VERxVE Trial: Study Design

• The multinational VERxVE trial evaluated the efficacy and safety of VIRAMUNE XR 400 mg once daily vs VIRAMUNE 200 mg twice daily in ARV treatment-naïve, HIV 1–infected adult patients¹
• VERxVE was a randomized, double-blind, double-dummy, parallel-group, active-controlled trial¹
  • In order to reduce the risk of serious and life-threatening hepatotoxicity, inclusion criteria included a baseline viral load (VL) of ≥1000 copies/mL and a CD4+ cell count >50 to <400 cells/mm³ (for males) and >50 to <250 cells/mm³ (for females)
• Patients were stratified by baseline VL: ≤100,000 copies/mL or >100,000 copies/mL¹
• The primary endpoint was sustained virologic response at Week 48²
• Sustained virologic response was defined as a confirmed VL <50 copies/mL measured at least 2 weeks apart prior to and at Week 48 without subsequent virologic rebound or change of ARV therapy

VERxVE Trial: Efficacy

• Virologic Success with VIRAMUNE XR was noninferior to VIRAMUNE; 75% and 80% of patients were Virologic Successes at Week 48 for the VIRAMUNE and VIRAMUNE XR groups, respectively¹
• In both treatment groups, patients with a baseline VL of ≤100,000 copies/mL had a higher response rate than those with a baseline VL >100,000 copies/mL²
• Mean CD4+ cell count increase from baseline at Week 48 was¹
  • 191 cells/mm³ for VIRAMUNE
  • 206 cells/mm³ for VIRAMUNE XR
• Virologic failure rates at Week 48 were¹
  • 13% in the VIRAMUNE group
  • 11% in the VIRAMUNE XR group

VERxVE Trial: Safety and Tolerability

• Selected adverse events during the randomization phase were¹
  • Any hepatic event: 9% for VIRAMUNE; 6% for VIRAMUNE XR
  • Symptomatic hepatic events: 3% for VIRAMUNE; 2% for VIRAMUNE XR
  • Grade 3 or 4 ALT/AST elevations: 7% for VIRAMUNE; 6% for VIRAMUNE XR
• Selected adverse reactions of at least moderate intensity (Grade 2 or higher) in ≥2% of adult patients were¹
• Rash: 3% for both VIRAMUNE and VIRAMUNE XR
• Clinical hepatitis: 3% for VIRAMUNE; 2% for VIRAMUNE XR
• Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of patients during the lead-in phase with VIRAMUNE, and in 1% in either treatment group during the randomization phase¹
• Five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of treatment¹

Pharmacokinetics

• The multiple-dose pharmacokinetics of VIRAMUNE XR was studied in 24 HIV-1–infected adult patients who switched from chronic VIRAMUNE to VIRAMUNE XR¹
• The bioavailability of 400-mg VIRAMUNE XR relative to 400-mg VIRAMUNE under fasted and fed conditions was 80% and 94%, respectively¹
• The difference in the bioavailability of nevirapine, when VIRAMUNE XR is dosed under fasted or fed conditions, is not considered clinically relevant¹

Dosing and Administration

• ARV/VIRAMUNE-naïve adult patients¹
  • Adult patients must initiate therapy with one 200-mg tablet of immediate-release VIRAMUNE once daily for the first 14 days in combination with other ARV agents
  • From Day 15 on, adult patients take just one 400-mg tablet of VIRAMUNE XR once daily in combination with other ARV agents
  • Due to the increased risk of serious and life-threatening hepatotoxicity, initiation of VIRAMUNE treatment is not recommended in the following populations unless the benefit outweighs the risk
    • Men with a CD4+ cell count >400 cells/mm³
    • Women with a CD4+ cell count >250 cells/mm³
• VIRAMUNE-experienced adult patients¹
  • Adult patients already on a regimen of VIRAMUNE 200 mg twice daily in combination with other ARV agents can be switched to VIRAMUNE XR 400 mg once daily in combination with other ARV agents
• Without the 14-day lead-in period of once-daily 200-mg VIRAMUNE
• Without the CD4+ cell count restrictions
• Once-daily VIRAMUNE XR can be taken with or without food¹
• VIRAMUNE XR tablets must be swallowed whole and must not be chewed, crushed, or divided¹

Please see Important Safety Information below.

INDICATIONS AND USAGE

VIRAMUNE is indicated for use in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection.

VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

Important Considerations:

• 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 > 250 cells/mm³ or in adult males with CD4+ cell counts > 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.


• Adult patients already on a regimen of immediate-release VIRAMUNE twice daily can be switched to
  VIRAMUNE XR^™ 400 mg once daily without the 14-day lead-in period of immediate-release VIRAMUNE.


• For patients who interrupt VIRAMUNE XR^™ dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release VIRAMUNE using one 200 mg tablet daily for the first 14 days.

IMPORTANT SAFETY INFORMATION

WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS

• HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patients at increased risk; women with CD4+ cell counts > 250 cells/mm³, including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell counts, and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is contraindicated. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.


• SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with immediate-release VIRAMUNE 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed.


• MONITORING: Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.


• CONTRAINDICATIONS: Nevirapine is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment or for use in occupational and non-occupational PEP.


• Patients taking nevirapine should not take St. John's wort or efavirenz. Please see full Prescribing Information for additional drug-to-drug interactions.


• Immune reconstitution syndrome has been reported in patients treated with combination ARV therapy, including nevirapine. Fat redistribution or accumulation of body fat has been reported in patients receiving ARV therapy. The mechanism and long-term consequences of this are unknown.


• Other less common side effects include nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia.

Please consult full Prescribing Information, including boxed WARNING for VIRAMUNE XR.

REFERENCES
1. VIRAMUNE^® XR™ (nevirapine) extended-release tablets Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc.
2. Data on File. Boehringer Ingelheim Pharmaceuticals, Inc.