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New Dosing Regimen for Saquinavir Approved by FDA

NUTLEY, N.J., Jan. 6 /PRNewswire/ -- Roche today announced U.S. Food and Drug Administration (FDA) approval of its protease inhibitor INVIRASE® (saquinavir mesylate 1000 mg) for use with ritonavir (100 mg) in combination regimens for the treatment of HIV infection. This new dosing strategy increases ("boosts") blood levels of saquinavir to enable twice-daily dosing and eliminates the inadequate drug levels associated with use of INVIRASE alone.

FDA approval of Roche's supplemental New Drug Application (sNDA) for INVIRASE was based on data which showed that INVIRASE 1000 mg with ritonavir 100 mg twice-daily provides similar to or greater levels of saquinavir over a 24-hour period than those achieved with another formulation of saquinavir, Fortovase®, 1200 mg three times per day. Fortovase with ritonavir was studied in a heterogeneous population of 148 HIV-infected patients. Results showed that 91 of 148 subjects (61 percent) achieved and/or sustained an undetectable HIV RNA levels (

"INVIRASE with ritonavir is an attractive option for the treatment of HIV because it is designed to provide consistently therapeutic levels of saquinavir with twice-daily dosing," said Dr. Frank Palella, Assistant Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago. "With saquinavir, physicians and patients have the benefit of eight years of clinical experience on which to base treatment decisions. Today's news confirms that only low, 100 mg doses of ritonavir are needed to achieve effective levels of saquinavir when given with 1000 mg INVIRASE."

INVIRASE capsules do not require refrigeration and are smaller in size than Fortovase capsules. Roche is developing a 500 mg formulation of INVIRASE, designed to be used in the new boosted dosing regimen, that will cut daily pill count in half. A filing for the 500 mg formulation is projected for submission to the FDA for review in 2004.

It is important to note that INVIRASE and Fortovase are not bioequivalent and cannot be used interchangeably. INVIRASE may be used only if it is to be combined with ritonavir, which significantly inhibits saquinavir's metabolism and provides plasma saquinavir levels at least equal to those achieved with Fortovase. Fortovase is the recommended formulation when using saquinavir as the sole protease inhibitor in an antiviral regimen.

"The approval of INVIRASE for boosted dosing is another important step in Roche's ongoing efforts to define the optimal use of saquinavir, which was developed from our company's laboratories as the first protease inhibitor for HIV," said Kathy Presto, Vice President, U.S. HIV Franchise, Roche. "We have invested significantly in clinical trials and will continue our commitment through development of the INVIRASE 500 mg tablet formulation."

Dosing of Boosted INVIRASE

The FDA approved dosing for boosted INVIRASE is 1000 mg of INVIRASE (5 x 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 protease- inhibitor 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 greater than or equal to 2% 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 greater than or equal to 2% 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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