Aptivus

Tipranavir may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• diarrhea
• weight loss
• headache
• stomach pain

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• fever, chills, cough, or other signs of infection
• rash
• redness, blistering, or peeling of skin
• itching
• throat tightness
• shortness of breath
• weakness, numbness and pain, in hands and feet
• difficulty breathing or swallowing
• muscle or joint pain or stiffness

Tipranavir may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Black Box Warnings

Hepatitis and hepatic decompensation, including some fatalities, reported; extra vigilance warranted with chronic hepatitis B or hepatitis C coinfection because of increased risk of hepatotoxicity

Intracranial hemorrhage, both fatal and nonfatal, reported

Contraindications

Hypersensitivity

Moderate-severe hepatic impairment (Child-Pugh Class B & C)

Drugs that are contraindicated with tipranavir (when coadministered 'boosted' with ritonavir) include alpha1-adrenoreptor agonists (eg, alfuzosin), antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine), rifampin, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lovastatin, simvastatin, lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam

Cautions

Caution in mild hepatic impairment

Risk of severe, potentially fatal hepatotoxicity

Not recommended in treatment-naive patients

May have antiplatelet/anticoagulant action

Risk of potentially fatal intracranial hemorrhage

Risk of immune reconstitution syndrome if used in combination with other antiretroviral drugs

Fat redistribution with "cushingoid appearance" and "buffalo hump" may occur

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

Must be coadministered with ritonavir

Sulfonamide allergy

Coadministration with other CYP3A4 substrates (ritonavir inhibits CYP3A4 and increases toxicity risk for drugs metabolized by CYP3A4)

Increased risk of rash, especially with hormonal contraceptives

Risk of large increase in total cholesterol and triglycerides

Contains 116 IU/mL vitamin E (>RDA); limit supplemented vitamin E

APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients 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 age 2 to 18 years. 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 [see WARNINGS AND PRECAUTIONS].
• The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response [see CLINICAL PHARMACOLOGY and Clinical Studies].
• Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir [see CLINICAL PHARMACOLOGY]. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir [see CLINICAL PHARMACOLOGY].
• Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment [see WARNINGS AND PRECAUTIONS].
• Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment [see WARNINGS AND PRECAUTIONS].
• The drug-drug interaction potential of APTIVUS/ritonavir when co-administered with other drugs must be considered prior to and during APTIVUS/ritonavir use [see CONTRAINDICATIONS and DRUG INTERACTIONS].
• 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 [see WARNINGS AND PRECAUTIONS].
• The risk-benefit of APTIVUS/ritonavir has not been established in pediatric patients < 2 years of age.

There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.

Included as part of the PRECAUTIONS section.

Aptivus is a prescription medication used to treat Human Immunodeficiency Virus (HIV) in adults. Aptivus belongs to a group of drugs called protease inhibitors, which limit the production of new viruses. 

This medication comes in capsule and liquid forms and is taken twice a day. Aptivus is always taken with Norvir (ritonavir), another HIV medication, and at the same time as Norvir. Norvir increases the level of Aptivus in the blood, helping Aptivus to work better. 

Common side effects of Aptivus include diarrhea, nausea, headache, and fatigue.

You should not use this medicine if you are allergic to tipranavir or ritonavir (Norvir, Kaletra), or if you have moderate to severe liver disease.

Life-threatening side effects can occur if you take tipranavir with any of the following medications:

• alfuzosin (Uroxatral);

• amiodarone (Cordarone, Pacerone);

• cisapride (Propulsid);

• atorvastatin (Lipitor, Caduet), lovastatin (Mevacor, Altoprev, Advicor), simvastatin (Zocor, Simcor, Vytorin, Juvisync);

• flecainide (Tambocor), propafenone (Rythmol), quinidine (Quinaglute);

• midazolam (Versed) or triazolam (Halcion);

• pimozide (Orap);

• rifampin (Rifadin, Rifamate, Rimactane);

• sildenafil (Revatio for pulmonary arterial hypertension);

• St. John's wort; or

• ergot medicines for migraine headache (Ergomar, Cafergot, D.H.E. 45, Migranal, Ergotrate, or Methergine).

To make sure you can safely take tipranavir, tell your doctor if you have any of these other conditions:

• liver disease (especially hepatitis B or C);

• diabetes;

• high cholesterol or triglycerides;

• a bleeding disorder such as hemophilia; or

• if you are allergic to sulfa drugs.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

Tipranavir can make birth control pills less effective. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking tipranavir.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Tipranavir should not be given to a child younger than 2 years old.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Tipranavir is taken in combination with ritonavir (Norvir). Use tipranavir and ritonavir regularly to get the most benefit. Get your prescriptions refilled before you run out of medicine completely.

Take your medicine with food if you take tipranavir with ritonavir tablets.

You may take your medicine with or without food if you take tipranavir with ritonavir capsules or liquid.

Swallow the tipranavir capsule whole. Do not break or chew it.

Measure tipranavir liquid with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Tell your doctor if the child using this medicine has any changes in height or weight. Tipranavir doses are based on body surface area (height and weight) in children, and any changes may affect your dose.

While using tipranavir, you may need frequent blood tests.

If you need surgery, tell the surgeon ahead of time that you are using tipranavir.

HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Store an unopened bottle of tipranavir capsules in the refrigerator. Do not freeze.

After opening the bottle of capsules for the first time, you may store the medicine at room temperature. Store tipranavir liquid at room temperature away from moisture and heat. Do not store the liquid in the refrigerator.

Throw away any capsules or liquid you have not used within 60 days after you first opened the medicine bottle.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Some people taking tipranavir with ritonavir have developed fatal medical problems including liver damage and bleeding in the brain. Stop taking this medicine and get emergency medical attention if you have:

• unusual bleeding, sudden severe headache, numbness, problems with speech or vision; or

• nausea, upper stomach pain, tired feeling, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have:

• severe skin rash, blistering, peeling, redness or sunburn;

• skin rash and also joint or muscle pain, fever, or tightness in your throat; or

• increased thirst, increased urination, hunger, dry mouth.

Tipranavir may increase your risk of certain infections or autoimmune disorders by changing the way your immune system works. Symptoms may occur weeks or months after you start treatment with tipranavir. Tell your doctor if you have:

• signs of a new infection--fever, night sweats, swollen glands, mouth sores, diarrhea, stomach pain, weight loss;

• chest pain (especially when you breathe), dry cough, wheezing, feeling short of breath;

• cold sores, sores on your genital or anal area;

• rapid heart rate, feeling anxious or irritable, weakness or prickly feeling, problems with balance or eye movement;

• severe lower back pain, loss of bladder or bowel control; or

• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence, loss of interest in sex.

Common side effects may include:

• nausea, vomiting, diarrhea, stomach pain;

• skin rash (especially in children);

• headache, fever, tired feeling; or

• changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥2 years of age.1 Must be used in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretrovirals.1

Used in patients who are antiretroviral-experienced and infected with HIV-1 resistant to multiple HIV PIs.1

Not labeled by FDA for initial treatment in antiretroviral-naive patients,1 and use in such patients is not recommended.200 Not recommended for initial treatment in antiretroviral-naive adults and adolescents because of inferior virologic efficacy and higher rate of adverse events compared with other ritonavir-boosted PIs and because higher ritonavir dosage required for boosting plasma tipranavir concentrations compared with other PIs.200

Not recommended for initial treatment in antiretroviral-naive pediatric patients because higher ritonavir dosage required for boosting plasma tipranavir concentrations compared with other ritonavir-boosted PIs and rare, but serious, adverse events reported (i.e., intracranial hemorrhage).201

Consider the following factors when initiating ritonavir-boosted tipranavir: Use with other active antiretrovirals is associated with greater likelihood of treatment response; genotypic or phenotypic viral resistance testing and/or treatment history should guide therapy; number of baseline primary PI mutations affects virologic response to the drug; caution advised in patients at increased risk of hepatotoxicity or bleeding or in patients receiving certain drugs concomitantly.1 (See Cautions and see Interactions.)

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).1 200 Do not use without low-dose ritonavir.1 200

Take tipranavir and low-dose ritonavir at same time.1

If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.1

If tipranavir is taken with ritonavir tablets, take the drugs with a meal.1

Swallow tipranavir capsules whole; do not chew.1

Assess children for ability to swallow capsules; consider oral solution in those unable to reliably swallow capsules.1

Use oral solution in those who have difficulty swallowing capsules.1

Oral solution is a clear yellow viscous liquid; supplied with an oral dispensing syringe.1

Dosage

Pediatric Patients

Dosage is based on body weight or body surface area.1 To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1

Children 2–18 years of age: 14 mg/kg (375 mg/m2) twice daily with ritonavir 6 mg/kg (150 mg/m2) twice daily.1 If this dosage is not tolerated due to adverse effects, consider reducing dosage to 12 mg/kg (290 mg/m2) twice daily with ritonavir 5 mg/kg (115 mg/m2) twice daily provided the virus is not resistant to multiple HIV PIs.1

Adults

500 mg twice daily with low-dose ritonavir (200 mg twice daily).1

Prescribing Limits

Pediatric Patients

Do not exceed adult dosage.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not necessary.1

Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.1

Renal Impairment

Renal clearance of tipranavir negligible; decreased total body clearance not expected in renal impairment.1 Some experts state dosage adjustment not necessary.200

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Absorption

Bioavailability

Tipranavir is administered concomitantly with low-dose ritonavir (ritonavir-boosted tipranavir).1 Ritonavir decreases metabolism of tipranavir, resulting in increased tipranavir plasma concentrations.1

Following >2 weeks of multiple oral doses given without regard to meals, peak plasma tipranavir concentrations attained approximately 3 hours after a dose.1

Steady state attained in most patients after 7–10 days.1 Steady-state trough concentrations are 70% lower than day 1, presumably due to intestinal P-gp induction.1

Food

Compared with administration in the fasting state, administration of tipranavir (as capsules or oral solution) and ritonavir (as capsules) with a meal (500–682 kcal, 23–25% calories from fat) does not have a clinically important effect on tipranavir peak plasma concentrations or AUC.1

Effect of food on administration of tipranavir (as capsules or oral solution) with ritonavir (as tablets) not evaluated.1

Distribution

Extent

Not known whether distributed into CSF or semen.1

Not known whether distributed into milk.1 202

Plasma Protein Binding

>99%.1

Binds to albumin and α1-acid-glycoprotein.1

Elimination

Metabolism

Tipranavir extensively metabolized by CYP3A4.1 Only minimal metabolism of tipranavir occurs when administered with ritonavir 200 mg.1

Oral clearance of tipranavir decreased when administered with ritonavir; this may indicate decreased first-pass effect.1

Elimination Route

Following administration of ritonavir-boosted tipranavir, eliminated principally in feces as unchanged tipranavir.1 Approximately 82% of tipranavir dose excreted in feces and 4% excreted in urine.1

Half-life

Effective mean elimination half-life at steady-state is 4.8–6 hours following administration of ritonavir-boosted tipranavir with a light meal.1

Special Populations

Renal impairment: Pharmacokinetics not studied, but decreased total body clearance not expected since renal clearance of tipranavir is negligible.1

Mild hepatic impairment (Child-Pugh class A): Increased plasma concentrations, but dosage adjustments not needed.1

Moderate or severe impairment (Child-Pugh class B and C): Pharmacokinetics not evaluated.1

Higher tipranavir concentrations reported in females compared with males; dosage adjustments not required.1

Tipranavir is used in combination with ritonavir (Norvir®) to treat an infection caused by the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). This medicine is usually given to patients who have received HIV treatment in the past.

Tipranavir will not cure or prevent HIV infection or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay the development of problems usually related to AIDS or HIV disease from occurring. Tipranavir will not keep you from spreading HIV to other people. People who receive this medicine may continue to have the problems usually related to AIDS or HIV disease.

This medicine is available only with your doctor's prescription.

Aptivus, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients 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 age 2 to 18 years. 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 [see Warnings and Precautions (5.1)].
• The use of other active agents with Aptivus/ritonavir is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14)].
• Genotypic or phenotypic testing and/or treatment history should guide the use of Aptivus/ritonavir [see Clinical Pharmacology (12.4)]. The number of baseline primary protease inhibitor mutations affects the virologic response to Aptivus/ritonavir [see Clinical Pharmacology (12.4)].
• Use caution when prescribing Aptivus/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment [see Warnings and Precautions (5.1)].
• Liver function tests should be performed at initiation of therapy with Aptivus/ritonavir and monitored frequently throughout the duration of treatment [see Warnings and Precautions (5.1)].
• The drug-drug interaction potential of Aptivus/ritonavir when co-administered with other drugs must be considered prior to and during Aptivus/ritonavir use [see Contraindications (4.2) and Drug Interactions (7)].
• 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 [see Warnings and Precautions (5.4)].
• The risk-benefit of Aptivus/ritonavir has not been established in pediatric patients <2 years of age.

There are no study results demonstrating the effect of Aptivus/ritonavir on clinical progression of HIV-1.

Capsules: 250 mg, pink, oblong capsules imprinted with TPV 250

Oral solution: 100 mg/mL, yellow, viscous clear liquid with a buttermint-butter toffee flavor

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.

  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.

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.

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.

The following adverse reactions are described, in greater detail, in other sections:

• Hepatic Impairment and Toxicity [see WARNINGS AND PRECAUTIONS]
• Intracranial Hemorrhage [see WARNINGS AND PRECAUTIONS]
• Rash [see WARNINGS AND PRECAUTIONS]

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 [see Clinical Studies].

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)

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

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-na�ve 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.

Read the entire FDA prescribing information for Aptivus (Tipranavir)