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Investigational Formulation of Saquinavir Mesylate Granted Priority Review Status

NUTLEY, N.J., Aug. 17 /PRNewswire/ -- Roche today announced that the U.S. Food and Drug Administration (FDA) has granted priority review status to the New Drug Application (NDA) for a 500 mg tablet formulation of its HIV protease inhibitor, Invirase® (saquinavir mesylate). If approved, the new formulation of Invirase will simplify dosing regimens by reducing pill count for each dose by more than half (from five pills to two, twice-daily).

The priority review designation establishes a target six-month review period for the Invirase NDA, which was submitted by Roche on June 21, 2004. According to FDA policies and procedures, priority designation is granted to medications that, if approved, address unmet medical needs, offering a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious or life-threatening disease.

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. This 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.

"We are very pleased that the FDA has granted an expedited review of the Invirase 500 mg tablet, which could mean faster access for patients to a simpler saquinavir dosing regimen," said Malte Schutz, M.D., Medical Director, Roche. "Roche has an ongoing commitment to developing Invirase. A comprehensive clinical program will begin this year to further define the role of the 500 mg tablet in the treatment of HIV."

Invirase boosted with ritonavir is listed as a recommended component of initial antiretroviral regimens in the new International AIDS Society-USA antiretroviral guidelines. The guidelines, published in the July 14 issue of the Journal of the American Medical Association (JAMA), gave boosted Invirase a 1A rating, which is the highest position in the guidelines based on strength of clinical evidence.

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.

Source: Roche

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