Prezista Now Available for Pediatric Patients Six Years of Age and Older as Part of HIV Combination Therapy

Bridgewater, NJ -- Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P., today announced the availability of a lower-dose (75 mg) formulation of PREZISTA® (darunavir) for pediatric patients with HIV. The announcement follows the FDA approval of PREZISTA, co-administered with ritonavir (PREZISTA/r) and with other antiretroviral agents, for the treatment of HIV infection in pediatric patients six years of age and older, granted December 18, 2008. PREZISTA was developed by Tibotec Pharmaceuticals, Ltd. and is marketed in the U.S. by Tibotec Therapeutics.

According to the most recent reports from the Centers for Disease Control (CDC), there were 2,587 children under 13 years of age living with HIV and 1,116 children under 13 years of age living with AIDS in the U.S. at the end of 2006. The CDC estimates that 56,500 young people between the ages of 13 and 24 years were living with HIV in 2006.

"The HIV epidemic continues to affect thousands of children in the U.S., and these patients have fewer treatment options than adults," said Ram Yogev, M.D., Director of Pediatric, Adolescent and Maternal HIV Infection at Children's Memorial Hospital in Chicago. "The availability of PREZISTA in a formulation designed especially for children over the age of six provides an important new option for these patients."

In October 2008, PREZISTA received traditional (full) approval for treatment-naïve and treatment-experienced adult patients as part of combination therapy.

The pediatric indication for PREZISTA is based on 24-week analyses of pharmacokinetics, safety, tolerability and antiviral activity from DELPHI (TMC114-C212), an open-label Phase 2 trial in which antiretroviral treatment-experienced HIV-1 infected pediatric patients (6 to <18 years of age and weighing at least 44 lbs [20 kg]) received twice-daily PREZISTA/r in combination with other antiretroviral agents.

The following points should be considered when initiating therapy with PREZISTA/r in treatment-experienced pediatric patients:

• 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.

Pediatric Dosing Information

For pediatric patients (6 to <18 years of age and weighing at least 44 lbs [20 kg]), the dosage of PREZISTA/r is based on body weight and should not exceed the recommended treatment-experienced adult dose. PREZISTA tablets should be taken with ritonavir twice daily and with food.

Specific pediatric dosing is based on weight as follows:

• >44 lbs - < 66 lbs: 375 mg PREZISTA/50 mg ritonavir twice daily
• >66 lbs - < 88 lbs: 450 mg PREZISTA/60 mg ritonavir twice daily
• >88 lbs: 600 mg PREZISTA/100 mg ritonavir twice daily

Before prescribing PREZISTA, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA tablets may not be appropriate. Do not use PREZISTA once daily dosing in pediatric patients. The safety and efficacy of PREZISTA/r in pediatric patients ages 3 to <6 have not been established. Do not use PREZISTA/r in pediatric patients below 3 years of age.

Tibotec will also be introducing PREZISTA 150 mg tablets for pediatric patients, and expects these tablets to be available in the next several months.

About the DELPHI Study

DELPHI (TMC114-C212) is an open-label, Phase 2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of PREZISTA/r in combination with other antiretrovirals in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to <18 years of age and weighing at least 44 lbs (20 kg). Virologic response rate was evaluated at week 24.

Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log₁₀ versus baseline. The mean baseline plasma HIV-1 RNA was 4.64 log₁₀ copies/mL, and the median baseline CD4+ cell count was 330 cells/mm³ (range: 6 to 1505 cells/mm³). Most pediatric subjects (79 percent) had previous use of at least one NNRTI and 96 percent of pediatric subjects had previously used at least one protease inhibitor PI.

Pediatric subjects who were at risk of discontinuing therapy due to intolerance of the ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

At week 24, 74 percent of subjects had at least 1 log₁₀ HIV-1 RNA decrease from baseline. The proportion of pediatric subjects reaching undetectable viral load (<50 HIV-1 RNA copies/mL) was 50 percent, and the proportion of pediatric subjects with <400 HIV-1 RNA copies/mL was 64 percent. The mean change in plasma HIV-1 RNA from baseline was -1.98 log₁₀ copies/mL. The mean CD4+ cell count increase from baseline was 117 cells/mm³.

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, 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.

Additional Important Safety Information

• Do not use PREZISTA/r in pediatric patients below 3 years of age. The safety and efficacy of PREZISTA/r in pediatric patients 3 to < 6 years of age have not been established.
• 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. 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.

• Cases of severe skin rashes and Stevens-Johnson syndrome have been reported in subjects receiving PREZISTA. 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 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.
• 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/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.
• 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.
• In treatment-experienced pediatric patients (6 to < 18 years of age), the most common adverse drug reactions ( 3 percent) reported regardless of severity with PREZISTA/r were vomiting (13 percent), diarrhea (11 percent), abdominal pain (10 percent), headache (9 percent), rash (5 percent), nausea (4 percent), and fatigue (3 percent).

This is not a complete list of all adverse drug reactions reported with the use of PREZISTA/r.
Please see full Prescribing Information for more details. Full prescribing information is also available at www.PREZISTA.com.