FDA Approves New Darunavir Dose and Etravirine Strength

		SUMMARY: The U.S. Food and Drug Administration (FDA) recently approved new dose regimens for 2 widely used antiretroviral drugs. The protease inhibitor darunavir (Prezista), boosted with ritonavir, is now approved for once-daily dosing for treatment-experienced adults with HIV who have no known pre-existing darunavir-associated resistance mutations. The agency also approved a 200 mg formulation of the NNRTI etravirine (Intelence), allowing patients to take fewer pills at a time.

Below is an announcement from the FDA describing the darunavir label change, followed by an excerpt from a Tibotec press release describing the new etravirine formulation.

New Labeling Approved for Prezista (darunavir)

On December 13, 2010, FDA approved new labeling for Prezista (darunavir) to include a once daily dosing for treatment-experienced adult patients with no darunavir resistance associated substitutions. The major revisions to the package insert are summarized below. Other minor changes to the package insert and patient package insert were made for consistency.

Summary of Revisions:

A DOSAGE AND ADMINISTRATION Section 2.1 Treatment-Experienced Adult patient was revised as follows:

The recommended oral dose for treatment-experienced adult patients with no darunavir resistance associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) is 800 mg Prezista once daily with ritonavir 100 mg once daily and with food.

The recommended oral dose for treatment-experienced adult patients with at least one darunavir resistance associated substitution (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) is 600 mg Prezista twice daily taken with ritonavir 100 mg twice daily and with food.

For antiretroviral treatment experienced patients genotypic testing is recommended. However, when genotypic testing is not feasible, Prezista/ritonavir 600/100 mg twice daily dosing is recommended.

The following statement was added to section 6: ADVERSE REACTIONS

The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.

Section 12.3 Pharmacokinetics Table 8 was updated to include the population pharmacokinetic estimates of darunavir from Trial TMC114-C229 Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily.

Overall, darunavir exposures following darunavir/ritonavir 800/100 mg once daily in treatment experienced subjects were consistent with those previously assessed in treatment-naive subjects

Section 12.4 Microbiology was updated to include the results from Trial TMC114-C229 as follows:

In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving Prezista/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving Prezista/ritonavir 600/100 mg twice daily.

Examination of isolates from subjects who failed on Prezista/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on Prezista/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the Prezista/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the Prezista/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.

Section 14 CLINICAL STUDIES subsection 14.3 Treatment-Experiened Adult Subjects was updated to include the results from Trial TMC114-C229 as follows:

Study TMC114-C229

Study TMC114-C229 is a randomized, open label trial comparing Prezista/ritonavir 800/100 mg once daily to Prezista/ritonavir 600/100 mg twice daily in treatment experienced HIV 1 infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of > 1,000 HIV 1 RNA copies/ml. Both arms used an optimized background regimen consisting of 2 NRTIs selected by the investigator.

HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.

Table 16 compares the demographic and baseline characteristics between subjects in the Prezista/ritonavir 800/100 mg once daily arm and subjects in the Prezista/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No imbalances between the 2 arms were noted.

Virologic success (defined as HIV-1 RNA < 50 copies/mL) at Week 48 was 69% for both Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily.

The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the Prezista/ritonavir 800/100 mg once daily arm and the Prezista/ritonavir 600/100 mg twice daily arm, respectively).

The revised labeling will be posted soon at Drugs@FDA.

FDA Approves New Dosage Strength for Intelence

- New formulation reduces number of Intelence tablets taken daily

Titusville, N.J. -- January 3, 2011 -- The U.S. Food and Drug Administration (FDA) approved a label update to include a 200 mg formulation of Intelence (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for the treatment of human immunodeficiency virus (HIV-1) in treatment-experienced adults with resistance to an NNRTI and other antiretroviral (ARV) agents.

The recommended oral dose of Intelence tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The new 200 mg product formulation is expected to launch in the U.S. later this month, and the 100 mg tablet will remain available. Patients who are unable to swallow Intelence tablets whole may disperse the tablets in a glass of water.

The FDA granted accelerated approval to Intelence in January 2008, and it has since been approved in more than 65 countries. Intelence received traditional FDA approval in November 2009, based on 48-week data from the DUET-1 and DUET-2 studies, and is currently marketed in the U.S. by Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P.

Intelence Indication

Intelence, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in ARV treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other ARV agents. This indication is based on Week 48 analyses from two randomized, double-blind, placebo-controlled trials of Intelence. Both studies were conducted in clinically advanced, three-class ARV (NNRTI, N[t]RTI, PI) treatment-experienced adults.

The following points should be considered when initiating therapy with Intelence:

Treatment history and, when available, resistance testing, should guide the use of Intelence.

The use of other active ARV agents with Intelence is associated with an increased likelihood of treatment response.

In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use Intelence in combination with only N[t]RTIs.

The risks and benefits of Intelence have not been established in pediatric patients or in treatment-naive adult patients.

About the DUET studies

The DUET studies, identical in design and conducted across the Americas, Australia, Canada, Europe and Thailand, examined the use of Intelence in combination with other ARV agents in adult treatment-experienced HIV-1 patients with documented resistance to NNRTIs and protease inhibitors (PIs). Participants in the DUET studies were randomized to receive Intelence 200 mg twice daily or placebo, each given in addition to a background regimen (BR). For all patients, the BR included darunavir/ritonavir, plus at least two investigator-selected antiretroviral drugs (N(t)RTIs with or without enfuvirtide).

Important Safety Information

Intelence does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

Warnings & Precautions

Severe Skin and Hypersensitivity Reactions:

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking Intelence. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme

Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure

In the DUET studies, Grade 3 and 4 rashes were reported in 1.3% of patients receiving Intelence compared to 0.2% of patients in the placebo arm. Discontinuation rate due to rash was 2.2% in patients taking Intelence. Rash occurred most commonly during the first 6 weeks of therapy.

Discontinue Intelence immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema)

Monitor clinical status including liver transaminases, and initiate appropriate therapy

Delay in stopping Intelence treatment after the onset of severe rash may result in a life-threatening reaction

Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral (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 ARV therapy, including Intelence

Use in Specific Populations

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

Pregnancy Category B: Intelence 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 (> or = 2%) of at least moderate intensity (> or = Grade 2) reported in patients taking Intelence and that occurred at a higher rate compared with placebo were rash (10% vs 3%) and peripheral neuropathy (4% vs 2%)

Drug Interactions

Intelence should not be coadministered with the following ARVs: tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, full-dose ritonavir (600 mg bid), protease inhibitors administered without low-dose ritonavir, and other NNRTIs

Intelence should not be co-administered with carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin (when part of a regimen containing protease inhibitor/ritonavir) or products containing St. John's wort (Hypericum perforatum)

Coadministration of Intelence with other agents such as substrates, inhibitors, or inducers of CYP3A, CYP2C9, CYP2C19, and/or P-glycoprotein may alter the therapeutic effect or adverse reaction profile of Intelence or the coadministered drug(s)

This is not a complete list of potential drug interactions

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

Please see full Prescribing Information for more details. Full prescribing information is also available at www.INTELENCE-info.com.

About Tibotec Therapeutics

Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P., headquartered in Titusville, N.J., is dedicated to delivering innovative virology therapeutics that help healthcare professionals address serious unmet needs in people living with HIV. For more information, see www.tibotec.com.