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Isentress FDA label update includes 156-week safety and efficacy data
 
 
  Updates to the Isentress (raltegravir) package insert were approved on April 18, 2012, to include results from the 156-week safety and efficacy data from Protocol 021-11, "A Multicenter, Double-Blind, Randomized, Active-Controlled Study to Evaluate the Safety and Antiretroviral Activity of raltegravir Versus Efavirenz in Treatment Naïve HIV-Infected Patients, each in Combination With TRUVADA™".

Section 1, Indication and Usage, was updated to reflect data from a trial conducted in treatment-naïve adults through 156 weeks.

Section 6, Adverse Reactions, was updated with the 156 week safety data.

Section 14, Clinical Studies, was updated with the 156-week virologic outcome data. The proportion of subjects with HIV-1 RNA less than 50 copies/mL was 76% for the Isentress treated group compared to 68% for the efavirenz treated group. The difference between treatment groups (95% CI) is 7.4% (-0.1%, 14.7%).

The complete updated labeling will be posted soon at Drugs@FDA.

Isentress is an HIV integrase strand transfer inhibitor manufactured by Merck & Co., Inc.

Richard Klein

Office of Special Health Issues

Food and Drug Administration

Kimberly Struble

Division of Antiviral Drug Products

Food and Drug Administration

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FDA Approves New Labeling for ISENTRESS (raltegravir) to Include 156-Week Data Demonstrating Long-Term Efficacy, Safety and Tolerability with ISENTRESS in Combination Therapy in Previously Untreated Adult Patients Infected with HIV-1

WHITEHOUSE STATION, N.J., May 21, 2012 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) approved a labeling update for ISENTRESS® (raltegravir) Film-coated Tablets to include 156-week data from the STARTMRK study with ISENTRESS in combination therapy compared to efavirenz in combination therapy in previously untreated (treatment-naïve) adult HIV-1-infected patients. The analyses showed that the regimen containing ISENTRESS demonstrated long-term viral suppression, a greater immunologic response and a proven safety and tolerability profile at 156 weeks. ISENTRESS is the first and only integrase inhibitor indicated for the treatment of HIV-1 in adult treatment-experienced and treatment-naïve patients as part of a combination treatment regimen.

ISENTRESS is 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 156 weeks.

The use of other active agents with ISENTRESS 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 treatment, immune reconstitution syndrome may occur. (See Important Selected Safety Information below.)

"As the continuum of HIV care continues to evolve, ISENTRESS remains an important treatment option for adult patients with HIV-1," said Jurgen Rockstroh, M.D., University of Bonn, Bonn-Venusberg, Germany. "Physicians now have new information about a regimen that includes long-term efficacy and tolerability of ISENTRESS, out to three years in treatment-naïve adult HIV-1 patients."

STARTMRK study design

In this ongoing, multi-center, double-blind, randomized, active-controlled, Phase III non-inferiority study, 563 previously untreated HIV-1 infected adult patients with HIV-1 RNA greater than 5000 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 and the evaluation of safety and tolerability 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, less than 400 copies/mL, and change from baseline in CD4-cell count, as well as safety. The 156-week data reported in the updated label for ISENTRESS represent three-year results from a planned five-year study.

Long-tem efficacy of ISENTRESS (raltegravir) in treatment-naïve adult patients with HIV-1 through three years

In the STARTMRK trial, the regimen containing ISENTRESS was as effective as the regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL). At study entry, the mean baseline plasma HIV-1 RNA for patients on a regimen containing ISENTRESS was 103,205 copies/mL, and for patients on a regimen containing efavirenz was 106,215 copies/mL. Results for the 156-week analysis showed long-term viral suppression for patients on a regimen containing ISENTRESS of 76 percent and 68 percent for the regimen containing efavirenz [treatment difference of 7.4 percent of patients with 95 percent confidence interval (CI): -0.1%, 14.7%].

The regimen containing ISENTRESS demonstrated a greater immunologic response than the regimen containing efavirenz at 156 weeks. At study entry, patients on the regimen containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm3, and at 156 weeks experienced a mean change of 281 cells/mm3. Patients on the regimen containing efavirenz had a mean baseline CD4 cell count of 217 cells/mm3, and experienced a mean change of 241 cells/mm3 at 156 weeks.

Safety and tolerability profile of ISENTRESS (raltegravir) in treatment-naïve adult patients with HIV-1

Patients on the regimen containing ISENTRESS demonstrated a lower treatment discontinuation rate due to clinical adverse reactions versus patients on the regimen containing efavirenz at 156 weeks. Nearly 50 percent fewer patients on the regimen containing ISENTRESS discontinued treatment versus the regimen containing efavirenz, with discontinuation rates at 5 percent for patients on the regimen containing ISENTRESS versus 9 percent for patients on the regimen containing efavirenz.

In the STARTMRK trial, through 156 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) and fatigue (2 percent versus 3 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.

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 144, shown in the table below.

lipid.gif

*Fasting (non-random) laboratory tests at week 144.

N = Number of subjects in the treatment group. The analysis is based on all available data.

If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis.

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 systematic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.

Health care 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.

Coadministration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 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.

Grade 2 to 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 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.

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 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.

 
 
 
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