Ridgefield/Conn., 24 June 2008 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) granted approval of Aptivus® (tipranavir) capsules/oral solution with dosing information for treatment-experienced pediatric patients between the ages of 2-18 infected with HIV-1. The oral solution formulation, which is a new dosage form of Aptivus, was also approved for treatment-experienced adults. The oral solution formulation will be available in the U.S.beginning in mid-September. The FDA granted full (traditional) approvalto Aptivus capsules for treatment-experienced adults in October 2007.
“Due to significant advances in HIV therapy and care, many perinatally infected children are growing into young adult hood and beyond. Most of these children have received multiple courses of anti-HIV medications and many have evidence that their HIV strains have developed resistance to the majority of currently approved antiretrovirals. An unmet need remains for pediatric indications and new formulations of antiretroviral therapies,” said Dr. Juan Salazar, Associate Professorin Pediatrics, University of Connecticut’s Department of Pediatrics, Division of Pediatric Infectious Diseases, and Director of the Pediatric and Youth HIV Program at the Connecticut Children’s MedicalCenter. “This approval is an important development for treatment-experienced children and teenagers who may have limited therapeutic options.”
Aptivus Indications and Usage
Aptivus, a protease inhibitor co-administered with ritonavir(Aptivus/r), 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.
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of Aptivus/r of 48 weeks duration in treatment-experienced adults and one open-label 48-week study inpediatric patients age 2 to 18 years. The adult studies were conductedin 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/r:
- The use of Aptivus/r in treatment-naïve patients is not recommended.
- The use of other active agents with Aptivus/r is associated with a greater likelihood of treatment response.
- Genotypic or phenotypic testing and/or treatment history should guide the use of Aptivus/r. The number of baseline primary protease inhibitor mutations affects the virologic response to Aptivus/r.
- Use caution when prescribing Aptivus/r 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/r and monitored frequently throughout the duration of treatment.
- The drug-drug interaction potential of Aptivus/r whenco-administered with other drugs must be considered prior to and during Aptivus/r use.
- Use caution when prescribing Aptivus/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding.
- The risk-benefit of Aptivus/r has not been established in pediatric patients less than 2 years of age.
- There are no study results demonstrating the effect of Aptivus/r on clinical progression of HIV-1.
- Aptivus/r does not cure HIV or help prevent passing HIV to others.
According to Centers for Disease Control and Prevention (CDC) data for 33 states, an estimated 8,545 children and adole scents under the age of 20 were living with HIV/AIDS in the U.S. at the end of 2006.1 The estimated number of 13 to 19-year-olds living with HIV/AIDS increased by 28 percent from 2003 to 2006.1
Aptivus/r 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 1,500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (study1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs.
All patients initially received Aptivus oral solution. Pediatric patients who were 12 or older and received the maximum dose of 500/200mg twice daily could subsequently change to Aptivus capsules at day 28. The trial primarily compared two doses for safety and tolerability based on adverse events and laboratory findings, and secondarily evaluated pharmacokinetics and virologic and immunologic response and time to treatment failure at 48 weeks.
Based on the results, the recommended pediatric dose of Aptivus for both capsules and oral solution is 14 mg/kg with 6 mg/kg ritonavir, or 375 mg/m2 co-administered with ritonavir 150 mg/m2, taken twice daily. A greater proportion of patients receiving this dose achieved a viralload of less than 400 copies/mL. For children who develop intolerance or toxicity and cannot continue with the higher dose, physicians may consider decreasing the dose to Aptivus 12 mg/kg with 5 mg/kgritonavir, 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.
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 of Aptivus 500 mgco-administered with ritonavir 200 mg twice daily.
At 48 weeks, 40 percent of patients had a viral load of less than 400 copies/mL. The proportion of patients with viral load less than 400 copies/mL tended to be greater (70 percent) in the youngest group of patients, who had less viral resistance at baseline, compared to the older groups (37 percent and 31 percent). Agents approved by the FDA in the past five months were not included in the trial.
The most frequent adverse reactions in pediatric patients were similar to those in adults. Fever, vomiting, cough, rash, nausea and diarrhea were most frequently reported, and rash was reported more frequently inpediatric patients than in adults. The most frequent treatment-emergent laboratory abnormalities were increases in CPK, ALT and amylase.
Patients taking Aptivus oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as Aptivusoral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
“The approval of a new formulation and the pediatric indication demonstrates Boehringer Ingelheim’s commitment to the community and patients with advanced stage HIV,” said Dr. Thor Voigt, Senior Vice President, Medicine and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Aptivus oral solution provides physicians and patients with an important treatment option in the fight againstHIV/AIDS.”
Important Safety Information for Aptivus
- Aptivus/r has been associated with reports of clinical hepatitisand hepatic decompensation, including some fatalities. Extra vigilanceis warranted in patients with chronic hepatitis B or hepatitis Cco-infection, as these patients have an increased risk of hepatotoxicity. Patients with signs or symptoms of clinical hepatitis should discontinue Aptivus/r treatment and seek medical evaluation.
- Aptivus/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).
- All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or Cco-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with Aptivus/r, and frequently throughout the duration of treatment.
- Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In the RESIST trials, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3 percent (10.9/100 PEY) of patients receiving Aptivus/r through week 48. In a study of treatment-naïve patients, 20.3 percent (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving Aptivus/r through week 48.
- Aptivus/r is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
- The drug-drug interaction potential of Aptivus/r when co-administered with multiple classes of drugs must be considered priorto and during Aptivus/r use.
- Aptivus/r is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, midazolam (oral) and triazolam due to the potential for serious and/or life-threatening events or loss of efficacy.
- A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of Aptivus/r and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing’s syndrome and adrenal suppression. Aptivus/r should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk.
- Caution should be used when prescribing sildenafil, tadalafil, and vardenafil with Aptivus/r because concentrations of these drugs may increase.
- Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. Aptivus may be less effective due to decreased tipranavir plasma concentrations.
- Caution should be used when prescribing valproic acid. Valproicacid may be less effective due to decreased valproic acid plasmaconcentrations.
- Use caution when prescribing Aptivus/r 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.
- Patients taking Aptivus oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as Aptivusoral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
- Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in patients receiving Aptivus/r. Insome, rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10 percent of females and in 8 percent of males receiving Aptivus/r 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 inclinical trials was 0.5 percent. In an uncontrolled compassionate use program (n=3,920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosalerosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21 percent. Most of these patients had mild rash and 5 percent had moderate rash. Overall, 3 percent interrupted Aptivus treatment due to rash and the discontinuation rate for rash was 0.9 percent. Discontinue and initiate appropriate treatment if severe skin rash develops.
- Aptivus should be used with caution in patients with a known sulfonamide allergy.
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Aptivus/r.
- Redistribution and/or accumulation of body fat have been observedin patients receiving antiretroviral therapy. A causal relationship has not been established.
- Treatment with Aptivus/r has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during Aptivus/r therapy.
- Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in Aptivus/r-treated patients, it is unknown what effect therapy with Aptivus will have on the activity of subsequently administered protease inhibitors.
- Aptivus must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer Aptivus with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will altersome drug interactions.
- Please refer to the complete ritonavir prescribing information for a description of ritonavir contrain dications and additional informationon precautionary measures.
- In adults, the most frequent adverse reactions (incidence greater than 4 percent) were diarrhea, nausea, fever, vomiting, fatigue, headache, and abdominal pain. 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.
Please see full Prescribing Information, including boxed WARNINGS, for Aptivus at www.aptivus.com.
Aptivus is also approved for the treatment of adult patients in Argentina, Australia, Canada, Finland, Switzerland, Mexico, Iceland,Taiwan and the European Union.About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 135 affiliates in 47 countries and approximately 39,800 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
In 2007, Boehringer Ingelheim posted net sales of US $15.0 billion (10.9 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.