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FDA approves new combination pill for HIV treatment for some patients - QUAD
 
 
  Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir╩disoproxil fumarate)╩Package Insert

The U.S. Food and Drug Administration today approved Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate), a new once-a-day combination pill to treat HIV-1 infection in adults who have never been treated for HIV infection.

FDA Aug 27 2012. Stribild contains two previously approved HIV drugs plus two new drugs, elvitegravir and cobicistat. Elvitegravir is an HIV integrase strand transfer inhibitor, a drug that interferes with one of the enzymes that HIV needs to multiply. Cobicistat, a pharmacokinetic enhancer, inhibits an enzyme that metabolizes certain HIV drugs and is used to prolong the effect of elvitegravir. The combination of emtricitabine and tenofovir disoproxil fumarate, approved in 2004 and marketed as Truvada, blocks the action of another enzyme that HIV needs to replicate in a person's body. Together, these drugs provide a complete treatment regimen for HIV infection.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in FDA's Center for Drug Evaluation and Research. "New combination HIV drugs like Stribild help simplify treatment regimens."

Stribild's approval is the latest HIV/AIDS-related action taken by the FDA this year. Other actions include approval of the first over-the-counter home-use rapid HIV test; approval of the first drug for pre-exposure prophylaxis in combination with safer sex practices to reduce the risk of sexually acquired HIV infection in adults at high risk; and commemoration of the full or tentative approvals of more than 150 antiretroviral products for the President's Emergency Plan for AIDS Relief (PEPFAR) to treat those in countries most affected by the HIV/AIDS epidemic.

The safety and effectiveness of Stribild was evaluated in 1,408 adult patients not previously treated for HIV in two double-blind clinical trials. Patients were randomly assigned to receive Stribild or Atripla, an HIV drug that contains Truvada and efavirenz, once daily in the first trial; and Stribild or Truvada plus atazanavir and ritonavir once daily in the second trial.

The studies were designed to measure the percentage of patients who had an undetectable amount of HIV in their blood at 48 weeks. Results showed between 88 percent and 90 percent of patients treated with Stribild had an undetectable amount of HIV in their blood, compared with 84 percent treated with Atripla and 87 percent treated with Truvada plus atazanavir and ritonavir.

Like labels of many other drugs used to treat HIV, Stribild's label carries a Boxed Warning alerting patients and health care professionals that the drug can cause a build up of lactic acid in the blood and severe liver problems, both of which can be fatal. The Boxed Warning also states that Stribild is not approved to treat chronic hepatitis B virus infection.

Common side effects observed in clinical trials include nausea and diarrhea. Serious side effects include new or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome). Stribild's label gives advice to health care providers on how to monitor patients for kidney or bone side effects.

Gilead Sciences, Stribild's manufacturer, is required to conduct additional studies to help further characterize the drug's safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs.

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U.S. FDA Approves Gilead's StribildTM, a Complete Once-Daily Single Tablet Regimen for Treatment-Naïve Adults with HIV-1 Infection

- Stribild is Gilead's Third Single Tablet Regimen for the Treatment of HIV and the First to Contain an Integrase Inhibitor -


FOSTER CITY, Calif.--(BUSINESS WIRE)--Aug. 27, 2012-- Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has approved StribildTM (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), a complete once-daily single tablet regimen for HIV-1 infection for treatment-naïve adults. Stribild, referred to as "Quad" prior to FDA approval, combines four compounds in one daily tablet: elvitegravir, an integrase inhibitor; cobicistat, a pharmacoenhancing agent; emtricitabine and tenofovir disoproxil fumarate.

"Over the past decade, co-formulated HIV medicines have simplified therapy for many patients and have become standard of care," said Paul Sax, MD, Clinical Director of the Division of Infectious Diseases at Brigham and Women's Hospital, Boston, Professor of Medicine at Harvard Medical School, and principal investigator of one of the Stribild pivotal studies. "Today's approval of Stribild will provide physicians and their patients an effective new single tablet treatment option for individuals starting HIV therapy for the first time."

The approval of Stribild is supported by 48-week data from two pivotal Phase 3 studies in which the single tablet regimen met its primary objective of non-inferiority compared to Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (Study 102) and to a regimen containing ritonavir-boosted atazanavir plus Truvada® (emtricitabine/tenofovir disoproxil fumarate) (Study 103). Today's approval is also supported by Chemistry, Manufacturing and Controls (CMC) information on the individual components of Stribild and the co-formulated single tablet regimen.

"For much of the company's 25-year history, Gilead has focused on the development of improved treatments and simplified regimens for HIV," said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. "Therapies that address the individual needs of patients are critical to enhancing adherence and increasing the potential for treatment success, and we are proud to introduce a new single tablet regimen for the healthcare and patient communities."

Stribild is the third single tablet HIV regimen developed by Gilead. The first, Atripla, was approved in 2006 and is marketed by Gilead and Bristol-Myers Squibb in the United States. The second single tablet regimen, Complera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), which combines Gilead's Truvada and Janssen R&D Ireland's rilpivirine, was approved in 2011.

In all studies of Stribild, most adverse events were mild to moderate. Stribild has Boxed Warnings of lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for important safety information.

Applications for marketing approval of Stribild are also pending in Australia, Canada and the European Union. In the developing world, Gilead has granted multiple Indian manufacturing partners and the Medicines Patent Pool the right to develop generic versions of Stribild and distribute them to 100 developing countries. These agreements include a complete technology transfer of the manufacturing process for the single tablet regimen.

Patient Assistance Programs

Gilead's U.S. Advancing Access® program provides assistance to patients in the United States who do not have insurance or who need financial assistance to pay for their medications, including Stribild. Patients may contact Advancing Access at 1-800-226-2056 between 9:00 a.m. and 8:00 p.m. (Eastern Time) to see if they are eligible for the program.

For patients with private insurance, Gilead's co-pay coupon program provides assistance with out-of-pocket expenses for Gilead's HIV medications, including Stribild, starting at the first dollar. Additionally, Gilead is working closely with the ADAP Crisis Task Force, as the company has done for each of its other HIV medications, to provide discounts to state AIDS Drug Assistance Programs (ADAPs) that will help ensure access to Stribild for patients who receive medications through these programs.

About Stribild

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil fumarate 300 mg. Stribild is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. Stribild does not cure HIV-1 infection.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead's agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights. Gilead submitted a New Drug Application (NDA) to FDA for elvitegravir on June 27, 2012.

Cobicistat is a pharmacoenhancing or "boosting" agent that enables elvitegravir once-daily dosing. It is a potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Cobicistat acts only as a pharmacoenhancer and has no antiviral activity. Gilead submitted an NDA to FDA for cobicistat on June 28, 2012.

Elvitegravir and cobicistat as standalone agents are investigational products and their safety and efficacy have not yet been established.

Important Safety Information about Stribild

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

· Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate ("tenofovir DF"), a component of Stribild, in combination with other antiretrovirals.

· Stribild is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Stribild have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Stribild. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Stribild. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications

· Coadministration:
Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Do not use with drugs that strongly induce CYP3A as this may lead to a loss of virologic response and possible resistance to Stribild. Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, and St. John's wort.

Warnings and Precautions

· New onset or worsening renal impairment:
Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF and Stribild. Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent.

· Use with other antiretroviral products: Stribild should not be coadministered with products containing any of the same active components; with products containing lamivudine; with adefovir dipivoxil; or with products containing ritonavir.

· Decreases in bone mineral density (BMD) and cases of osteomalacia have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss.

· Fat redistribution and accumulation have been observed in patients receiving antiretroviral therapy.

· Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.

Adverse Reactions

· Common adverse drug reactions
in clinical studies (incidence greater than or equal to 5%; all grades) were nausea, diarrhea, abnormal dreams, headache and fatigue.

Drug Interactions

· CYP3A substrates:
Stribild can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Do not use with drugs highly dependent on these factors for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events.

· CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of components of Stribild. Do not use with drugs that strongly induce CYP3A as this may lead to loss of virologic response and possible resistance to Stribild.

· Antacids: Separate Stribild and antacid administration by at least 2 hours.

· Prescribing information: Consult the full prescribing information for Stribild for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

· Adult dosage:
One tablet taken orally once daily with food.

· Renal impairment: Do not initiate in patients with CrCl below 70 mL/min. Discontinue in patients with CrCl below 50 mL/min.

· Hepatic impairment: Not recommended in patients with severe hepatic impairment.

Pregnancy and Breastfeeding

· Pregnancy Category B:
There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.

Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.

 
 
 
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