during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Prospective pregnancy data from the APR and an Expanded Access program are not sufficient to adequately assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Tipranavir use during pregnancy has been evaluated in a limited number of women as reported by the APR and an Expanded Access program, and available data show no birth defects in 13 first trimester exposures compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group.

The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In animal reproduction studies, fetal toxicities were observed with tipranavir at maternally toxic doses with systemic exposures (AUC) less than those in humans at the recommended human dose (RHD) . Data Human Data Based on prospective reports to the APR and an Expanded Access program for approximately 17 live births following exposure to tipranavir-containing regimens (including 13 live births exposed in the first trimester and 4 live births exposed in the second/third trimester), there were no birth defects reported in live-born infants. Tipranavir has been shown to cross the placenta.

Animal Data Tipranavir was administered orally to pregnant rats (at 0, 40, 400, or 1000 mg/kg/day from gestation day 6 to 17) and rabbits (at 0, 75, 150, or 375 mg/kg/day from gestation day 6 to 20). In rats, fetal toxicities including decreased body weight and sternebrae ossification occurred at maternally toxic doses (≥400 mg/kg/day) (approximately 0.8 times human exposure at the RHD). In rabbits, fetal toxicities including decreased fetal body weights, wavy ribs, and bent femurs occurred at a maternally toxic dose (375 mg/kg/day) (approximately 0.05 times human exposure at the RHD).

Maternal toxicity included an increased incidence of abortions at doses ≥150 mg/kg/day (approximately 0.05 times human exposure at the RHD). In the pre/post-natal development study, tipranavir was administered orally to rats at 0, 40, 400, 1000 mg/kg/day from gestation day 6 to lactation day 21. The only significant effect observed was growth inhibition of the offspring at maternally toxic doses (≥400 mg/kg/day) (approximately 0.8 times human exposure at the RHD).

The following adverse reactions are described, in greater detail, in other sections: Hepatic Impairment and Toxicity Intracranial Hemorrhage Rash 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. In pediatric subjects the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric subjects than in adults. To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 subjects received the dose of 500 mg/200 mg BID. Nine hundred nine adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks . 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 subjects and 10.8% for the comparator arm subjects.

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 Group a (48-week Analyses) Percentage of patients (rate per 100 patient-exposure years) APTIVUS/ritonavir (500/200 mg BID) + OBR c (n=749; 757.4 patient-exposure years) Comparator PI/ritonavir b + 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% 2.3% Neutropenia 2.0% 1.0% Gastrointestinal Disorders Diarrhea 15.0% 13.4% Nausea 8.5% 6.4% Vomiting 5.9% 4.1% Abdominal pain 4.4% 3.4% Abdominal pain upper 1.5% 2.3% General Disorders Pyrexia 7.5% 5.4% Fatigue 5.7% 5.6% Investigations Weight decreased 3.1% 2.2% ALT increased 2.0% 0.5% GGT increased 2.0% 0.4% Metabolism and Nutrition Disorders Hypertriglyceridemia 3.9% 2.0% Hyperlipidemia 2.5% 0.8% Dehydration 2.1% 1.1% Musculoskeletal and Connective Tissue Disorders Myalgia 2.3% 1.8% Nervous System Disorders Headache 5.2% 4.2% Peripheral neuropathy 1.5% 2.0% Psychiatric Disorders Insomnia 1.7% 3.7% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 2.1% 1.0% Skin and Subcutaneous Tissue Disorders Rash 3.1% 3.8% Less Common Adverse Reactions Other adverse reactions reported in <2% of adult subjects (n=1474) treated with APTIVUS/ritonavir 500 mg/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

1182.48Percentage 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 × 10 3 /µL 5.4% 4.8% Grade 4 <1.0 × 10 3 /µL 0.3% 1.1% Chemistry Amylase Grade 3 >2.5 × ULN 5.7% 6.4% Grade 4 >5 × ULN 0.3% 0.7% ALT Grade 2 >2.5-5 × ULN 14.9% 7.5% Grade 3 >5-10 × ULN 5.6% 1.7% Grade 4 >10 × ULN 4.1% 0.4% AST Grade 2 >2.5-5 × ULN 9.9% 8.0% Grade 3 >5-10 × ULN 4.5% 1.4% Grade 4 >10 × ULN 1.6% 0.4% ALT and/or AST Grade 2-4 >2.5 × ULN 26.0% 13.7% Cholesterol Grade 2 >300 – 400 mg/dL 15.6% 6.4% Grade 3 >400 – 500 mg/dL 3.3% 0.3% Grade 4 >500 mg/dL 0.9% 0.1% Triglycerides Grade 2 400 – 750 mg/dL 35.9% 26.8% Grade 3 >750 – 1200 mg/dL 16.9% 8.7% Grade 4 >1200 mg/dL 8.0% 4.3% In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of subjects 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.

6.2Clinical Trials in Pediatrics APTIVUS,

co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric subjects as combination therapy. Study 1182.14 enrolled HIV-1 infected, treatment-experienced pediatric subjects (with the exception of 3 treatment-naïve subjects), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten subjects were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 subjects 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.

However, rash (5.5%), was reported more frequently in pediatric subjects than in adults. The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%).