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FDA Approves Prescribing Information Update for EDURANT® (rilpivirine) to Include 96-Week Data in HIV-1-Infected Treatment-Naive Adult Patients

TITUSVILLE, N.J., Dec. 10, 2012 /PRNewswire/ -- Janssen Therapeutics, Division of Janssen Products, LP, announced today that the U.S. Food and Drug Administration (FDA) has approved a prescribing information update for EDURANT® (rilpivirine) tablets to include 96-week pooled data from the Phase 3 ECHO and THRIVE studies, which evaluated the efficacy and safety of EDURANT® for the treatment of human immunodeficiency virus type 1 (HIV-1) in antiretroviral treatment-naive adults.

In addition to the inclusion of the 96-week data in the prescribing information, the Indications and Usage section was revised to read: EDURANT®, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naive adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.

This indication is based on safety and efficacy analyses through 96 weeks from two randomized, double-blind, active-controlled Phase 3 trials in treatment-naïve subjects.

The following points should be considered when initiating therapy with EDURANT®:

More EDURANT® treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA greater than or equal to 50 copies/mL) compared to EDURANT® treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL.
Regardless of HIV-1 RNA at the start of therapy, more EDURANT® treated subjects with CD4+ cell count less than 200 cells/mm³ experienced virologic failure compared to EDURANT® treated subjects with CD4+ cell count greater than or equal to 200 cells/mm³.
The observed virologic failure rate in EDURANT® treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
More subjects treated with EDURANT® developed tenofovir- and lamivudine/emtricitabine-associated resistance compared to efavirenz.

EDURANT® is not recommended for patients less than 18 years of age.

The Warnings and Precautions section was updated with information on hepatotoxicity (liver damage). This section now states that patients with underlying hepatic (liver) disease, including hepatitis B or C, or marked elevations in transaminases (liver enzymes) before treatment may be at increased risk for worsening or development of liver enzyme elevations. Monitor liver function tests (LFTs) before and during treatment. A few liver damage cases occurred in patients with no pre-existing hepatic disease or other identifiable risk factors, therefore, monitoring of LFTs should be considered in all patients.

The full revised EDURANT® label is available at:
http://www.edurant.com/sites/default/files/EDURANT-PI.pdf

"EDURANT® is an important option for adult patients who are starting HIV therapy for the first time," said David Anderson, MD, Senior Medical Director, Janssen Therapeutics. "We are committed to continuing to provide information to help physicians and people living with HIV make the most appropriate treatment decisions."

The updated 96-week data in the prescribing information is based on results from pooled analyses of data from the Phase 3 trials ECHO and THRIVE, which were randomized, double-blind, and active-controlled studies in treatment-naive adult patients with HIV-1.

ECHO and THRIVE 96-Week Study Results
The ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and efavirenz, or TMC278-C209) and THRIVE (TMC278 against HIV, in a once-daily RegImen Versus Efavirenz, or TMC278-C215) studies evaluated EDURANT® (25 mg once daily) in antiretroviral treatment-naive adults. A pooled analysis showed that at 96 weeks:

76 percent of patients in the EDURANT® arm reached an undetectable viral load (the amount of virus in the blood, defined as less than 50 HIV-1 RNA copies/mL) vs. 77 percent of patients in the efavirenz arm.
Patients taking EDURANT® had a virologic failure rate of 16 percent compared to 10 percent experienced by patients taking efavirenz. Upon virologic failure, the emergence of resistance and cross-resistance to the NNRTI class was higher in the EDURANT® arm compared to the efavirenz arm.
Adverse events or deaths leading to discontinuation in the EDURANT® arm were 4 percent compared to 8 percent in the efavirenz arm.
The most common adverse drug reactions (ADRs) to EDURANT® (incidence > 2 percent) of at least moderate-to-severe intensity (greater than or equal to Grade 2) were depressive disorders (5 percent), headache (3 percent), insomnia (3 percent), and rash (3 percent). The proportion of patients who discontinued treatment with EDURANT® or efavirenz due to ADRs, regardless of severity, was 2 percent and 4 percent, respectively.

Additional Information About the ECHO and THRIVE Studies
ECHO and THRIVE evaluated the efficacy and safety of EDURANT® in 1,368 antiretroviral treatment-naive HIV-1-infected adults with plasma HIV-1 RNA greater than or equal to 5000 copies/mL. The studies were identical in design, with the exception of the background regimen (BR). Patients were randomized to receive either EDURANT® (25 mg once daily) plus BR (n=686), or efavirenz (600 mg once daily) plus BR (n=682).

In ECHO, the BR was fixed to the specific nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate plus emtricitabine.
In THRIVE, the BR consisted of two investigator-selected N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine.

In the pooled analysis, demographics and baseline characteristics were balanced between both arms and randomization was stratified by screening viral load in both trials, and by nucleos(t)ide backbone in THRIVE.

Important Safety Information

Contraindications

Coadministration of EDURANT® with the following drugs is contraindicated because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance and cross-resistance: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, proton pump inhibitors such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, systemic dexamethasone (more than single dose), and products containing St. John's wort (Hypericum perforatum)

Warnings and Precautions

Depressive Disorders: Severe depressive disorders, defined as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation, have been reported with EDURANT®. Immediate medical evaluation is recommended for severe depressive symptoms
Hepatotoxicity: Hepatic adverse events were reported. Patients with underlying hepatic disease, including hepatitis B or C, or marked elevations in transaminases before treatment may be at increased risk for worsening or development of transaminase elevations. Monitor liver function tests (LFTs) before and during treatment. A few hepatotoxicity cases occurred in patients with no pre-existing hepatic disease or other identifiable risk factors, therefore, monitoring of LFTs should be considered in all patients
Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established
Immune Reconstitution Syndrome has been reported in patients treated with combination ARV therapy, including EDURANT®. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment

Drug Interactions

EDURANT® should be used with caution when coadministered with drugs that may reduce the exposure of rilpivirine, such as antacids and H2-receptor antagonists
EDURANT® should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes
EDURANT® should not be used in combination with NNRTIs

This is not a complete list of potential drug interactions.

Please see full Prescribing Information for more details.

Use in Specific Populations

Hepatic Impairment: EDURANT® should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics of EDURANT® have not been evaluated in these patients
Pregnancy Category B: EDURANT® 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

Adverse Reactions

The most common adverse drug reactions reported (incidence >2%) of at least moderate intensity (≥ Grade 2) in patients taking EDURANT® through 96 weeks were: depressive disorders (5%), insomnia (3%), headache (3%), and rash (3%)

Please see full Prescribing Information for more details.

About Janssen Therapeutics
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in HIV and other infectious diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Headquartered in Titusville, New Jersey, Janssen Therapeutics, Division of Janssen Products, LP, is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Visit www.JanssenTherapeutics.com for more information and follow us on Twitter at @JanssenUS.

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FDA Approves Prescribing Information Update for EDURANT® (rilpivirine) to Include 96-Week Data in HIV-1-Infected Treatment-Naive Adult Patients

More EDURANT® treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA greater than or equal to 50 copies/mL) compared to EDURANT® treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL.
Regardless of HIV-1 RNA at the start of therapy, more EDURANT® treated subjects with CD4+ cell count less than 200 cells/mm³ experienced virologic failure compared to EDURANT® treated subjects with CD4+ cell count greater than or equal to 200 cells/mm³.
The observed virologic failure rate in EDURANT® treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
More subjects treated with EDURANT® developed tenofovir- and lamivudine/emtricitabine-associated resistance compared to efavirenz.

76 percent of patients in the EDURANT® arm reached an undetectable viral load (the amount of virus in the blood, defined as less than 50 HIV-1 RNA copies/mL) vs. 77 percent of patients in the efavirenz arm.
Patients taking EDURANT® had a virologic failure rate of 16 percent compared to 10 percent experienced by patients taking efavirenz. Upon virologic failure, the emergence of resistance and cross-resistance to the NNRTI class was higher in the EDURANT® arm compared to the efavirenz arm.
Adverse events or deaths leading to discontinuation in the EDURANT® arm were 4 percent compared to 8 percent in the efavirenz arm.
The most common adverse drug reactions (ADRs) to EDURANT® (incidence > 2 percent) of at least moderate-to-severe intensity (greater than or equal to Grade 2) were depressive disorders (5 percent), headache (3 percent), insomnia (3 percent), and rash (3 percent). The proportion of patients who discontinued treatment with EDURANT® or efavirenz due to ADRs, regardless of severity, was 2 percent and 4 percent, respectively.

In ECHO, the BR was fixed to the specific nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate plus emtricitabine.
In THRIVE, the BR consisted of two investigator-selected N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine.

Coadministration of EDURANT® with the following drugs is contraindicated because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance and cross-resistance: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, proton pump inhibitors such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, systemic dexamethasone (more than single dose), and products containing St. John's wort (Hypericum perforatum)

Warnings and Precautions

Depressive Disorders: Severe depressive disorders, defined as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation, have been reported with EDURANT®. Immediate medical evaluation is recommended for severe depressive symptoms
Hepatotoxicity: Hepatic adverse events were reported. Patients with underlying hepatic disease, including hepatitis B or C, or marked elevations in transaminases before treatment may be at increased risk for worsening or development of transaminase elevations. Monitor liver function tests (LFTs) before and during treatment. A few hepatotoxicity cases occurred in patients with no pre-existing hepatic disease or other identifiable risk factors, therefore, monitoring of LFTs should be considered in all patients
Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established
Immune Reconstitution Syndrome has been reported in patients treated with combination ARV therapy, including EDURANT®. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment

Drug Interactions

EDURANT® should be used with caution when coadministered with drugs that may reduce the exposure of rilpivirine, such as antacids and H2-receptor antagonists
EDURANT® should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes
EDURANT® should not be used in combination with NNRTIs

This is not a complete list of potential drug interactions.

Please see full Prescribing Information for more details.

Use in Specific Populations

Hepatic Impairment: EDURANT® should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics of EDURANT® have not been evaluated in these patients
Pregnancy Category B: EDURANT® 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

Adverse Reactions

The most common adverse drug reactions reported (incidence >2%) of at least moderate intensity (≥ Grade 2) in patients taking EDURANT® through 96 weeks were: depressive disorders (5%), insomnia (3%), headache (3%), and rash (3%)

Employees