Aptivus Drug Information

Dosage 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.

Recommended 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.

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 subjects received the dose of 500 mg/200 mg BID. 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. 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) 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. The risk of developing transaminase elevations is greater during the first year of therapy.

Clinical 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.

Potential for Aptivus/ritonavir to Affect Other Drugs

Aptivus co-administered with ritonavir at the recommended dose is a net inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Thus, co-administration of Aptivus/ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring.

Clinically significant drug-drug interactions of Aptivus co-administered with ritonavir are summarized in Table 4 below. A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of Aptivus/ritonavir capsule administration on the activity of hepatic CYP1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of Aptivus co-administered with 200 mg of ritonavir twice daily in capsule form.

There was no net effect on CYP2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP1A2, but there was moderate induction at steady state. There was modest inhibition of CYP2C19 at the first dose, but there was marked induction at steady state.

Potent inhibition of CYP2D6 and both hepatic and intestinal CYP3A4/5 activities were observed after first dose and steady state. Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of Aptivus/ritonavir followed by induction of P-gp over time.

Thus, it is difficult to predict the net effect of Aptivus administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin.

The clinical consequences of this finding have not been established.

Potential for Other Drugs to Affect Tipranavir Tipranavir is a CYP3A substrate and a P-gp substrate. Co-administration of Aptivus/ritonavir and drugs that induce CYP3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of Aptivus/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations.

Co-administration of Aptivus/ritonavir with drugs that inhibit CYP3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of Aptivus/ritonavir 500 mg/200 mg twice daily. Table 4 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction Midazolam is extensively metabolized by CYP3A4. Therefore, Aptivus should not be given with orally administered midazolam.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).

Pregnancy 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 (see Data ) 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) (see Data ). 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.

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 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).

Pediatric Use The safety and effectiveness of APTIVUS, co-administered with ritonavir have been established in pediatric patients for combination antiretroviral treatment of HIV-1 infected 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). The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS in those weighing 36 kg or higher were similar to those observed in adults. However, rash was reported more frequently in pediatric subjects than in adults.

The safety and effectiveness of APTIVUS, co-administered with ritonavir have been established in pediatric patients greater than 2 years of age or weighing less than 36 kg, but not recommended due to lack of a suitable pediatric formulation.

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 (see Table 1 ). 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) 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 Use with drugs highly dependent on CYP3A for clearance or are potent CYP3A inducers

There is no known antidote for APTIVUS overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage.

Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since tipranavir is highly protein bound, dialysis is unlikely to provide significant removal of the drug.