RIDGEFIELD, Conn., June 24 — Boehringer Ingelheim
Pharmaceuticals, Inc. today announced that the U.S. Food and Drug
Administration (FDA) granted approval of Aptivus(R) (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) approval to 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 adulthood 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 Professor in 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 Medical Center. “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 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/r:
– The use of APTIVUS/r in treatment-naive 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 when
co-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 adolescents 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-naive 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 (study 1182.14) 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 500/200 mg
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 viral load 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/kg ritonavir, 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 mg
co-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 in
pediatric 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 APTIVUS oral
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 against HIV/AIDS.”
Important Safety Information for APTIVUS
– APTIVUS/r has been associated with reports of clinical hepatitis and
hepatic decompensation, including some fatalities. Extra vigilance is
warranted in patients with chronic hepatitis B or hepatitis C co-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 C co-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-naive
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 prior to
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. Valproic acid
may be less effective due to decreased valproic acid plasma concentrations.
– 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 APTIVUS oral
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. In
some, 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 in clinical 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 mucosal erosions 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 observed in
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 alter some
drug interactions.
– Please refer to the complete ritonavir prescribing information for a
description of ritonavir contraindications and additional information on
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 http://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.
For more information, please visit http://us.boehringer-ingelheim.com.
References:
(1) Centers for Disease Control and Prevention. HIV/AIDS Surveillance
Report, 2006: Table 8 – Estimated numbers of persons living with HIV/AIDS,
by year and selected characteristics, 2003-2006-33 states and 5 U.S.
dependent areas with confidential name-based HIV infection reporting. April
1, 2008. Available at:
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2006report/tab
le8 .htm (due to the length of this URL, please copy and paste into
browser). Accessed 21 April 2008.
SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.