U.S. Food and Drug Administration Approves Labeling Update for PREZISTA(R) To Include 96-Week Data in HIV-1 Infected Adult Patients

BRIDGEWATER, N.J., Jan. 27 /PRNewswire/ -- Tibotec Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has approved a labeling update for PREZISTA® (darunavir) tablets to include 96-week data from the ARTEMIS and TITAN studies. Both ARTEMIS and TITAN evaluated the efficacy and safety of PREZISTA with ritonavir (r) vs. lopinavir/r in combination with other antiretrovirals (ARVs) for the treatment of human immunodeficiency virus (HIV-1) in treatment-naive and treatment-experienced adult patients, respectively.

Based on the ARTEMIS results, the United States Department of Health & Human Services (DHHS) Guidelines for HIV recommended once daily PREZISTA/r, in combination with tenofovir/emtricitabine, as one of two preferred protease inhibitors (PIs) for patients starting therapy for the first time, in a December 2009 guidelines update.  

"The addition of this information to the PREZISTA label demonstrates our commitment to providing information on the durability and safety profile of our medications over the long-term.  In addition, Tibotec continues to invest in its long-standing research and development efforts to bring new options to people living with HIV," said Glenn Mattes, President of Tibotec Therapeutics.

PREZISTA was developed by Tibotec Pharmaceuticals and is marketed in the U.S. by Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P. PREZISTA, co-administered with ritonavir (PREZISTA/r), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults.

This indication is based on analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naive and treatment-experienced patients and two controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

In treatment-experienced adult patients, 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.

ARTEMIS 96-Week Study Results

The ARTEMIS study compared the efficacy and safety of PREZISTA/r 800/100 mg once daily (n=343) versus lopinavir/r 800/200 mg total daily dose (n=346) in treatment-naive adults with HIV-1. All patients received a fixed-dose combination of tenofovir and emtricitabine once daily. At 96 weeks, PREZISTA was shown to be non-inferior to lopinavir/r. The study showed that:

• 78 percent of patients in the PREZISTA/r arm reached an undetectable viral load (<50 copies/mL) vs. 74 percent of patients in the lopinavir/r arm.
• The most common treatment-related adverse reactions (greater than or equal to 5 percent) of grade 2-4 among patients in the PREZISTA/r arm vs. lopinavir/r arm were: diarrhea (8 percent vs. 15 percent); headache (6 percent vs. 5 percent); abdominal pain (5 percent vs. 6 percent); and rash (5 percent vs. 6 percent).

Additional Information About the ARTEMIS Study

ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects) is an international, randomized, controlled, open-label, non-inferiority, phase 3 trial that compared the efficacy and safety of PREZISTA/r versus lopinavir/r in treatment-naive HIV-1-infected adult patients with viral load greater than 5,000 copies/mL.

The main objective of the study was to demonstrate non-inferiority of PREZISTA/r versus lopinavir/r in proportion of patients achieving virologic response, defined as confirmed HIV RNA <50 copies/mL. Non-inferiority of PREZISTA/r vs. lopinavir/r was defined as a maximum allowable difference of 12 percent for virologic response, with a one-sided significance level of alpha equals to 0.025.

TITAN 96-Week Study Results

The TITAN study compared the efficacy and safety of PREZISTA/r 600 mg with 100 mg ritonavir (r) twice daily versus lopinavir/r 400 mg/100 mg twice daily, each with an optimized background regimen (OBR) of at least two antiretrovirals (NRTIs with or without NNRTIs), in lopinavir/r-naive, treatment-experienced adults with HIV-1 infection. At 96 weeks, PREZISTA/r 600/100mg twice daily (n=298) was shown to be non-inferior to lopinavir/r 400/100mg twice daily (n=297) in achieving viral load <400 copies/mL. The study showed that:

• 58 percent of patients in the PREZISTA/r arm reached a plasma viral load of <50 copies/mL vs. 52 percent of patients in the lopinavir/r arm.
• The most common treatment-related adverse reactions (greater than or equal to 5 percent) of grade 2-4 among patients in the PREZISTA/r arm vs. lopinavir/r arm were: diarrhea (14 percent vs. 20 percent); nausea (7 percent vs. 6 percent); rash (7 percent vs. 3 percent); abdominal pain (6 percent vs. 3 percent); and vomiting (5 percent vs. 3 percent).

Additional Information About the TITAN Study

TITAN (TMC114/r In Treatment Experienced patients Naive to lopinavir/ritonavir) is a Phase 3, 96-week, randomized, controlled, open-label study. All patients had an HIV viral load greater than or equal to 1,000 copies/mL at screening.

The main objective of the study was to demonstrate non-inferiority of PREZISTA/r versus lopinavir/r in proportion of patients achieving virologic response, defined as confirmed HIV RNA <400 copies/mL. Non-inferiority of PREZISTA/r vs. lopinavir/r was defined as a maximum allowable difference of 12 percent for virologic response, with a one-sided significance level of alpha equals to 0.025.

Important Safety Information

PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

Drug Interactions

• Coadministration of PREZISTA/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, alfuzosin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, oral midazolam, triazolam, lovastatin, or simvastatin)
• Coadministration of PREZISTA/r is also contraindicated with rifampin and products containing St. John's wort (Hypericum perforatum) because this may cause significant decrease in plasma concentration of darunavir, resulting in loss of therapeutic effect and development of resistance
• Coadministration is not recommended with indinavir, lopinavir/ritonavir, saquinavir, and pravastatin
• 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

Warnings & Precautions

• PREZISTA must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures
• Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/r. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/r. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events

Post-marketing cases of liver injury, including some fatalities, have been reported. A causal relationship with PREZISTA/r therapy has not been established

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/r and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/r treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/r should prompt consideration of interruption or discontinuation of treatment

• Severe Skin Reactions:  Severe skin reactions (0.4%), accompanied by fever and/or elevations of transaminases in some cases, Stevens-Johnson Syndrome (<0.1%), and toxic epidermal necrolysis (post-marketing experience) have been reported in patients receiving PREZISTA/r.  Discontinue PREZISTA/r immediately if signs or symptoms of severe skin reactions develop (including, but not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or join aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia)  

In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of patients receiving PREZISTA/r. Discontinuation due to rash was 0.5%

• Sulfa Allergy: PREZISTA should be used with caution in patients with known sulfonamide allergy
• Diabetes Mellitus / Hyperglycemia and Hemophilia: New-onset or exacerbations of preexisting diabetes mellitus, hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. A causal relationship between protease inhibitors and these events has not been established
• Fat Redistribution: 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
• Resistance / Cross Resistance: The potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/r-treated patients

Use in Specific Populations

• Hepatic impairment: PREZISTA/r is not recommended for use in patients with severe hepatic impairment. There are no pharmacokinetic or safety data available in patients with severe hepatic impairment
• Pregnancy: PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women

Adverse Reactions

• In treatment-naive adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (8%), headache (6%), abdominal pain (5%), and rash (5%)
• In treatment-experienced adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (14%), nausea (7%), rash (7%), abdominal pain (6%), and vomiting (5%)

This is not a complete list of all adverse drug reactions reported with the use of PREZISTA/r.

Please see accompanying full Prescribing Information for more details. Full prescribing information is also available at www.PREZISTA.com.

You are encouraged to report negative side effects of prescription drugs to the FDA.  Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

About Tibotec Therapeutics

Tibotec Therapeutics, a division of Centocor 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.

SOURCE Tibotec Therapeutics