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Invirase (saquinavir) - New 500 mg Tablet To Simplify Dosing Regimens
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NUTLEY, New Jersey (June 21, 2004) - Roche today announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval to market a new 500 mg tablet formulation of its HIV protease inhibitor Invirase® (saquinavir mesylate). The new formulation of Invirase is smaller in size than the currently available 200 mg Invirase capsule and, if approved, will reduce pill count for each dose by more than half (from five pills to two, twice-daily). A filing for approval to market the new formulation in the European Union (EU) will be submitted to the European Medicines Agency (EMEA) within days of the U.S. filing.
The U.S. FDA approved Invirase 1000 mg for use in combination with ritonavir 100 mg and other anti-HIV drugs in December 2003. Co-administering Invirase with ritonavir provides therapeutic blood levels of the drug and enables simplified, twice-daily dosing. Today's filing is based on a bioequivalence study demonstrating that two 500 mg tablets of Invirase, together with 100 mg of ritonavir, achieve similar levels of Invirase in the blood as five Invirase 200 mg capsules with 100 mg ritonavir.
"It is important to develop anti-HIV therapies that are not only potent and well-tolerated but will improve convenience for patients and help to maximize adherence to a treatment regimen," said Nicholas Bellos, M.D., President, Southwest Infectious Disease Associates, Dallas, Texas. "The new formulation of Invirase will provide significantly reduced pill count to patients with continuing potency and a well-characterized safety profile."
"The 500 mg tablet is another important example of Roche's commitment to the treatment of HIV and to the continued optimization of dosing for Invirase. If approved, it will offer patients a smaller pill and the ability to take a full dose with fewer pills," said Malte Schultz, M.D., Medical Director, Roche. "We will extend our commitment to Invirase through a comprehensive clinical program that will further explore its role in the treatment of HIV."
Current Dosing of Boosted Invirase
The FDA approved dosing for boosted Invirase is 1000 mg of Invirase (five 200 mg capsules) in combination with ritonavir 100 mg, twice a day. Ritonavir should be taken at the same time as Invirase. Invirase and ritonavir should be taken within 2 hours after a meal.
Indication and Safety Information
Invirase capsules (saquinavir mesylate) in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV infection (1000 mg saquinavir mesylate with 100 mg ritonavir). The twice daily administration of Invirase in combination with ritonavir is supported by safety data from the MaxCmin 1 study and pharmacokinetic data. The efficacy of Invirase with ritonavir or Fortovase (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.
Invirase capsules and Fortovase soft gelatin capsules are not bioequivalent and cannot be used interchangeably. Invirase may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with Fortovase. When using saquinavir as the sole protease inhibitor in an antiviral regimen, Fortovase is the recommended formulation.
Invirase should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam, ergot derivatives, rifampin or antiarrhymic medications, which include amiodarone, bepridil, flecainide, propafenone, and quinidine. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.
Concomitant use of Invirase with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Invirase, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Concomitant use of Invirase and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Garlic capsules should not be used while taking saquinavir as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations. No data are available for the coadministration of Invirase/ritonavir and garlic capsules.
New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy.
The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 100 mg ritonavir twice-daily. Coadministration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease.
Invirase when administered with ritonavir is contraindicated in patients with severe hepatic impairment. Caution should be exercised when Invirase in combination with ritonavir is used by patients with hepatic impairment. Patients with severe renal impairment have not been studied and caution should be exercised when prescribing Invirase in combination with ritonavir. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.
Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of Fortovase or Invirase with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. A causal relationship between antiretroviral therapy and these events has not been established and the long-term consequences are currently unknown.
The following grade 2 to grade 4 adverse events, (considered at least possibly related to study drug or of unknown relationship) occurred in at least two percent of patients receiving Invirase 600 mg tid alone or in combination with zidovudine and/or HIVID: abdominal discomfort, abdominal pain, appetite disturbances, asthenia, buccal mucosa ulceration, diarrhea, dizziness, dyspepsia, extremity numbness, headache, mucosa damage, musculoskeletal pain, myalgia, nausea, paresthesia, peripheral neuropathy, pruritus, and rash.
The following grade 2 to grade 4 adverse events (all causality) occurred in at least two percent of patients receiving Fortovase with ritonavir (1000/100 mg twice daily): abdominal pain, back pain, bronchitis, constipation, diabetes mellitus/hyperglycemia, diarrhea, dry lips/skin, eczema, fatigue, fever, influenza, lipodystrophy, nausea, pneumonia, pruritis, rash, sinusitis, and vomiting.
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of Invirase therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.
Invirase is not a cure for HIV infection or AIDS. Invirase does not prevent the transmission of HIV.
About Roche
Hoffmann-La Roche (Roche), based in Nutley, N.J., is the U.S. prescription drug unit of the Roche Group, a leading research-based health care enterprise that ranks among the world's leaders in pharmaceuticals and diagnostics. Roche discovers, develops, manufactures and markets numerous important prescription drugs that enhance people's health, well being and quality of life. Among the company's areas of therapeutic interest are: dermatology; genitourinary disease; infectious diseases, including influenza; inflammation, including arthritis and osteoporosis; metabolic diseases, including obesity and diabetes; neurology; oncology; transplantation; vascular diseases; and virology, including HIV/AIDS and hepatitis C. For more information on the Roche pharmaceuticals business in the United States, visit the company's website at: http://www.rocheusa.com.
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