This message describes the following important changes affecting Prezista (darunavir)

• Traditional approval of Prezista

• New dosing regimen for treatment-naive patients

• New 400 mg tablets

• Revised Pregnancy Category

On October 21, 2008, FDA granted traditional approval to Prezista (darunavir) 600 mg, co-administered with 100 mg ritonavir and with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced adult patients.

Prezista was granted accelerated approval on June 23, 2006, based on analysis of plasma HIV-1 RNA levels in two controlled studies of 24 weeks duration. The traditional approval is based on a 48 week phase 3 study (TMC114-C214) in treatment-experienced patients and continuation of two controlled trials of 96 weeks duration in clinically advanced, treatment-experienced patients, confirming durability of the virologic response.

In addition to the traditional approval, a new dosing regimen for treatment-naive patients was approved. The recommended dose for treatment-naive adult patients is Prezista 800 mg (two 400 mg tablets) taken with ritonavir 100 mg once daily, with food. The type of food does not affect exposure to darunavir.

The dosing regimen for treatment-experienced patients remains unchanged as Prezista 600 mg taken with ritonavir 100 mg twice daily, with food.

The dosing regimen in treatment-naive patients was based on a randomized, controlled, open-label Phase 3 study (Study TMC114-C211) comparing Prezista/ritonavir 800/100 mg once daily versus Kaletra (lopinavir/ritonavir) 800/200 mg per day (given as twice daily or as once daily regimen). Both arms used a fixed background regimen consisting of tenofovir and emtricitabine. The proportion of patients who were virologic responders (HIV RNA < 50 copies/mL) was 84% for Prezista/ritonavir and 78% for Kaletra.

Additionally, the pregnancy category was changed from B to C (section 8.1). Additional details regarding the supportive animal data for the reproduction studies and juvenile toxicity studies are included. The section now reads:

Pregnancy Category C: 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. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice, rats and rabbits. However, due to limited bioavailability and/or dosing limitations, animal exposures (based on AUC) were only 50% (mice and rats) and 5% (rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir.

In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.

In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.

Several other changes were made to the package insert and include the following major revisions. Additionally, the label was converted to Physician Labeling Rule (PLR) format to make product labeling more informative and applicable to clinicians.

• Section 6: Adverse Reactions was updated to include safety data from studies TMC114-C211 and TMC114-C214. Additionally serious adverse drug reactions of at least moderate intensity during the Phase 2B and 3 studies were added to section 6.

• Section 6.6 Postmarketing Experience includes rare events of hypersensitivity including facial edema and rhabdomyolysis associated with coadministration with HMG-CoA reductase inhibitors.

• Section 7, Drug Interactions, Table 6: Established and Other Potentially Significant Drug Interactions was updated to include appropriate dosing of carbamazepine and rifabutin in combination with Prezista/ritonavir.

• Section 8.4 Pediatric Use was revised to state Prezista should not be used in pediatric patients below 3 years of aged in view of the toxicity and mortality observed in juvenile rats observed up to post natal day 26.

• Section 12.4 Microbiology was updated to include additional resistance data and updated baseline genotype/phenotype and virologic outcome analyses from the treatment-experienced studies using the IAS resistance mutations.

• Section 12.2 Pharmacodynamics was added to describe the results of the negative QT study.

• A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species (mice and rats) as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms.

• Section 14. Clinical Studies was updated to include the 48 week efficacy results from the treatment-naïve study TMC114-C211 and the treatment-experienced study TMC114-C214 and the 96 Week data from pooled studies TMC114-C202 and TMC114-C213

Forty-eight week results from ARTEMIS in treatment-naive adults:

• Eighty-four [44] percent of patients in the PREZISTA/r arm (n=343) reached an undetectable viral load (<50 copies/mL) vs. 78 percent of patients in the lopinavir/r arm (n=346) (study demonstrated non-inferiority, p = not statistically significant).

• The median change in CD4+ cell count from baseline was similar between PREZISTA/r and lopinavir/r arms (137 cells per cubic millimeter vs. 141 cells per cubic millimeter) (p = not statistically significant). 

• Low rates of gastrointestinal adverse drug reactions (ADRs) were observed in the PREZISTA/r arm.

• Gastrointestinal ADRs of at least moderate intensity (> Grade 2) in > 1 percent of patients were: diarrhea (6 percent vs. 13 percent), abdominal pain (4 percent vs. 5 percent), nausea (3 percent vs. 3 percent), vomiting (2 percent vs. 3 percent) respectively for PREZISTA/r vs. lopinavir/r arm.

• In treatment-naive adult patients, the most common ADRs (>2 percent) reported of at least moderate intensity (> Grade 2) in the PREZISTA/r arm were diarrhea (6 percent), headache (5 percent ), abdominal pain (4 percent), nausea (3 percent), vomiting (2 percent), and rash (2 percent).  

Forty-eight week results from TITAN in lopinavir/r-naive, treatment-experienced adults:

• Seventy-seven [77] percent of patients in the PREZISTA/r arm (n=298) vs. 67 percent of patients in the lopinavir/r arm (n=297) reached less than 400 copies/mL, (study demonstrated non-inferiority, p<0.0001).
  
  
• In treatment-experienced adult patients, the most common ADRs (> 2 percent) reported of at least moderate intensity (> Grade 2) in the PREZISTA/r arm were diarrhea (12 percent), nausea (7 percent), rash (6 percent), abdominal pain (5 percent), vomiting (4 percent), asthenia (3 percent), headache (2 percent), abdominal distension (2 percent), and dyspepsia (2 percent).

Ninety-six week results from POWER in clinically advanced, treatment-experienced adults:

• Fifty-seven [57] percent of patients in the PREZISTA/r arm (n=131) vs. 10 percent of patients in the comparator protease inhibitor arm (n=124) achieved a virologic response defined as greater than or equal to a 1.0 log₁₀ reduction (90 percent reduction) in viral load from baseline.

he latest recommendations from the International AIDS Society-USA Panel, current which were published in the August 6, 2008 issue of the Journal of the American Medical Association, recommend PREZISTA as one of the initial treatment options as part of combination therapy for adults living with HIV. “Tibotec is proud to reach this important milestone that makes PREZISTA available to those who are just starting HIV treatment for the first time,” said Glenn Mattes, President of Tibotec Therapeutics. “We look forward to continuing to provide treatment options that will add to the arsenal of anti-HIV therapies.”

Dosing

Recommended dosing for treatment-naive adult patients is 800 mg (two 400 mg tablets) taken with 100 mg ritonavir once daily. The new 400 mg tablet will be available by November 1. For treatment-experienced adult patients, the dosing for PREZISTA remains 600 mg taken with 100 mg ritonavir twice daily. PREZISTA must be taken with food and in combination with other ARVs. PREZISTA/r is not recommended for use in patients with severe hepatic impairment.

Tibotec will discontinue production of the 300 mg tablet of PREZISTA as a result of decreasing demand following the introduction of the 600 mg tablet earlier this year. The 600 mg tablet allows treatment-experienced adult patients who currently take two 300 mg of PREZISTA twice daily to now take one 600 mg tablet twice daily. 

The sNDA submission included the 48-week findings of ARTEMIS (AntiRetroviral Therapy with TMC114 Examined In naive Subjects), an ongoing phase 3, randomized, controlled, open-label study that compared the efficacy and safety of PREZISTA/r with lopinavir/r in treatment-naïve HIV-1-infected adult patients. Patients with HIV-1 viral load >5,000 copies/mL were randomized to receive a PREZISTA/r dose of 800 mg/100 mg once daily, or lopinavir/r given as 400 mg/100 mg twice daily or 800 mg/200 mg once daily. All patients received a fixed dose background regimen of tenofovir and emtricitabine once daily. The primary objective was to demonstrate non-inferiority of PREZISTA/r compared with lopinavir/r in virologic response (confirmed HIV-1 viral load <50 copies/mL) at week 48.

At week 48, six percent of patients in the PREZISTA/r arm experienced virological failure vs. 10 percent of patients in the lopinavir/r arm.

The sNDA submission also included 48-week data from TITAN (TMC114/r In Treatment-experienced pAtients Naïve to lopinavir/ritonavir), a phase 3, randomized, controlled, open-label study, comparing the efficacy and safety of a PREZISTA/r dose of 600 mg/100 mg twice daily with 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 treatment-experienced HIV-1-infected adult patients who were lopinavir/r-naïve. All patients had an HIV viral load greater than or equal to 1,000 copies/mL, and had been receiving antiretroviral therapy for at least 12 weeks. The primary objective was to demonstrate non-inferiority of PREZISTA/r compared with lopinavir/r in virologic response (HIV-1 viral load <400 copies/mL) at week 48.

At week 48, 11 percent of patients in the PREZISTA/r arm experienced virological failure vs. 21 percent of patients in the lopinavir/r arm.

The sNDA submission also included 96-week data from POWER (TMC114-C213 and TMC114-C202), two controlled, phase 2b trials in clinically advanced, treatment- experienced adults with a high level of protease inhibitor resistance.

Patients with HIV-1 viral load > 1000 copies/mL, who had one or more primary protease inhibitor mutations, and were failing a protease inhibitor-based regimen, were randomized to receive PREZISTA/r 600 mg/100 mg twice daily plus OBR (at least two NRTIs with or without enfuvirtide) versus an investigator-selected ritonavir-boosted comparator protease inhibitor plus OBR.

At week 96, 29 percent of patients in the PREZISTA/r arm experienced virological failure vs. 80 percent of patients in the comparator protease inhibitor arm.

About Tibotec Pharmaceuticals

Tibotec Pharmaceuticals, 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.

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. Ortho Biotech Products, L.P. and Tibotec Pharmaceuticals are subsidiaries of Johnson & Johnson.