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This message describes the following important changes affecting Prezista (darunavir)
· Traditional approval of Prezista
· New dosing regimen for treatment-naïve 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-naïve patients was approved. The recommended dose for treatment-naïve 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-naïve 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 6.3
· 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.
o The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
o Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e. a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary
· 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
· The following text was added to section 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility
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
Prezista is a product of Tibotec, Inc.
The complete, revised label will be posted and available at Drugs @FDA.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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