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PR Newswire
Study Demonstrates New FORTOVASE(R) Dosing Strategy Maintains

April 22, 2002
NUTLEY, N.J. -- Roche today announced clinical study results indicating that HIV patients who modified their twice-daily protease inhibitor regimen of FORTOVASE(R) (saquinavir soft gel capsules) with ritonavir (FORTOVASE/r) by increasing the FORTOVASE dose and minimizing the ritonavir dose were able to maintain viral suppression below 400 copies/mL with substantial reductions in triglycerides and cholesterol. A second study found similar saquinavir exposure levels among patients taking INVIRASE(R) (saquinavir mesylate) with ritonavir (INVIRASE/r) or FORTOVASE/r, when given at the same dose either once- or twice-daily. These data were presented at the 3rd International Workshop on the Clinical Pharmacology of HIV Therapy in Washington, D.C., April 11-13, 2002.

About the Switch Study

In the Switch Study, 21 patients who had been receiving twice-daily FORTOVASE/r dosed at 400 mg/400 mg for at least six months and who exhibited undetectable (less than 400 copies/mL) plasma HIV-RNA levels were randomized to continue on FORTOVASE/r 400/400 or to switch to twice-daily FORTOVASE/r, dosed at 1000 mg/100 mg. After six months, in patients with dose modification (n=11), fasting serum triglyceride levels fell from 488 to 329 mg/dl, and cholesterol levels fell from 259 to 227 mg/dl. In the control group (n=10), fasting serum triglyceride levels were increased from 210 to 237 mg/dl, and cholesterol levels were increased from 206 to 231 mg/dl. None of the patients in the study who switched their dosing regimen had increases in viral load above 400 copies/ml after 24 weeks, while four patients in the control group had such increases.

"Long-term viral load suppression has been demonstrated with a twice-daily regimen of FORTOVASE/r, though the doses most commonly used in the past may not be optimized for patient tolerability. FORTOVASE/r 1000/100 provides therapeutic levels of FORTOVASE while minimizing ritonavir-associated adverse events," said Dr. William O'Brien, Professor of Infectious Diseases, University of Texas Medical Branch, and lead investigator in the Switch Study "After increasing the dose of FORTOVASE and decreasing the dose of ritonavir in the Switch Study, we found reductions in triglycerides, reductions in cholesterol levels, and improved tolerability after six months. Consistent blood levels of saquinavir and the continuation of viral suppression in study participants also support the use of this dosing regimen."

Two patients withdrew from the 1000/100 arm, both due to pancreatitis. One patient withdrew from the 400/400 arm, due to markedly elevated cholesterol and triglycerides, and six weeks later expired due to neuroleptic malignant syndrome.

Comparing pharmacokinetics of INVIRASE/r or FORTOVASE/r

Two studies showed that saquinavir exposure with INVIRASE/r is at least equivalent to that achieved with FORTOVASE/r when given once- or twice-daily. (In the absence of ritonavir, FORTOVASE has been shown to provide significantly higher exposures of saquinavir.)

"These studies show that similar blood levels of saquinavir can be achieved with INVIRASE/r or FORTOVASE/r, dosed once- or twice-daily," said Dr. David M. Burger, University Medical Centre, Nijmegen, The Netherlands. "As long as it is used with ritonavir, INVIRASE may have some advantages over FORTOVASE, including smaller pill size, no refrigeration requirement, and better gastrointestinal tolerability. In fact, several ongoing studies are examining the use of INVIRASE/r as an alternative regimen for patients who exhibit transient gastrointestinal side effects with FORTOVASE/r."

The first study, a pharmacokinetic substudy of patients in Thailand, evaluated subjects who had been using once-daily FORTOVASE/r 1600 mg/100 mg as part of HIV combination therapy for at least 48 weeks. They were given INVIRASE/r 1600 mg/100 mg once-daily for one week, and switched back to FORTOVASE/r. Pharmacokinetic measurements were taken after one week with INVIRASE/r and after one week with FORTOVASE/r, demonstrating higher saquinavir exposure with INVIRASE/r. The Cmax (maximum concentration achieved) for once-daily INVIRASE/r and FORTOVASE/r were 6.30 mg/L and 5.27 mg/L, respectively; the AUC 24h ("area under curve" or time curve from zero to 24 hours) were 49.95 mg/L.h and 35.48 mg/L.h, respectively; and the Cmin (lowest concentration in dosing interval) were 0.21 mg/L and 0.07 mg/L, respectively.

One patient had diarrhea during therapy with both FORTOVASE/r and INVIRASE/r, and one patient had diarrhea while using FORTOVASE/r.

The second study found that twice-daily INVIRASE/r led to significantly higher plasma saquinavir levels than FORTOVASE/r for all pharmacokinetic variables evaluated. In this study, twice-daily INVIRASE 1000 mg or FORTOVASE 1000 mg was given with ritonavir 100 mg to 24 healthy volunteers at a center in Germany. Half of the subjects were randomized to receive FORTOVASE/r or INVIRASE/r for 10 days; participants were then switched to the alternative formulation for 10 days. The pharmacokinetics of each regimen were evaluated after 10 days of dosing. The Cmax for twice-daily INVIRASE/r and FORTOVASE/r were 1228 ng/L and 983 ng/L, respectively; the AUC 24h were 15798 ng.h/mL and 11655 ng.h/mL, respectively; and the Cmin were 232 ng/L and 166 ng/L, respectively.

Results showed that INVIRASE/r was better tolerated than FORTOVASE/r, with gastrointestinal disorders occurring less frequently during the INVIRASE/r period (eight patients versus 23 patients). The incidence of diarrhea was significantly higher with FORTOVASE/r than with INVIRASE/r (15 patients versus four patients). There was no significant correlation between saquinavir drug levels and the incidence of either diarrhea or abdominal symptoms.

More About FORTOVASE

The most frequently reported adverse events at least possibly related to treatment with FORTOVASE and of at least moderate intensity -- observed in trials evaluating the approved 1200 mg three-times-daily dosing regimen -- include nausea (17.8 percent), diarrhea (15.6 percent), abdominal discomfort (13.3 percent) and dyspepsia (8.9 percent). FORTOVASE should not be co-administered with astemizole, terfenadine, ergot derivatives, cisapride, midazolam or triazolam, due to the potential for serious and/or life-threatening events. Concomitant use with lovastatin or simvastatin is also not recommended; caution should be exercised with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway. Exacerbation of chronic liver dysfunction has been reported in patients treated with FORTOVASE. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time. There have also been reports of hyperglycemia, new onset or exacerbation of diabetes and of spontaneous bleeding in patients with hemophilia. Please refer to the complete product information for detailed safety information for FORTOVASE.

More About INVIRASE

INVIRASE delivers the same active ingredient as FORTOVASE, and the safety and drug interaction information provided above for FORTOVASE also applies to INVIRASE. The INVIRASE product labeling warns that INVIRASE capsules and FORTOVASE soft gelatin capsules are not bioequivalent and cannot be used interchangeably. When using saquinavir as part of an antiviral regimen FORTOVASE is the recommended formulation. In rare circumstances, INVIRASE may be considered if it is to be combined with antiretrovirals, such as ritonavir, that significantly inhibit saquinavir's metabolism.

About Roche

Hoffmann-La Roche Inc. (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, diagnostics and vitamins. 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.

For further information about FORTOVASE(R)

Patients can call: (800) 910-4687

Healthcare Professionals: (800) 526-6367

Roche HIV Therapy Assistance Program: (800) 282-7780

FORTOVASE Web site: http://www.Fortovase.com

For a copy of the FORTOVASE or INVIRASE product package inserts with complete prescribing information please call: Heather Van Ness at (973) 562-2203.

FORTOVASE(R) (saquinavir) is a registered trademark of HLR Technology Corporation, an affiliated company of Hoffmann-La Roche Inc.

SOURCE Hoffmann-La Roche Inc. Web Site: http://www.rocheusa.com



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