FDA approves new U.S. labeling for 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) has approved new labeling for ISENTRESS® (raltegravir) Film-coated Tablets, Merck’s integrase inhibitor for the treatment of HIV-1 infection in adult patients as part of combination HIV therapy. The updated prescribing information now includes 240-week results from the STARTMRK study, the longest double-blind Phase III non-inferiority study evaluating an integrase inhibitor in treatment-naïve adult patients with HIV-1 infection. The results show that the regimen containing ISENTRESS in combination therapy demonstrated long-term viral suppression and a greater immunologic response than the efavirenz-containing regimen, as well as a proven, long-term safety and tolerability profile through 240 weeks in previously untreated (treatment-naïve) adult HIV-1 infected patients.

ISENTRESS is an integrase inhibitor indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adult patients through 96 weeks and one was conducted in treatment-naïve adults through 240 weeks.

The use of other active agents with ISENTRESS (raltegravir) is associated with a greater likelihood of treatment response.

Severe, potentially life-threatening and fatal skin reactions have been reported with ISENTRESS. Additionally, during the initial phase of combination ARV treatment, immune reconstitution syndrome may occur. (See Important Selected Safety Information below.)

“As the care of HIV evolves, ISENTRESS continues to be an important treatment option for adult patients with HIV-1,” said Jürgen Rockstroh, M.D., University of Bonn, Bonn-Venusberg, Germany. “These 240-week results are important for physicians to consider when initiating treatment with ISENTRESS in combination therapy in treatment-naïve adult patients with HIV-1.”

“Merck has been at the forefront of HIV research for close to 30 years. The discovery of ISENTRESS and its clinical development program are a testament to Merck’s long-term commitment to the research and development of medicines for HIV,” said Daria Hazuda, Ph.D., vice president of Early Development and Discovery Sciences Research for infectious diseases, Merck.

STARTMRK study design

STARTMRK was a multi-center, double-blind, randomized, active-controlled, Phase III non-inferiority study. In the study, 563 previously untreated HIV-1 infected adult patients with HIV-1 RNA greater than 5,000 copies/mL received either 400 mg ISENTRESS orally twice daily (n=281) or 600 mg efavirenz orally once daily (n=282), each in combination with tenofovir/emtricitabine. The primary endpoint of the study was a reduction in HIV-1 viral load to less than 50 copies/mL at week 48. Secondary endpoints included ARV activity, as measured by the proportion of patients achieving HIV-1 viral load to less than 50 copies/mL at 96 weeks, as well as achieving viral load less than 400 copies/mL and change from baseline in CD4 cell count, both measured at 48 and 96 weeks. Pre-specified exploratory endpoints also included the proportion of patients achieving HIV-1 viral load to less than 50 copies/mL at 240 weeks, as well as change from baseline in CD4 cell count at 240 weeks. Safety was evaluated throughout the study period.Merck presented the 240-week STARTMRK study results for the first time at AIDS 2012 in Washington, D.C. and the results were subsequently published in Journal of Acquired Immune Deficiency Syndromes (JAIDS) in May 2013.

ISENTRESS (raltegravir) in combination therapy shows long-term efficacy in previously untreated adult HIV-1 patients through 240 weeks

In the STARTMRK trial, the regimen containing ISENTRESS was non-inferior to the regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL) at 240 weeks. At the study entry, the geometric mean baseline plasma HIV-1 RNA for patients was over 100,000 copies/mL (103,205 copies/mL for those on a regimen containing ISENTRESS (raltegravir) and 106,215 copies/mL for patients on a regimen containing efavirenz). Results for the 240-week analysis showed long-term viral suppression (HIV-1 RNA less than 50 copies/mL) for patients on the regimen containing ISENTRESS of 66 percent and 60 percent for the regimen containing efavirenz [treatment difference of 6.6 percent of patients with 95 percent confidence interval (CI): -1.4 percent, 14.5 percent].

The regimen containing ISENTRESS demonstrated a greater immunologic response than the regimen containing efavirenz at 240 weeks. Patients on the regimen containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm3 compared to 217 cells/mm3 for patients on the regimen containing efavirenz. From study entry to week 240, patients on the regimen containing ISENTRESS had a mean baseline increase in CD4 cell count of 295 cells/mm3 versus 236 cells/mm3 for patients on the regimen containing efavirenz.

Safety and tolerability profile for ISENTRESS (raltegravir) through 240 weeks in STARTMRK

In the STARTMRK trial, through 240 weeks, there was a low incidence of drug-related adverse reactions of moderate to severe intensity that occurred in greater than or equal to 2 percent of patients treated with ISENTRESS. These adverse drug reactions as compared to efavirenz were insomnia (4 percent, in both arms), headache (4 percent versus 5 percent), nausea (3 percent versus 4 percent), fatigue (2 percent versus 3 percent) and dizziness (2 percent versus 6 percent). “Moderate” reactions were defined as discomfort enough to cause interference with usual activity. “Severe” reactions were defined as incapacitating with inability to work or do usual activity.

Patients on the regimen containing ISENTRESS also demonstrated a lower treatment discontinuation rate due to clinical adverse reactions versus patients on the regimen containing efavirenz through 240 weeks (5 percent versus 10 percent, respectively). Additionally, ISENTRESS in combination therapy had less effect on lipids [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol] and triglycerides fasting serum lipids at week 240, as shown in the table below.

Important Selected Safety Information

ISENTRESS (raltegravir) does not cure HIV-1 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 systemic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Co-administration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT1A1) may result in reduced plasma concentrations of raltegravir. Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS for adults should be increased to 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.

The most commonly reported (≥2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-naïve adult patients receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs 5%), nausea (3% vs 4%), fatigue (2% vs 3%), and dizziness (2% vs 6%), respectively. 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 to 4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS (raltegravir). 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 plus 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 three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

About ISENTRESS (raltegravir)

ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1 infection in adult patients and pediatric patients ages 2 years and older and weighing at least 10 kg as part of combination HIV therapy. 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. ISENTRESS is now approved in combination therapy in more than 76 countries for use in treatment-naïve adult patients with HIV-1 and in more than 110 countries for use in treatment-experienced adult patients with HIV-1. ISENTRESS, in combination therapy, for use in pediatric patients with HIV-1 has also been approved for use in 33 countries. 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.

Please see Prescribing Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf and Patient Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.

ISENTRESS® is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., USA INFC-1083968-0000 7/1