Rx Product News: Profile: A Closer Look at New FDA Actions: Isentress
Isentress is the first medicine to be approved by the FDA in a new class of antiretroviral drugs called integrase inhibitors.
Dr. Holmberg is a pharmacy resident at the Carl T. Hayden Veterans Affairs Medical Center in Phoenix, Arizona.
The FDA has granted accelerated approval to raltegravir (Isentress) for the treatment of human immunodeficiency virus (HIV-1) infection when used in addition to other antiretroviral agents in adults who have used other antiretroviral medications, demonstrated viral replication, and exhibited HIV-1 strains that are resistant to multiple antiretroviral medications.1,2 Categorized as an integrase inhibitor, Isentress is the first medication in this class to be approved. Isentress is marketed by Merck & Co Inc.1
Mechanism of Action
HIV-1 integrase is an encoded enzyme involved in viral replication. Isentress exerts its effect by inhibiting the catalytic activity of this enzyme, thus preventing the formation of the HIV-1 provirus. Without the provirus, the production of progeny virus cannot occur. As a result, the viral infection cannot be propagated.2
The efficacy of Isentress is based on data at 24 weeks from 2 ongoing, phase 3, randomized, double-blind, placebo-controlled trials of 699 patients with HIV-1. Patients were at least 16 years old and had resistance to at least 1 drug in each antiretroviral class. These trials, BENCHMRK-1 and BENCHMRK-2, aimed to compare Isentress 400 mg twice daily in addition to optimized background therapy (OBT) with OBT alone. Patients were stratified based on the degree of resistance to a protease inhibitor and the presence of enfuvirtide as OBT. At 24 weeks, patients using Isentress were associated with lower levels of HIV viral RNA and higher cluster differentiation 4 counts than those patients using OBT alone.1,2
Isentress should be dosed as 400 mg orally twice a day and can be administered without regard to food or meals.2 In preclinical trials, Isentress did not appear to be metabolized by cytochrome P-450 enzymes.1 Concomitant treatment with a strong inducer of uridine diphosphate glucuronosyltransferase 1A1, such as rifampin, may decrease the plasma level of Isentress; this combination should be used with caution. No dose adjustment is required in renal dysfunction or moderate hepatic impairment. Isentress has not been studied in patients with severe hepatic impairment.2
Contraindications, Warnings, and Precautions
Currently, no contraindications exist to treatment with Isentress. Health care providers should be aware of the potential for patients to develop immune reconstitution syndrome during the early stage of treatment. This syndrome is characterized by the body's reaction to antiretroviral therapy with an inflammatory response to certain opportunistic infections. Potential organisms to trigger immune reconstitution syndrome in clude Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus. Should this syndrome occur, further evaluation and treatment are required.2
Isentress is not indicated as monotherapy or in patients who have never used any antiretroviral treatment before. No long-term studies have assessed the efficacy of Isentress on the clinical progression of HIV-1.1
A Pregnancy Category C drug, Isentress should be used only if the benefits of treatment are expected to outweigh its risks to the fetus. Isentress should not be used during breast-feeding. Isentress has not been studied in patients <16 years of age and should not be used in these patients. Its use in patients >65 years of age has not been studied extensively.2
In clinical trials, the most commonly reported adverse effects during treatment with Isentress were diarrhea, nausea, and headache.3 An elevation in creatine kinase has been noted in patients using Isentress. Myopathy and rhabdomyolysis also have been reported in patients using Isentress, but the clinical relationship of these events to treatment with Isentress has not yet been established.1
- FDA approves Isentress (raltegravir) tablets, first-in-class oral HIV-1 integrase inhibitor. www.merck.com/newsroom/press_releases/product/2007_1012.html [press release]. Accessed December 2007.
- Isentress Prescribing Information. www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed December 2007.
- FDA approves new HIV drug: raltegravir tablets used in combination with other antiretroviral agents [press release]. www.fda.gov/bbs/topics/NEWS/2007/NEW01726.html. Accessed December 2007.