FDA Notifications

New etravirine tablet approved by FDA

On Dec. 22, 2010, the Food and Drug Administration approved a new 200 mg etravirine (Intelence®) tablet. Etravirine was originally approved in 2008, in only a 100 mg tablet formulation. The new 200 mg dosage form can help reduce pill burden for patients taking Intelence.

The Dosage and Administration section was changed to state: 200 mg (one 200 mg or two 100 mg tablets) taken twice daily following a meal.

Etravirine is a Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI), made by Tibotec Therapeutics.

The revised product label, reflecting the 200 mg tablet approval can be found at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022187s007lbl.pdf.

Once daily dosing of darunavir approved

On Dec. 13, 2010, the FDA approved new labeling for darunavir (Prezista®) 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-naïve subjects."

The revised labeling will be posted soon at Drugs@FDA. Darunavir is a product of Tibotec Pharmaceuticals.

Comment period open on guidance for INDs

The Food and Drug Administration (FDA) is providing an opportunity to comment on a new draft guidance for industry entitled "Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination." This guidance is intended to assist sponsors in the codevelopment of two or more novel (not previously marketed) drugs to be used in combination to treat a disease or condition.

This guidance provides recommendations and advice on how to address certain scientific and regulatory issues that will arise during codevelopment.

The guidance is not intended to apply to development of fixed-dose combinations of already marketed drugs or to development of a single new investigational drug to be used in combination with an approved drug or drugs, nor to vaccines, gene or cellular therapies, blood products, or medical devices.

Recent scientific advances have increased our understanding of the pathophysiological processes that underlie many complex diseases, such as cancer, cardiovascular disease, and infectious diseases, including HIV. This increased understanding has provided further impetus for new therapeutic approaches that rely primarily or exclusively on combinations of drugs directed at multiple therapeutic targets to improve treatment response and minimize development of resistance.

In settings in which combination therapy provides significant therapeutic advantages, there is growing interest in the development of combinations of investigational drugs not previously developed for any purpose. Because the existing developmental and regulatory paradigm focuses primarily on assessment of the effectiveness and safety of a single new investigational drug acting alone, or in combination with an approved drug, FDA believes guidance is needed to assist sponsors in the codevelopment of two or more unmarketed drugs.

This guidance is intended to describe a high level, generally applicable approach to codevelopment of two or more unmarketed drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues.

Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by Feb. 14, 2011.

Electronic comments on the draft guidance may be submitted to http://www.regulations.gov. Address comments to Docket No. FDA–2010–D–0616.

Submit written comments to the Division of Dockets Management (HFA–305) Food and Drug Administration, 5630 Fishers Lane, rm. 1061 Rockville, MD 20852.

Comment period open on combination drugs

The Food and Drug Administration (FDA) is providing an opportunity to comment on a new draft guidance for industry entitled "Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination." This guidance is intended to assist sponsors in the codevelopment of two or more novel (not previously marketed) drugs to be used in combination to treat a disease or condition.

This guidance provides recommendations and advice on how to address certain scientific and regulatory issues that will arise during codevelopment.

The guidance is not intended to apply to development of fixed-dose combinations of already marketed drugs or to development of a single new investigational drug to be used in combination with an approved drug or drugs, nor to vaccines, gene or cellular therapies, blood products, or medical devices.

Recent scientific advances have increased our understanding of the pathophysiological processes that underlie many complex diseases, such as cancer, cardiovascular disease, and infectious diseases, including hepatitis. This increased understanding has provided further impetus for new therapeutic approaches that rely primarily or exclusively on combinations of drugs directed at multiple therapeutic targets to improve treatment response and minimize development of resistance.

In settings in which combination therapy provides significant therapeutic advantages, there is growing interest in the development of combinations of investigational drugs not previously developed for any purpose. Because the existing developmental and regulatory paradigm focuses primarily on assessment of the effectiveness and safety of a single new investigational drug acting alone, or in combination with an approved drug, FDA believes guidance is needed to assist sponsors in the codevelopment of two or more unmarketed drugs.

This guidance is intended to describe a high-level, generally applicable approach to codevelopment of two or more unmarketed drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues.

Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by February 14, 2011.

Electronic comments on the draft guidance may be submitted to http://www.regulations.gov. Address comments to Docket No. FDA–2010–D–0616.

Submit written comments to the Division of Dockets Management (HFA–305) Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

New Zerit labeling approved

On Dec. 10, 2010, the FDA approved new labeling for stavudine (Zerit©) capsules and Zerit for oral solution. The revisions to the Dosage and Administration, Warnings and Precautions, Adverse Reaction sections in both package inserts are outlined below.

Other important changes include conversion of the package insert to physicians labeling rule (PLR) format), and conversion of the patient package insert to Medication Guide. Minor changes to the package inserts were made for consistency.

Summary of Revisions:

Under Dosage and Administration, Dosage Adjustment (Section 2.3) was modified to remove statements for dose reductions for peripheral neuropathy because dose reductions for peripheral neuropathy have not been established, and importantly dose reduction is less relevant in the current setting of HIV infection and multiple available HIV treatment options.

Warnings and Precautions (Section 5.5 ) for Fat Redistribution was modified in both package inserts as shown below. The changes reflect the strong causal relationship of lipodystrophy with stavudine demonstrated in clinical trials. Data from longitudinal clinical trials in both antiretroviral naïve and treatment-experienced patients demonstrate a higher frequency of clinical lipoatrophy in subjects receiving stavudine-containing regimens compared to regimens containing other nucleotides, specifically tenofovir or abacavir (Haubrich RH AIDS 2009, Podzamczer D AIDS 2007). Additionally, stavudine use was associated with decreases in limb fat compared to increases in limb fat observed with other nucleotides. Other published reports indicate lipoatrophy did not completely resolve following stavudine discontinuation, although modest increase in limb fat was observed after discontinuation (Carr A JAMA 2002, Martin A AIDS 2004).

Section 5.5 Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving ZERIT should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using ZERIT including lipoatrophy and lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

Adverse Reactions (Section 6.3 ) were modified to include neutropenia, lipoatrophy, and lipodystrophy under Postmarketing Events in the package inserts. The revised labeling will be posted soon at Drugs@FDA.