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FDA Approves Invirase (saquinavir) 1000mg + Ritonavir 100mg: boosted PI regimen
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"U.S. FDA Approves INVIRASE(R) Boosted With Ritonavir for Use in Treatment of
HIV/AIDS: New Dosing Strategy Offers Potent Option in Combination with Other
Anti-HIV Drugs"
NUTLEY, N.J., Jan. 6 /PRNewswire/ -- Roche today announced U.S.
Food and Drug Administration (FDA) approval of its protease
inhibitor INVIRASE(R) (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(R), 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 (<400 copies/mL) at the
completion of 48 weeks of treatment. 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 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.
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.
Ritonavir is manufactured by Abbott Laboratories.
SOURCE Roche
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