VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
The approval is based on one principal clinical trial (1100.1486) that demonstrated prolonged suppression of HIV-1 RNA through 48-weeks, and a supportive trial (1100.1526).
Additional important information regarding the use of VIRAMUNE XR for the treatment of HIV-1 infection:
* Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk
** The 14-day lead-in period with immediate-release VIRAMUNE 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash.
*** If rash persists beyond the 14-day lead-in period with immediate-release VIRAMUNE, do not begin dosing with VIRAMUNE XR. The lead-in dosing with 200 mg once-daily immediate-release VIRAMUNE should not be continued beyond 28 days, at which point an alternative regimen should be sought.
DOSAGE AND ADMINISTRATION
Patients not currently taking immediate-release VIRAMUNE
Patients must initiate therapy with one 200 mg tablet of immediate-release VIRAMUNE daily for the first 14 days in combination with other antiretroviral agents (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of VIRAMUNE XR once daily. Patients must swallow VIRAMUNE XR tablets whole. They must not be chewed, crushed, or divided. For concomitantly administered therapy, the manufacturer’s recommended dosage and monitoring should be followed. VIRAMUNE XR can be taken with or without food.
Switching Patients from immediate-release VIRAMUNE to VIRAMUNE XR
Patients already on a regimen of immediate-release VIRAMUNE twice daily in combination with other antiretroviral agents can be switched to VIRAMUNE XR 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of immediate-release VIRAMUNE.
Patients must never take more than one form of nevirapine at the same time.
Monitoring of patients receiving VIRAMUNE XR is the same as immediate-release VIRAMUNE and includes intensive clinical and laboratory monitoring, including liver enzyme tests at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release VIRAMUNE, prior to initiation of VIRAMUNE XR, and at two weeks after initiation of VIRAMUNE XR therapy.
After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE XR treatment.
Patients already on a regimen of immediate-release VIRAMUNE twice daily who switch to VIRAMUNE XR once daily should continue with their ongoing clinical and laboratory monitoring.
VIRAMUNE XR package insert includes the same Contraindications, Warnings and Precautions and Drug Interactions as immediate release VIRAMUNE.
ADVERSE REACTIONS:
Clinical Trial Experience
Trial 1100.1486 (VERxVE)
In Trial 1100.1486 (VERxVE) treatment-naïve subjects received a lead-in dose of immediate-release VIRAMUNE 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily (n=506) or VIRAMUNE XR 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for men. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subjects’s completion of the 48 week primary endpoint in the trial (mean observation period 61 weeks).
After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release VIRAMUNE group and 6% in the VIRAMUNE XR group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 7% in the immediate-release VIRAMUNE group and 6% in the VIRAMUNE XR group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.
Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release VIRAMUNE, and in 1% of subjects in either treatment group during the randomization phase. In addition, five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of nevirapine treatment.
No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release VIRAMUNE (200 mg once daily), with the exception of rash which occurred in 4% of subjects.
Adverse reactions of at least moderate intensity (Grades 2 or above) and considered to be related to treatment by the investigator in at least 2% of treatment-naive subjects receiving either immediate-release VIRAMUNE or VIRAMUNE XR after randomization in Trial 1100.1486 are rash – 3% for each for VIRAMUNE immediate release and VIRAMUNE XR and clinical hepatitis 3% for VIRAMUNE immediate release vs 2% VIRAMUNE XR.
CLINICAL TRIAL RESULTS:
The clinical efficacy of VIRAMUNE XR is based on 48-week data from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 24-week data in an ongoing, randomized, open-label trial in subjects who switched from immediate-release VIRAMUNE tablets administered twice daily to VIRAMUNE XR tablets administered once daily (Trial 1100.1526, TRANxITION).
Treatment-naïve Subjects
Trial 1100.1486 (VERxVE) is a Phase 3 trial in which treatment-naïve subjects received immediate-release VIRAMUNE 200 mg once daily for 14 days and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily or VIRAMUNE XR 400 mg once daily. All subjects received tenofovir + emtricitabine as background therapy. Randomization was stratified by screening HIV-1 RNA level (less than or equal to 100,000 copies/mL and greater than 100,000 copies/mL). Subject demographic and baseline disease characteristics were balanced between the two treatment groups. With respect to demographics: 85% of the subjects were male, 75% were white, 20% were black, and approximately 29% were from North America. With respect to baseline disease characteristics: mean viral load was 4.7 log10 copies/mL, mean CD4 cell count was 228 cells/mm3 and 73% of subjects had clade B HIV-1 subtype. Approximately two-thirds of the subjects had a baseline HIV-RNA level of less than or equal to 100,000 copies/mL.
The Week 48 outcomes in the Trial 1100.1486 (VERxVE) were as follows: Virologic success (HIV RNA < 50 copies/mL): 75% VIRAMUNE Immediate Release vs 80% VIRAMUNE XR, Virologic failure 13% VIRAMUNE Immediate Release vs 11% VIRAMUNE XR, Virologic failure. These outcomes include all subjects who were randomized after the 14 day lead-in with immediate-release VIRAMUNE and received at least one dose of blinded study medication.
At 48 weeks, mean change from baseline in CD4+ cell count adjusting for baseline HIV-1 viral load stratum was 191 cells/mm3 and 206 cells/mm3 for the groups receiving immediate-release VIRAMUNE and VIRAMUNE XR, respectively.
Subjects Switching from Immediate-release VIRAMUNE to VIRAMUNE XR
Trial 1100.1526 (TRANxITION) is a Phase 3 trial to evaluate safety and antiviral activity of switching from immediate-release VIRAMUNE to VIRAMUNE XR. In this open-label trial, 443 subjects already on an antiviral regimen containing immediate-release VIRAMUNE 200 mg twice daily with HIV-1 RNA less than 50 copies/mL were randomized in a 2:1 ratio to VIRAMUNE XR 400 mg once daily or immediate-release VIRAMUNE 200 mg twice daily. Approximately half of the subjects had tenofovir+emtricitabine as their background therapy, with the remaining subjects receiving abacavir sulfate+lamivudine or zidovudine+lamivudine. Approximately half of the subjects had at least 3 years of exposure to immediate-release VIRAMUNE prior to entering the trial.
At 24 weeks after randomization in Trial 1100.1526, 94% of subjects receiving immediate-release VIRAMUNE 200 mg twice daily and 95% of subjects receiving VIRAMUNE XR 400 mg once daily continued to have HIV-1 RNA less than 50 copies/mL.
The complete product label will be posted shortly on the Drugs@FDA web site.
VIRAMUNE, an Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) is a product of Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.
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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