FDA Approves One-Pill, Once-Daily Viramune® XR™ (nevirapine) Extended-Release Tablets for Use in Combination With Other Antiretroviral Agents for Treatment of HIV-1 Infection in Adults

RIDGEFIELD, Conn., April 4, 2011 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Viramune® XR™ (nevirapine) extended-release tablets, a one-pill, once-daily (400 mg) formulation of nevirapine for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.  

"With the approval of once-daily VIRAMUNE XR, patients in the U.S. now have the benefit of a new HIV treatment option for use in combination with their other HIV medications," said Joseph Gathe, Jr.,  M.D., clinical instructor, Department of Internal Medicine, Baylor College of Medicine and lead investigator of the VERxVE clinical trial. "Physicians in the U.S. can now switch their current VIRAMUNE patients to a once-daily product with demonstrated comparable safety and efficacy."

Women with CD4+ > 250 cells/mm3, or men with CD4+ > 400 cells/mm3, should not begin taking VIRAMUNE or VIRAMUNE XR before consulting with their doctor due to potential serious and life-threatening hepatotoxicity. Patients can decide with their doctor whether the benefit of doing so outweighs the risk.

The approval of VIRAMUNE XR was based on data from the Phase III VERxVE study, which demonstrated that VIRAMUNE XR achieved a virologic response non-inferior to twice-daily immediate-release VIRAMUNE (200 mg) through 48 weeks, both used in combination with Truvada®, in treatment-naive HIV-1 infected adult patients. Results also showed that in treatment-naive patients, VIRAMUNE XR had a safety and tolerability profile comparable to immediate-release VIRAMUNE.

"Boehringer Ingelheim is committed to improving HIV therapy by providing physicians and patients with innovative antiretroviral medicines like VIRAMUNE XR," said Peter Piliero, M.D., executive director, Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "For patients switching from VIRAMUNE, the new formulation of nevirapine provides a dosing option that may decrease pill burden and dosing frequency."

A supportive study, TRANxITION, demonstrated that HIV-1 infected VIRAMUNE-experienced adult patients can safely and effectively switch from immediate-release VIRAMUNE to VIRAMUNE XR. This study was a Phase III, randomized, open-label, non-inferiority study to assess the efficacy, safety and tolerability of switching adult HIV-1 infected patients from a twice-daily, immediate-release VIRAMUNE (200 mg) based regimen to a once-daily VIRAMUNE XR (400 mg) based regimen.

For adult patients not currently on immediate-release VIRAMUNE, a 14-day lead-in dose of 200 mg immediate-release VIRAMUNE, once-daily, is necessary prior to taking VIRAMUNE XR once-daily because it has been demonstrated to reduce the frequency of rash. If rash persists beyond the 14-day lead-in period with immediate-release VIRAMUNE, patients should not begin dosing with VIRAMUNE XR until the rash has resolved. The lead-in dosing should not be continued beyond 28 days, at which point an alternative regimen should be sought. If dosing is interrupted for greater than seven days, patients should restart the 14-day lead-in dosing.

The recommended dose for VIRAMUNE XR is one 400 mg tablet taken once-daily, with or without food, in combination with other antiretroviral agents. For adult patients switching from immediate-release VIRAMUNE twice-daily to VIRAMUNE XR, there is no lead-in dosing and no CD4+ cell count restrictions.

To help patients reduce the cost of their prescription medicine co-pay for their VIRAMUNE XR therapy, Boehringer Ingelheim created the VIRAMUNE XR Co-Pay Savings Card so that financial considerations are less of a factor in maintaining their prescribed treatment. The VIRAMUNE XR Co-Pay Savings Card will pay for the first initial co-pay of VIRAMUNE XR therapy and up to $100 off each monthly VIRAMUNE XR prescription. Rules and eligibility requirements apply. For eligible patients, the program is available for up to one year. Patients can ask their healthcare providers for a card for more information.

Boehringer Ingelheim is committed to making its HIV medications more accessible to patients in financial need. As part of this commitment, Boehringer Ingelheim has expanded its Virology Patient Assistance program (BI PAP) to allow more patients to qualify to receive its medicines for free. BI is working with Heinz-Welvista to create a partnership that will provide access to its HIV medicines for patients on ADAP waiting lists. For more information on the BI PAP and eligibility, and to apply, patients in need should call 800-556-8317 or visit www.RxHope.com.

About the VERxVE Study

VERxVE is a randomized, double-blind, double-dummy, parallel group, active controlled, multinational trial conducted to evaluate the antiviral efficacy and safety of once-daily VIRAMUNE XR (400 mg) compared to twice-daily, immediate-release VIRAMUNE (200 mg), and the first large study in the U.S. to prospectively incorporate the CD4+ cell count criteria for VIRAMUNE. The study enrolled females with CD4+ cell counts less than 250 cells/mm3 and males with CD4+ cell counts less than 400 cells/mm3. A total of 1,068 treatment-naive adult patients were entered in VERxVE, and 1,011 adult patients were randomized to receive either VIRAMUNE XR or immediate-release VIRAMUNE after a required 14-day lead-in period with immediate-release VIRAMUNE for all patients. All patients also received a nucleoside reverse transcriptase inhibitor (NRTI) backbone of Truvada®.

Of the patients who received VIRAMUNE XR in the study, 80 percent (404/505) vs. 75 percent (379/506) of patients taking immediate-release VIRAMUNE (200 mg) achieved the study endpoint of viral load <50 copies/mL in the week 48 +/- 4 window, using the last viral load measurement if multiple measurements were taken in the window (Snapshot analysis). This demonstrated non-inferiority of VIRAMUNE XR to immediate-release VIRAMUNE. In patients with a HIV-RNA >100,000 copies/mL at baseline, the response rate was 73 percent for VIRAMUNE XR vs. 70 percent for immediate-release VIRAMUNE. In patients with baseline HIV-RNA </=100,000 copies/mL, the response rate was 82 percent for patients taking VIRAMUNE XR compared to 78 percent for patients taking immediate-release VIRAMUNE.

VERxVE results also showed that VIRAMUNE XR had a safety and tolerability profile comparable to immediate-release VIRAMUNE in treatment-naïve patients. After the lead-in period, the incidence of any hepatic event was six percent for adult patients taking VIRAMUNE XR and nine percent for adult patients taking immediate-release VIRAMUNE. The rate of symptomatic hepatic events was comparable in adult patients taking VIRAMUNE XR to those taking VIRAMUNE (two percent vs. three percent). Three percent of patients in both the VIRAMUNE XR and VIRAMUNE arms experienced grade 2 or higher rash. Five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of nevirapine treatment.

The most common side effect of VIRAMUNE XR and immediate-release VIRAMUNE is rash, which can be severe or life-threatening. The most serious adverse reactions associated with VIRAMUNE XR and immediate-release VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity, which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis (pink eye), facial edema, eosinophilia (an abnormally high number of eosinophils in the blood), granulocytopenia (an abnormally low concentration of granulocytes in the blood), lymphadenopathy (swelling/enlargement of the lymph nodes) or renal dysfunction.

INDICATION

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.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. 

For full VIRAMUNE XR Prescribing Information, including boxed WARNING and Medication Guide, please visit www.viramunexr.com or contact Boehringer Ingelheim Drug Information Unit at 1-800-542-6257.  

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of US $17.7 billion (12.7 billion euro) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

Truvada® is a registered trademark of Gilead Sciences, Inc.

Reference:

(1) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1-166. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 3, 2011.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.