Healthcare Industry News: midazolam
News Release - September 18, 2007
New Phase 3 Study in Treatment-Naive Adults with HIV Evaluates Efficacy and Safety of Once-Daily PREZISTA(TM)/ritonavir vs. KALETRA(R) as Part of HIV Combination TherapyPREZISTA/ritonavir data presented at ICAAC
BRIDGEWATER, N.J., Sept. 18 (HSMN NewsFeed) -- Results from a new ongoing, randomized, controlled, open-label Phase 3 study showed that 84 percent of treatment-naive HIV-1 infected adults taking an investigational dose of PREZISTA(TM) (darunavir) 800 mg (two 400 mg tablets) with 100 mg ritonavir once daily with TRUVADA«(1) (emtricitabine and tenofovir disoproxil fumarate) reached an undetectable viral load (<50 copies/mL) at week 48, compared with 78 percent of patients taking KALETRA«(2) (lopinavir/ritonavir) 800 mg/200 mg once daily (or 400 mg/100 mg twice daily) with TRUVADA. The mean difference in response between the treatment groups was 5.3 percent (95 percent confidence interval -0.5; 11.2).
ARTEMIS (AntiRetroviral Therapy with TMC114 examined in na´ve subjects) compared the efficacy and safety of PREZISTA/r with the protease inhibitor (PI) lopinavir/r in treatment-naive adult patients. In a pre-planned analysis, the study met the primary endpoint of non-inferiority (95 percent confidence interval lower limit for the difference in treatment response .12 percent or greater for HIV RNA of less than 50 copies per mL in plasma at week 48).
"This is an important study because it provides information regarding the potential use of a once daily PREZISTA regimen for the treatment of adult patients who have never taken HIV medications before," said Edwin DeJesus, MD, Medical Director of the Orlando Immunology Center and the HUG-Me Program's adult clinic at Orlando Regional Medical Center.
The use of PREZISTA/r in treatment-naive patients and the once-a-day 800 mg dose have not been approved by the FDA. The 48-week primary analysis from ARTEMIS will be submitted to the FDA later this year as part of the post-marketing commitment for PREZISTA.
PREZISTA, co-administered with 100 mg ritonavir and with other antiretroviral agents, is currently indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
This indication is based on week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled trials of PREZISTA/r in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with PREZISTA/r:
-- Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/r.
-- The use of other active agents with PREZISTA/r is associated with a greater likelihood of treatment response.
-- The risks and benefits of PREZISTA/r have not been established in treatment-naive adult patients or pediatric patients.
PREZISTA received accelerated approval in June 2006 based on the 24-week analysis of HIV viral load and CD4+ cell counts from the pooled analysis of the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) Phase 2b studies. As part of the post-marketing commitment, 48-week data from ongoing Phase 3 studies, including ARTEMIS, and 96-week data from POWER 1, 2, and 3 will be required before the FDA can consider traditional approval for PREZISTA.
About the ARTEMIS study
ARTEMIS is an international ongoing, randomized, open-label Phase 3 trial in which 689 treatment-naive adult patients were treated. The participants enrolled in the study had not previously received treatment with HIV medications and had a viral load greater than 5,000 copies. Overall the study population had a mean baseline viral load of 4.85 log10 copies per mL and a median CD4+ cell count of 225 cells per cubic millimeter.
Patients were randomized to receive PREZISTA/r 800 mg/100 mg once daily (n=343) or, based on approved dosing in each country, either lopinavir/r 800 mg/200 mg once daily or 400 mg/100 mg twice daily (n=346), plus a background regimen of tenofovir and emtricitabine once daily. Patient randomization was stratified based on viral load and CD4+ cell count.
ARTEMIS: 48-week study results
In the per-protocol analysis of 689 patients, among patients randomized to the once-daily PREZISTA/r arm (n=343) vs. the lopinavir/r arm (n=346), the 48-week analysis showed that:
-- 84 percent of patients in the PREZISTA/r arm reached an undetectable viral load (<50 copies/mL) vs. 78 percent of patients in the lopinavir/r arm.
-- The median change in CD4+ cell count from baseline was similar between the PREZISTA/r and lopinavir/r arms (137 cells per cubic millimeter vs. 141 cells per cubic millimeter).
ARTEMIS: Safety findings
-- In the two study arms the adverse events at least Grade 2 in severity included diarrhea, nausea and rash. Diarrhea was 4.1 percent in the PREZISTA/r arm vs. 9.8 percent in the lopinavir/r arm. Nausea was 1.7 percent in the PREZISTA/r arm vs. 2.9 percent in the lopinavir/r arm. Rash was 2.6 percent in the PREZISTA/r arm vs. 1.2 percent in the lopinavir/r arm.
-- Incidence of Grade 3-4 lipid-related adverse events reported in PREZISTA/r arm were 1.7 percent vs. 5.2 percent in the lopinavir/r arm.
-- In both treatment arms there was a low incidence of discontinuation. Discontinuations due to adverse events were 3.4 percent in the PREZISTA/r arm vs. 6.9 percent in the lopinavir/r arm.
Important safety information
PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.
PREZISTA is contraindicated in patients with known hypersensitivity to any of its ingredients.
Coadministration of PREZISTA/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).
Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/r. This list of potential drug interactions is not complete.
PREZISTA must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentration of PREZISTA that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.
Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving PREZISTA during the clinical development program. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with PREZISTA; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. PREZISTA should be discontinued if severe rash develops.
PREZISTA should be used with caution in patients with known sulfonamide allergy.
New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.
PREZISTA should be used with caution in patients with hepatic impairment. There are no data regarding the use of PREZISTA in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.
Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
Immune reconstitution syndrome has been reported in patients treated with ARV therapy.
The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in PREZISTA/r treated patients.
PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. There are no adequate and well-controlled studies in pregnant women. The effects of PREZISTA on pregnant women or their unborn babies are not known.
In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving PREZISTA/r-containing regimen were headache (3.8 percent), diarrhea (2.3 percent), abdominal pain (2.3 percent), constipation (2.3 percent), and vomiting (1.5 percent).
Please see full Prescribing Information for more details. A copy of full Prescribing Information can be obtained by visiting PREZISTA.com.
PREZISTA was developed by Tibotec Pharmaceuticals Ltd. and is marketed in the U.S. by Tibotec Therapeutics, a division of Ortho Biotech Products, L.P. In the European Union, Russia, Switzerland and other countries, PREZISTA is marketed by Tibotec, a division of Janssen-Cilag. In Canada, PREZISTA is marketed by Tibotec, a division of Janssen-Ortho Inc. Applications for approval of PREZISTA also have been submitted or are planned for submission in many other countries.
About Tibotec Therapeutics
Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., headquartered in Bridgewater, N.J., is dedicated to delivering innovative virology therapeutics that help healthcare professionals address serious unmet needs in people living with HIV.
About Tibotec Pharmaceuticals Ltd.
Tibotec Pharmaceuticals Ltd., based in Cork, Ireland, is a pharmaceutical research and development company. The Company's main research and development facilities are in Mechelen, Belgium with offices in Yardley, PA. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need.
Tibotec Pharmaceuticals is developing a Global Access Program to facilitate access to its antiretrovirals for patients living with HIV/AIDS in developing countries. The Global Access Program for PREZISTA includes access pricing, registration, medical education for appropriate use and voluntary licensing.
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the Company's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2006. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from the Company. The Company does not undertake to update any forward-looking statements as a result of new information or future events or developments.
1. Truvada« (emtricitabine and tenofovir disoproxil fumarate) is a trademark owned by Gilead Sciences, Inc.
2. Kaletra« (lopinavir/ritonavir) is a trademark owned by Abbott Laboratories
Source: Tibotec Therapeutics
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