FDA Notifications
January 1, 2009
Final rule issued on condom classification
The Food and Drug Administration (FDA) published a final rule on Nov. 10, 2008 amending the classification regulation for male condoms made of natural rubber latex (latex condoms) and latex condoms with spermicidal lubricant containing nonoxynol-9 (N-9), designating a guidance document containing labeling recommendations as a special control for latex condoms.
The final rule will become effective January 9, 2009.
The FDA is establishing the labeling guidance as a special control because it ensures that manufacturers will address the issues identified in the guidance. Regular guidance imposes no requirements. However, where a guidance document has been designated as a special control by a rule, manufacturers must address the issues identified in the guidance, either by following the recommendations in the guidance, or by some other means that provides equivalent assurances of safety and effectiveness.
Establishing a guidance document as a special control affords greater flexibility than a rule mandating specific labeling language, and can facilitate updating of the labeling as new scientific information becomes available because the special control permits manufacturers to use any labeling that affords equivalent assurances of safety and effectiveness for latex condoms.
In developing the rule and guidance, FDA evaluated a variety of scientific evidence and information about condoms and STIs. to assess the overall effectiveness of latex condoms in preventing transmission of STIs,
Based on review of scientific information and of existing latex condom labeling, FDA concluded that existing latex condom labeling was medically accurate in presenting the conclusion that, overall, condoms are effective in reducing the risk of sexually transmitted infections (STIs).
However, to help consumers make appropriate choices for their particular needs, and therefore to ensure the safe and effective use of condoms, FDA is establishing the labeling special control to address some additional, more nuanced information about condoms and STIs, as well as to provide information about contraception, and about appropriate directions and precautions for use of latex condoms.
The regulatory changes are intended to help ensure that latex condoms are used safely and effectively by providing labeling that conveys a concise, accurate message that neither exaggerates the degree of protection provided by latex condoms, nor undervalues overall STI-risk reduction provided by latex condom use.
The Nov. 10, 2008 Federal Register Notice of Final Rulemaking, which contains detailed information about the rule, and FDA's findings regarding effectiveness of latex condoms for a variety of STIs, is available on the FDA web site at http://www.fda.gov.
Background information is also available about the earlier Proposed Guidance for Condom Labeling.
New ART adult guidelines released
On Nov. 3, 2008, the Department of Health and Human Services' Panel on Antiretroviral Guidelines for Adults and Adolescents released a revised version of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
The following changes have been made to the Jan. 29, 2008 version of the guidelines. Key new updates are highlighted throughout the posted document (see below).
Format Changes: This revision is developed under a new format, whereby the relevant tables and references for each section are incorporated into the body of the document. Some larger tables are placed in an appendix at the end of the document. A separate PDF file with all the tables can be found at the AIDSinfo Web site.
Rating Changes: A new rating scheme is used in this guideline to be more consistent with other guidelines in infectious diseases.
The changes are outlined below:
- Strength of Recommendations - The D (should usually not be offered) and E (should never be offered) ratings have been removed. The A, B, and C ratings rate the strength of the statement. For example, an A rating for "not to initiate nevirapine in women with pre-treatment CD4 cell count >250 cells/mm3" indicates a strong recommendation to not initiate nevirapine in these patients.
- Quality of Evidence - Previously, only randomized trials with clinical endpoints were given a I ranking. In this new rating scheme, a I ranking includes randomized trials with either clinical or validated laboratory outcomes (e.g., viral load). A II rating includes non-randomized trials or well-designed observational cohort studies with long term clinical outcomes. A III rating remains a recommendation based on expert opinion.
- Content Changes - The key changes to the different sections of the guidelines are outlined below:
- Laboratory Monitoring - A new table (Table 3) provides recommendations for laboratory tests to obtain at baseline and while receiving antiretroviral therapy to monitor for safety and treatment responses.
- The Panel recommends that resistance testing be considered in patients with viral loads of 500–1,000 copies/mL but recognizes that it may not always be reliable at those levels (BII).
What to Start in Antiretroviral-Naïve Patients:
- Protease Inhibitor–Based Regimens: Ritonavir-boosted darunavir has been added as a preferred PI component (AI). Once-daily ritonavir-boosted lopinavir has been moved from alternative to preferred PI component (except for pregnant women) (AI).
- Dual-NRTI Options: Abacavir + lamivudine has been moved from a preferred to an alternative dual-NRTI component because of concerns regarding an increased risk of myocardial infarction in patients with high cardiac risk factors, as suggested by large observational cohort studies, and concerns regarding virologic potency in patients with baseline viral loads >100,000 copies/mL (BI).
- Combinations Not to Use or to Use with Caution: A combination of unboosted atazanavir + didanosine + emtricitabine (or lamivudine) is not recommended because of efficacy concerns (BI). A combination of nevirapine + tenofovir + emtricitabine (or lamivudine) should be used with caution and with close monitoring of virologic responses because of reports of early virologic failure in several small studies (CII).
- Management of Treatment-Experienced Patients:
- Regimen Simplification: A new section on Regimen Simplification for virologically suppressed patients has been added to the discussion of Management of the Treatment-Experienced Patient.
- Additional Updates: The following sections and their relevant tables have been updated:
- Introduction
- CD4+ T-cell count
- Viral Load Testing
- Coreceptor Tropism Assay
- What Not to Use
- Exposure Response and Therapeutic Drug Monitoring (and table for recommended antiretroviral drug concentrations)
- HIV-Infected Adolescents
- HIV-Infected Illicit Drug Users
- HIV-Infected Women
- Adherence to Antiretroviral Therapy (with a new table)
- Antiretroviral-Associated Adverse Effects (and table for detection and management of adverse effects)
- Antretroviral Drug Interactions (with a new format for interactions between antiretroviral and other drugs)
- Tables describing the characteristics of antiretroviral drugs.
The complete Nov. 3, 2008 version of the adult treatment guidelines is available on the AIDSinfo web site at http://aidsinfo.nih.gov.
Maraviroc approved for use in treatment-experienced CCR5-tropic HIV-1
On Nov. 25, 2008, the FDA granted full, traditional approval for the use of maraviroc in treatment-experienced patients infected with CCR5-tropic HIV-1. The change from accelerated to traditional approval was based on 48-week data from two double-blind, randomized, placebo-controlled,multicenter studies in subjects infected with CCR5-tropic HIV-1(A4001027 and A4001028).
Subjects were required to have an HIV-1 RNA of greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least one agent from three of the four antiretroviral drug classes or documented resistance or intolerance to at least one member of each class. All subjects received an optimized background therapy (OBT) consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the OBT, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo.
After 48 weeks of therapy, the proportion of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared to placebo was 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to week 48 were –1.84 log10 copies/mL for subjects receiving maraviroc + OBT compared to –0.78 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (124 cells/mm3) than on placebo + OBT (60 cells/mm3 ).
Some of the major labeling changes associated with the approval are shown below:
- Under the "Indications and Usage" section of the label the first bullet now reads "Tropism testing is required for the appropriate use of SELZENTRY."
- Under the "Warnings and Precautions" section of the label the second sentence under subsection 5.2 Cardiovascular Events now reads "Eleven subjects (1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies [total exposure 609 patientyears, (300 on once daily + 309 on twice daily SELZENTRY)], while no subjects who received placebo had such events (total exposure 111 patient-years)."
- Under the "Use in Specific Population" section of the label, subsection 8.7 Hepatic Impairment, now reads "Maraviroc is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because maraviroc concentrations may be increased. Maraviroc has not been studied in subjects with severe hepatic impairment. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]."
- Under the "Clinical Pharmacology" section of the label, Hepatic Impairment section was added following the Excretion section and reads, "Maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of SELZENTRY in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh class B, n=8) hepatic impairment to pharmacokinetics in healthy subjects (n=8). The mean Cmax and AUC were 11% and 25% higher, respectively, for subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with moderate hepatic impairment compared to subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 mg is administered with a strong CYP3A inhibitor compared to following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a strong CYP3A inhibitor should be monitored closely for maraviroc associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment. [see Warnings and Precautions (5.1)]"
- Under the "Clinical Pharmacology" section of the label, subsection Effects of Maraviroc on the Pharmacokinetics of Concomitant Drugs, the following was added after the first paragraph: "Maraviroc does not induce CYP1A2 in vitro. In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs."
Selzentry is distributed by Pfizer Labs.
The Food and Drug Administration (FDA) published a final rule on Nov. 10, 2008 amending the classification regulation for male condoms made of natural rubber latex (latex condoms) and latex condoms with spermicidal lubricant containing nonoxynol-9 (N-9), designating a guidance document containing labeling recommendations as a special control for latex condoms.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content