Side Effects of Aptivus (tipranavir)

Aptivus (tipranavir) is a non-peptidic protease inhibitor (PI) of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides, which is co-administered with 200 mg of ritonavir, and indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.

Common side effects of Aptivus include:

• diarrhea,
• nausea,
• vomiting,
• stomach pain,
• tiredness and
• headache.

Women taking birth control pills may get a skin rash. It may be hard to tell the difference between side effects caused by Aptivus, by the other medicines you are also taking, or by complications of HIV infection.

Serious side effects of Aptivus include:

• liver problems (including liver failure and death),
• rash,
• increased bleeding in patients with hemophilia,
• diabetes and high blood sugar (hyperglycemia),
• increased blood fat (lipid) levels, and
• changes in body fat (which may include an increased amount of fat in the upper back and neck, breast, and around the back, chest, and stomach area, along with loss of fat from the legs, arms, and face).

Drug interactions of Aptivus co-administered with 200 mg of ritonavir include drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring.

Co-administration of Aptivus/ritonavir and drugs that induce CYP3A and/or P-gp may decrease tipranavir plasma concentrations. Coadministration of Aptivus/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations.

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. To monitor maternal-fetal outcomes of pregnant women exposed to Aptivus, an Antiretroviral Pregnancy Registry has been established.

The Centers for Disease Control and Prevention recommends HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse effects of tipranavir, breastfeeding is not recommended while using Aptivus.

Aptivus may cause serious side effects, including:

• Liver problems, including liver failure and death. Your doctor should do blood tests to monitor your liver function during treatment with Aptivus. Patients with liver diseases such as Hepatitis B and Hepatitis C may have worsening of their liver disease with Aptivus and should have more frequent monitoring blood tests.
• Rash. Mild to moderate rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving Aptivus. Some patients who developed rash also had joint pain or stiffness, throat tightness, or generalized itching.
• Increased bleeding in patients with hemophilia. This can happen in patients taking Aptivus or other protease inhibitor medicines.
• Diabetes and high blood sugar (hyperglycemia). This can happen in patients taking Aptivus or other protease inhibitor medicines. Some patients have diabetes before starting treatment with Aptivus which gets worse. Some patients get diabetes during treatment with Aptivus. Some patients will need changes in their diabetes medicine. Some patients will need new diabetes medicine.
• Increased blood fat (lipid) levels. Your doctor should do blood tests to monitor your blood fat (triglycerides and cholesterol) during treatment with Aptivus. Some patients taking Aptivus have large increases in triglycerides and cholesterol. The long-term chance of having a heart attack or stroke due to increases in blood fats caused by Aptivus is not known at this time.
• Changes in body fat. These changes have happened in patients taking Aptivus and other anti-HIV medicines. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen.

The cause and long-term health effects of these conditions are not known. The most common side effects include:

• diarrhea,
• nausea,
• vomiting,
• stomach pain,
• tiredness and
• headache.

Women taking birth control pills may get a skin rash. It may be hard to tell the difference between side effects caused by Aptivus, by the other medicines you are also taking, or by the complications of HIV infection. For this reason, it is very important that you tell your doctor about any changes in your health.

You should report any new or continuing symptoms to your doctor right away. Your doctor may be able to help you manage these side effects. The list of side effects is not complete. Ask your doctor or pharmacist for more information.

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.

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.

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 Group^a (48-week Analyses)

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)

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.

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.

Potential For Aptivus/Ritonavir To Affect Other Drugs

Aptivus co-administered with ritonavir at the recommended dose is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of Aptivus/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A 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 CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP 3A4/5 (midazolam) and Pglycoprotein (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. Aptivus oral solution co-administered with ritonavir capsules demonstrated similar effects as Aptivus capsules co-administrated with ritonavir.

There was no net effect on CYP 2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP 1A2, but there was moderate induction at steady state. There was modest inhibition of CYP 2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4/5 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 CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the coadministered drugs for CYP 3A 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 CYP 3A substrate and a P-gp substrate. Co-administration of Aptivus/ritonavir and drugs that induce CYP 3A 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 CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steadystate administration of Aptivus/ritonavir 500/200 mg twice daily.

Clinically significant drug-drug interactions of Aptivus co-administered with ritonavir are summarized in Table 4 below.

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