FDA approves Merck’s ISENTRESS® (raltegravir)

Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) recently approved the use of ISENTRESS® (raltegravir) in combination with other antiretroviral (ARV) medicines, for the treatment of HIV-1 infection in pediatric patients two years of age and older and weighing at least 10 kg. This new indication is based on the evaluation of safety, tolerability, pharmacokinetic parameters and efficacy of ISENTRESS through at least 24-weeks, in a multicenter, open-label, non-comparative study, in HIV-1-infected children and adolescents two to 18 years of age. The safety and efficacy of ISENTRESS have not been established in children less than two years of age. The FDA also has approved a chewable tablet formulation of ISENTRESS for the treatment of children two to less than 12 years of age. For children ages two to less than 12 years of age, the dosing of ISENTRESS is based on the formulation administered and the patient’s age and weight. The chewable table formulation is expected to be available by mid-year of 2012.

Severe potentially life-threatening and fatal skin reactions have been reported with ISENTRESS. Additionally, during the initial phase of treatment, immune reconstitution syndrome may occur. The chewable tablet formulation contains phenylalanine, a component of aspartame, which may be harmful to patients with phenylketonuria. (See Important Selected Safety Information below.)

“ISENTRESS is now a new treatment option as part of a regimen for children ages two years and older living with HIV-1 in the U.S.,” said Hedy Teppler, Senior Director, Clinical Research, Merck. “This advancement underscores Merck’s longstanding commitment to help in the fight against HIV, which spans more than 25 years.” ISENTRESS, used in combination with other ARV medicines, was approved by the FDA for use in the treatment of adult patients starting HIV-1 therapy for the first time (treatment-naïve) in 2009, and in treatment-experienced adult patients with HIV-1 in 2007.

IMPAACT P1066 Study Design

This new FDA approval to expand the indication for ISENTRESS to include pediatric patients ages two years and older infected with HIV-1 was based on 24-week results from an ongoing Phase I/II open-label, multicenter trial (IMPAACT P1066) that evaluated the pharmacokinetic profile, safety, tolerability and efficacy of ISENTRESS in HIV-1-infected children and adolescents used with optimized background therapy. The IMPAACT trial enrolled 126 treatment-experienced HIV-1-infected children and adolescents ranging from two to 18 years of age (median age 13 years). Most subjects had previously used at least one non-nucleoside reverse transcriptase inhibitor (78 percent) or one protease inhibitor (83 percent). Ninety-six patients received either the 400 mg film-coated tablet formulation (six to 18 years of age) or the chewable tablet formulation (two to less than 12 years of age) of ISENTRESS, dosed orally twice-daily in combination with optimized background therapy. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL and the mean CD4 cell count was 481 cells/mm3. Ninety-three patients (97 percent) completed 24 weeks of treatment. At Week 24, 54 percent of patients achieved a viral load of less than 50 copies/mL, and the mean CD4 cell count increase from baseline was 119 cells/mm3 (3.8 percent).

In the IMPAACT 1066 study, the frequency, type and severity of drug-related adverse reactions experienced through Week 24 by these 96 treatment-experienced children and adolescents were comparable to those observed in adults.

Important Selected Safety Information

ISENTRESS does not cure HIV infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systematic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely.

Healthcare providers should know that during the initial phase of treatment, immune reconstitution syndrome can occur, which may necessitate further evaluation and treatment. Monitor for immune reconstitution syndrome.

The most common adverse reactions of moderate to severe intensity greater than or equal to two percent that occurred at a higher rate than the comparator were insomnia (four percent) in treatment-naïve adult patients and headache (2 percent) in treatment-experienced adult patients. Intensities were defined as follows: Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all 3 groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

About ISENTRESS

ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1 infection in adult patients and pediatric patients ages two years and older as part of combination HIV therapy. ISENTRESS is currently the only approved integrase inhibitor for the treatment of HIV-1. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only approved drug that inhibits the integrase enzyme. ISENTRESS is now approved in combination therapy in more than 45 countries for use in treatment-naïve adult patients with HIV-1 and in more than 90 countries for use in treatment-experienced adult patients with HIV-1. Merck is continuing to move forward with filings in additional countries around the world.

To assist patients taking ISENTRESS, Merck offers the SUPPORT™ program, which provides personal support and patient advocacy regarding individual reimbursement issues. For more information about the SUPPORT™ program, please visit www.merckhelps.com or call 1-800-850-3430.

Dosage and Administration

ISENTRESS can be taken with or without food. For the treatment of adult patients and patients 12 years of age and older with HIV-1 infection, the dosage of ISENTRESS is one 400 mg film-coated tablet orally, twice daily. For children ages two to less than 12 years of age, the dosing of ISENTRESS is based on the formulation administered and the patient’s age and weight. During co-administration with rifampin, the recommended dosage of ISENTRESS in adults is 800 mg twice-daily. Rifampin a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS in adults should be increased during co-administration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.