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Human Immunodeficiency Virus and
Acquired Immunodeficiency Syndrome

FDA HIV/AIDS List Serve Archive 2007

On December 20, 2007, FDA granted tentative approval for a generic formulation of efavirenz tablets, 600 mg, manufactured by Emcure Pharmaceuticals of Pune, India The application was reviewed under the expedited review provisions of the President’s Emergency Plan for AIDS Relief (PEPFAR).

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.  

However, although tentatively approved generic products meet required standards, they cannot yet be fully approved and sold in the U.S. because of existing patents and/or exclusivity rights. But the tentative approval does make the product eligible for consideration for purchase under the PEPFAR program for use in nations where PEPFAR is active.

This product is a generic formulation of Sustiva tablets, 600 mg, made by Bristol Myers Squibb Co. which is subject to existing patents, as listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

Efavirenz is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) indicated for treatment of HIV infection in combination with other antiretroviral agents.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The  Lexiva (fosamprenavir) label was recently updated to include new drug-drug interaction information regarding phenytoin (an anticonvulsant)  and paroxetine (an antidepressent).

Details of the newly added information are shown below.

Table 6. Established And Other Potentially Significant Drug Interaction

In addition, section 12.3 Pharmacokinetics, Table 10 and 12, were updated to show the results of the interaction study with phenytoin as follows:

Table 10. Drug Interactions: Pharmacokinetic Parameters for Amprenavir After Administration of LEXIVA in the Presence of the Coadministered Drug(s)

Table 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir After Administration of LEXIVA

The complete revised label is available at  http://www.fda.gov/cder/foi/label/2007/021548s014lbl.pdf 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The FDA issued a final rule on December 18, 2007 requiring manufacturers of over-the-counter (OTC) stand-alone vaginal contraceptive and spermicidal products containing the chemical ingredient nonoxynol 9 (N9) include a warning stating that the chemical N9 does not provide protection against infection from HIV (the virus that causes AIDS) or other sexually transmitted diseases (STDs).

Stand-alone spermicides include gels, foams, films, or inserts containing N9 that are used by themselves for contraception. Consumers can protect themselves from the transmission of STDs and HIV by practicing abstinence, being in a monogamous relationship where neither partner is infected, and using condoms consistently and correctly.

FDA is issuing the rule in an effort to correct misconceptions that N9 protects against sexually transmitted diseases, including HIV infection.

Nonoxynol 9 is approved as a vaginal contraceptive that works by damaging the cell membrane of sperm. It has been shown in laboratory studies to damage the cell walls of certain organisms that cause STDs and to be active against some STD-causing bacteria and viruses. Over the years, many consumers have come to believe that N-9 could reduce the potential for transmission of HIV and other STDs.  FDA believes that the membrane-damaging effect can harm the cell lining of the vagina, cervix and rectum, thereby increasing the risk of HIV and STD transmission.

FDA is requiring that the labels warn consumers that the chemical N9 in stand-alone vaginal contraceptives and spermicides can irritate the vagina and rectum, which may increase the risk of contracting HIV/AIDS from an infected partner.

In January, 2003 FDA proposed new warning statements and other labeling information for these products after results from a major clinical study in Africa and Thailand showed that women using a contraceptive gel product containing N9 were not protected against HIV and other STDs and were, in fact, at higher risk for HIV infection than women using a placebo gel. Because these and other studies have shown that use of products containing N9 cause vaginal and rectal irritation that can heighten the chance of becoming infected with HIV from an infected partner, FDA believes the warning will empower consumers to make better informed decisions about the use of these products, and better protect the public health.

This rule is being finalized following a public comment period and a thorough analysis of information and views from consumers, health care providers, academicians and industry. FDA is requiring that labeling of OTC vaginal contraceptive/spermicidal products containing N9 bear the following warnings:

• For vaginal use only
• Not for rectal (anal) use
• Sexually transmitted diseases (STDs) alert: This product does not protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner
• Do not use if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control.
• When using this product you may get vaginal irritation (burning, itching, or a rash)
• Stop use and ask a doctor if you or your partner get burning, itching, a rash or other irritation of the vagina or penis

Other information in the new labeling includes:

• Studies have raised safety concerns that products containing the spermicide nonoxynol 9 can irritate the vagina and rectum. Sometimes this irritation has no symptoms. This irritation may increase the risk of getting HIV/AIDS from an infected partner.
• You can use nonoxynol 9 for birth control with or without a diaphragm or condom if you have sex with only one partner who is not infected with HIV and who has no other sexual partners or HIV risk factors
• When used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate the risk of catching or spreading HIV, the virus that causes AIDS.
• Use a latex condom without nonoxynol 9 if you or your sex partner has HIV/AIDS, multiple sex partners, or other HIV risk factors
• Ask a health professional if you have questions about your best birth control and STD prevention methods

FDA is issuing the final rule to provide a clear, consistent message that N9 is not effective in preventing HIV transmission, and that N9 may actually facilitate transmission of the disease for those who are at risk for HIV/AIDS. The final rule is consistent with FDA’s draft guidance for N9 use with condoms.

The full text of the final rule is available at www.fda.gov/OHRMS/DOCKETS/98fr/80n-0280-nfr0003.pdf

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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From the Morbidity and Mortality Weekly Report (MMWR) <http://www.cdc.gov/mmwr/index.html>   
December 14, 2007  / 56(49);1291-1292

In 1996, the U.S. Public Health Service first recommended using  antiretrovirals as postexposure prophylaxis (PEP) after occupational  exposure to human immunodeficiency virus (HIV) (1 <http://www.cdc.gov/mmwr/preview/mmwrhtml/00042200.htm> ).  Since the updated HIV PEP recommendations in 2005 (2 <http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm> ),  two important changes to antiretroviral use have occurred that affect the  management of occupational exposures.  

First, Kaletra® (Abbott Laboratories, Abbott Park,  Illinois), a combination protease inhibitor, is no longer available in its  original formulation: capsules containing 133 mg of lopinavir and 33 mg of  ritonavir. Although the recommended daily prescribed amount of Kaletra  ingredients is unchanged, the dosing regimen has changed as a result of  the new Kaletra formulation. The previous dosing regimen for the capsule  formulation was three capsules twice daily.Kaletra is now manufactured  only in tablet form, with each tablet containing 200 mg of lopinavir and  50 mg of ritonavir. To achieve the same recommended daily prescribed  amount of the tablet formulation, two tablets of 200 mg of lopinavir and  50 mg of ritonavir should be taken twice daily. Health-care providers  should not prescribe three tablets twice a day of the new Kaletra  formulation; that dose would be the equivalent of 1,200 mg of lopinavir  and 300 mg of ritonavir daily, a higher dose than the recommended 800 mg  of lopinavir and 200 mg of ritonavir daily.

Second, on September 10, 2007, Pfizer, Inc. issued a letter* warning  health-care providers about the use of Viracept® (nelfinavir)  (Pfizer, Inc., New York, New York), another protease inhibitor, because  the Viracept manufactured in Europe contained high levels of ethyl methane  mesylate (EMS). EMS is a byproduct of the manufacturing process and a  known animal carcinogen, mutagen, and teratogen. The level at which EMS  might become carcinogenic or teratogenic in humans is not known. The  warning in the letter applies to pregnant women and states that  information about the ability of EMS to cross the placenta or to enter  breast milk is currently unknown. A review of data from the Antiretroviral  Pregnancy Registry, which collects data on approximately 6,000  HIV-infected pregnant women, indicated that, during January 1989--January  2007, no statistically significant difference was observed in the  prevalence of birth defects among the infants of women who used Viracept  compared with those whose mothers used other antiretroviral therapies  (3). Nonetheless, the Food and Drug Administration (FDA) recommends  that pregnant women limit their exposure to EMS during pregnancy. Until  further notice, pregnant women who need to begin antiretroviral therapy or  HIV PEP should not be offered regimens containing Viracept. As a  precautionary measure, pregnant women currently receiving Viracept should  be switched to an alternative antiretroviral therapy while Pfizer and FDA  work to implement a long-term EMS specification for Viracept. Specific  recommendations for use of antiretroviral agents in pregnant  HIV-1--infected patients are indicated in the U.S. Department of Health  and Human Services guidelines (4) and can be consulted to determine  an alternative treatment option.

Because nearly 80% of U.S. health-care personnel are female (5)and many of these women are of child-bearing age, this updated information  about Viracept might be relevant to the choice of drugs included in an HIV  PEP regimen taken by female health-care personnel. Additional information and guidance regarding management of specific exposures are available from the National Clinicians' Post-Exposure Prophylaxis Hotline by telephone(888-448-4911) or online (http://www.ucsf.edu/hivcntr).

References

1. CDC.  Update: provisional Public Health Service recommendations for  chemoprophylaxis after occupational exposure to HIV. MMWR 1996;  45:468--72. <http://www.cdc.gov/mmwr/preview/mmwrhtml/00042200.htm>
2. CDC.  Updated U.S. Public Health Service guidelines for the management of  occupational exposures to HIV and recommendations for postexposure  prophylaxis. MMWR 2005;54(No. RR-9):1--17. <http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm>
3. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral  Pregnancy Registry international interim report for 1 January 1989  through 31 January 2007. Wilmington, NC: Registry Coordinating Center;  2007. Available at http://www.apregistry.com <http://www.apregistry.com/> .
4. US Department of Health and Human Services, Panel on Clinical  Practices for Treatment of HIV Infection. Guidelines for the use of  antiretroviral agents in HIV-1-infected adults and  adolescents---December 1, 2007. Available at http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.
5. US Department of Labor, Bureau of Labor Statistics. Employed persons  by detailed industry and sex, 2006 annual average. Available at http://www.bls.gov/cps/wlf-table14-2007.pdf.
   

* Available at http://www.viracept.com/pdf/viracept_hcpletter_9_10_07.pdf.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Food and Drug Administration (FDA) proposes to revise and update the regulations applicable to blood and blood components, including Source Plasma and Source Leukocytes, to add donor requirements that are consistent with current practices in the blood industry, and to more closely align the regulations with current FDA recommendations. FDA is taking this action to help ensure the safety of the national blood supply and to help protect donor health by requiring establishments to evaluate donors for factors that may adversely affect the safety, purity, and potency of blood and blood components, or the health of a donor during the donation process.

Through the years, FDA has issued a number of guidance documents containing recommendations intended to assure a safe, pure, and potent blood supply. The Notice of Proposed Rulemaking discusses the recommendations contained in current guidance that fall under the proposed regulation, including donor eligibility and screening for HIV and certain other transfusion-transmitted infections.  FDA believe the proposed rule will more explicitly describe donor eligibility standards and will clarify the relationship between the regulations and the applicable recommendations.

The proposed rule, among other things, provides for the establishment of minimum criteria for the assessment of donor eligibility, and the suitability of the donation of blood and blood components. The rule is expected to have a minor net impact on blood establishments because it is already usual and customary business practice in the blood industry to assess donors for eligibility, and donations for suitability. FDA believes the primary impact of the rule will be the one-time review of current SOPs that the proposed rule would require each blood collecting establishment to conduct. 

Written or electronic comments on the proposed rule, identified by Docket No. 2006N- 0221, may be submitted to the agency until February 6, 2008 through any of the following methods:

Electronic Submissions Submit electronic comments in the following ways: Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. Follow the instructions for submitting comments.

Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. Follow the instructions for submitting comments on the agency Web site.

Written Submissions: Submit written submissions in the following ways: FAX: 301-827-6870. Mail/Hand delivery/Courier [For paper, disk, or CD-ROM submissions]: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

Richard Klein
HIV/AIDS Program Director
Food and Drug Administration

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On December 1, 2007, the DHHS 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 several sections of the October 10, 2006 version of the guidelines. Additional revisions to other sections of these guidelines will be released during 2008.

Laboratory Assessment

• Drug Resistance Testing – The Panel recommends performing genotypic drug resistance testing for all treatment-naïve patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated (AIII). This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated (CIII).
• Tropism Assay – The Panel recommends tropism testing prior to the initiation of a CCR5 antagonist, such as maraviroc (AII). Coreceptor tropism testing might also be considered for patients exhibiting virologic failure on maraviroc (or any CCR5 inhibitor) (BIII).
• HLA-B*5701 Testing – The Panel recommends HLA-B*5701 testing prior to initiating abacavir therapy to reduce the risk of hypersensitivity reaction (AI). HLA-B*5701-positive patients should not be prescribed abacavir (AI), and the positive status should be recorded as an abacavir allergy in the patient’s medical record (AII). When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counselling and monitoring for any signs of abacavir-associated hypersensitivity reaction(CIII).

When to Start Antiretroviral Therapy

1. The Panel recommends that antiretroviral therapy should be initiated in patients with history of an AIDSdefining illness or with a CD4 T-cell count <350 cells/mm3; the data supporting this recommendation are stronger for those with a CD4 T-cell count <200 cells/mm3 and with a history of AIDS (AI) than for those with CD4 T-cell counts between 200 and 350 cells/mm3 (AII).
2. The Panel also recommends treatment for the following groups regardless of CD4 T-cell count:
   1. pregnant patients (AI);
   2. patients with HIV associated nephropathy (AI)
   3. patients coinfected with hepatitis B when treatment for hepatitis B virus is indicated (BIII).
3. The optimal time to initiate therapy in asymptomatic patients with CD4 T-cell count >350 cells/mm3 is not well defined. The decision of whether or not to start therapy in these patients should take into account the potential benefits and risks associated with therapy, comorbidities, and patient readiness and willingness to adhere to long-term treatment.

Management of Treatment-Experienced Patients

This section was revised to include (1) a review of the newer classes of antiretroviral agents (CCR5 antagonists and integrase inhibitors) and their roles in the management of treatment-experienced patients with virologic failure; and (2) a discussion of immunologic failure.

Tables Update

Various tables have been updated to reflect new recommendations and new information on specific antiretroviral drugs.

The complete December 1, 2007 version of the adult treatment guidelines is available on the AIDSinfo web site at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On November 30, 2007, FDA granted tentative approval for a generic version of Tenofovir Disoproxil Fumarate Tablets, 300 mg, manufactured by Matrix Laboratories Limited, of Hyderabad, India.  The application was reviewed under the expedited review provisions of the President's Emergency Plan for AIDS Relief (PEPFAR).

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it is not yet eligible to be marketed in the U.S. because of existing patents and/or exclusivity rights. However, this tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.
This is a generic version of Viread Tablets, 300 mg, manufactured by Gilead Sciences, Inc,, which is subject to existing patent protection.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Tenofovir is a nucleoside reverse transcriptase inhibitor (NRTI) indicated for treatment of HIV infection in adults and adolescents in combination with other antiretroviral agents.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On November 29, 2007, FDA granted tentative approval under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR), for a generic formulation of combination lamivudine/zidovudine tablets, 150 mg/300 mg, manufactured by Matrix Laboratories, Inc. of Hyderabad, India.

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, the tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts on-site inspections of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

This is a generic formulation of Combivir Tablets, 150 mg/300 mg, marketed by GlaxoSmithKline, which is subject to patent and pediatric exclusivity protections.

Effective patent dates and additional marketing exclusivities can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

Lamivudine and zidovudine are both Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for used in combination with other antiretroviral agents in the treatment of HIV infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On November 9, 2007, FDA approved a new half-strength Kaletra tablet formulation. Each film-coated tablet contains 100 mg lopinavir and 25 mg ritonavir. The major changes to the label include clear instructions regarding accurate calculation of the dose of Kaletra to minimize the risk for medication errors, overdose, or under dose, and the addition of tablet dosing to section 2.2, Pediatric Patients. Labeling for Kaletra is availble on the FDA web site at Drugs@FDA.

Kaletra is a combination protease inhibitor product containing lopinavir and ritonavir, manufactured by Abbott Laboratories. The original formulation was approved on September 15, 2000.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On November 9, 2007, FDA approved a new half-strength Kaletra tablet formulation. Each film-coated tablet contains 100 mg lopinavir and 25 mg ritonavir. The major changes to the label include clear instructions regarding accurate calculation of the dose of Kaletra to minimize the risk for medication errors, overdose, or under dose, and the addition of tablet dosing to section 2.2, Pediatric Patients. Labeling for Kaletra is availble on the FDA web site at Drugs@FDA.

Kaletra is a combination protease inhibitor product containing lopinavir and ritonavir, manufactured by Abbott Laboratories. The original formulation was approved on September 15, 2000.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

The Food and Drug Administration is publishing final Guidance for Industry on the Role of HIV Resistance Testing in Antiretroviral Drug Development. This final guidance discusses the nonclinical studies (mechanism of action; antiviral activity in vitro; cytotoxicity/therapeutic index; and the effects of serum protein binding on antiviral activity) the agency recommends be completed prior to the initiation of phase 1 clinical studies in HIV-infected patients. In addition, the guidance addresses the use of resistance testing in the clinical phases of drug development and recommends the type of information that should be collected and the types of analyses that should be conducted to characterize an antiretroviral's resistance profile.

The guidance also discusses the role of resistance testing in initial activity and dose-finding, for study enrollment criteria, for background regimen selection, and to establish an indication.

The guidance represents the agency's current thinking on the role of HIV resistance testing in antiretroviral drug development. As with all FDA guidance for industry, it does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

You may find this and other Guidance for Industry on the FDA web site at http://www.fda.gov/cder/guidance/index.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On November 2, 2007, the Food and Drug Administration (FDA) granted tentative approval for a fixed dose combination of lamivudine/stavudine (150 mg/40 mg & 150 mg/30 mg combination tablets) under expedited procedures for the President's Emergency Plan for AIDS Relief (PEPFAR) program. The product is made by Matrix Laboratories Limited, of Hyderabad, India.

Lamivudine and stavudine, are anti-viral drugs indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Combination products such as this one can decrease pill burden and could result in improved compliance for HIV infected individuals.

FDA's tentative approval of this product means that although existing patents and/or exclusivity prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under PEPFAR.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On October 29, 2007, FDA granted tentative approval for a generic formulation of stavudine for oral solution, manufactured by Cipla, Limited, of Mumbai, India.

Stavudine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for used in combination with other antiretroviral agents in the treatment of HIV infection. This is the second tentatively approved generic version of the approved product, Zerit for oral solution, manufactured by Bristol-Myers Squibb. This child-friendly product is indicated for use in pediatric patients with HIV from birth through adolescence.

Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under the President’s Emergency Fund for AIDS Relief, commonly referred to as the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On October 25, 2007, FDA published draft guidance intended to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug to cause severe liver injury (i.e., fatal, or requiring liver transplantation).  The document may be of interest to those involved in drug development related to HIV/AIDS, although the guidance is broader in scope. 

In particular, the guidance addresses how laboratory measurements that signal the potential for such drug-induced liver injury (DILI) can be obtained and evaluated during drug development. This evaluation is important because most drugs that cause severe DILI do so infrequently; typical drug development databases with up to a few thousand subjects exposed to a new drug may not show any cases. Databases do, however, often show evidence of a drug’s potential for severe DILI if the clinical and laboratory data are properly evaluated for evidence of lesser injury that may not be severe, but may predict the ability to cause more severe injuries.

The guidance describes an approach that can be used to distinguish signals of DILI that identify drugs likely to cause significant hepatotoxicity from signals that do not suggest such a potential. The guidance does not address issues of preclinical evaluation for potential DILI, nor the detection and assessment of DILI after drug approval and marketing.

FDA is soliciting comments on the proposed guidance during the next 60 days.  Comments and suggestions regarding this draft document should be submitted before December 24, 2007 to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, room 1061, Rockville, MD 20852. Comments should be identified with docket number 2007D-0396.

You can view the draft guidance on the FDA web site at http://www.fda.gov/cder/guidance/7507dft.htm. The Federal Register Notice can be found at http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-21060.htm.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On October 12, 2007,  the Food and Drug Administration (FDA) approved a supplemental new drug application for Lexiva (fosamprenavir calcium; FPV) Oral Tablets, adding a new indication for once-daily dosing of 1400 mg of Lexiva with 100 mg ritonavir for the treatment of HIV infection in therapy-naïve adults.  The approval was based on a bioavailability study demonstrating that this dosing regimen produced drug levels bracketed within those of the already approved 1400 mg once daily plus ritonavir 200 mg once daily regimen, and the Lexiva1400 mg twice daily dosing regimen.

Lexiva is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection, and is distributed by GlaxoSmithKline, Research Triangle Park, NC.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Food and Drug Administration (FDA), on, October 12, 2007, granted accelerated approval for raltegravir tablets (400 mg) for treatment of Human Immunodeficiency Virus (HIV)-1 infection in combination with other antiretroviral agents.  Raltegravir, sold under the trade name Isentress, is the first agent of the pharmacological class of antiretroviral agents known as HIV integrase strand transfer inhibitors, commonly referred to as integrase inhibitors.  They are designed to slow the advancement of HIV-1 infection by blocking the HIV integrase enzyme that the virus needs in order to multiply.

When used with other anti-HIV medicines, raltegravir may reduce the amount of HIV in the blood and may increase white blood cells, called CD4+ (T) cells, that help fight other infections.

Raltegravir received a priority review by the FDA. The review and approval of the New Drug Application was completed in within six months.

FDA’s approval of raltegravir is based on efficacy and safety data from two double-blind, placebo-controlled studies (BENCHMRK 1 and BENCHMRK 2) in 699 highly antiretroviral treatment-experienced HIV-1 infected adult patients (16 years or older, with documented resistance to at least 1 drug in each of 3 Classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies).  462 patients used the recommended 400 mg dose twice daily in combination with other currently available HIV medications; 237 patients received a placebo in combination with other currently available HIV medications.   The mean changes in plasma HIV-1 RNA from baseline were -1.85 log10 copies/mL in the ISENTRESS 400 mg twice daily arm and -0.84 log10 copies/mL for the control arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving ISENTRESS 400 mg twice daily (89 cells/mm3) than in the control arm (35 cells/mm3).

The most common adverse events reported with raltegravir were diarrhea, nausea, and headache.  Blood tests showed abnormal elevated levels of a muscle enzyme in some patients receiving raltegravir.  Caution is advised when using raltegravir in patients at increased risk for certain types of muscle problems, such as patients taking other medications that can cause muscle problems.

Raltegravir has not been studied in pregnant women. Women who are taking HIV medications when they get pregnant are advised to ask their physician about registering with the Antiretroviral Pregnancy Registry.

As with other treatments for HIV, patients taking raltegravir may still develop infections, including opportunistic infections or other conditions that may develop in patients living with HIV-1 infection, and can still pass the virus on to others through sexual contact, sharing needles, or being exposed to blood.

The long-term effects of raltegravir are not known at this time, and its safety and effectiveness in children less than 16 years of age has not been studied.

Raltegravir is distributed by New Jersey-based Merck & Co., Inc.

Please refer to the product labeling and patient information sheet for additional information about raltegravir.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On October 4, 2007, FDA granted traditional approval to Aptivus (tipranavir), for combination antiretroviral treatment of HIV-1 infected adults with evidence of viral replication, who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor. Aptivus was granted accelerated approval on June 22, 2005, based on analysis of plasma HIV-1 RNA levels in two controlled phase 3 studies of 24 weeks duration of Aptivus/ritonavir. The traditional approval is based on continuation of the RESIST trials through 48 weeks and beyond, confirming durability of the virologic response. Aptivus is a product of Bohringer Ingelheim.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Viracept (nelfinavir mesylate) is a protease inhibitor antiretroviral medicine used in combination with other anti-HIV medications to treat infection with HIV. It is approved for use in adults and in children older than 2 years of age who are infected with human immunodeficiency virus (HIV-1), the virus that causes acquired immune deficiency syndrome (AIDS). 

Earlier this summer, Viracept was recalled from the European market due to high levels of a harmful substance known as ethyl methane mesylate (EMS), a byproduct of the Viracept manufacturing process. EMS is known to be an animal carcinogen (can cause cancer) mutagen (can be harmful to DNA, the genetic material in cells) and a teratogen (can be harmful to the development of an unborn child). The level at which EMS may become carcinogenic in humans is not known.

While Roche manufactures and distributes Viracept in Europe, Pfizer manufactures and markets Viracept in the United States. The levels of EMS detected in Viracept manufactured by Pfizer are lower than the levels of EMS detected in Viracept manufactured by Roche.

The FDA and Pfizer have agreed to specific limits of exposure of EMS to allow for continued use in populations where the benefit of using Viracept outweighs thepotential risk.

At this time, FDA and Pfizer consider the risks of unintended interruption of HIV treatment that may result from a recall to be greater than the risks associated with taking Pfizer manufactured Viracept.

Pfizer is issuing the following Dear Healthcare Professional letter to describe the current situation.

- (begin letter) -

VIRACEPT® (nelfinavir mesylate) 250 mg, 625 mg tablets, and Powder for Oral Suspension

IMPORTANT INFORMATION FOR PRESCRIBERS

Dear Healthcare Professional:

The purpose of this letter is to inform you of the presence of ethyl methanesulfonate (EMS), a process-related impurity in Viracept (nelfinavir mesylate) and to provide guidance on the use of Viracept in pregnant women and pediatric patients.

In June 2007, excess levels of EMS were detected in Roche Ltd- manufactured active pharmaceutical ingredient of Viracept; subsequently Roche recalled Viracept from all their European Union (EU) markets. EMS is a process-related impurity formed during manufacture of Viracept. EMS is a potential human carcinogen (Class 2B). Data from animal studies indicate EMS is teratogenic, mutagenic and carcinogenic; however, no data from humans exists.

In response to the Roche EU recall, the Food and Drug Administration (FDA) asked Pfizer to implement a new specification to limit the presence of EMS in Pfizer- manufactured Viracept products marketed in the United States. Pfizer commenced testing all active ingredients and found levels of EMS ubstantially lower than those associated with the Roche EU recall. Testing continues. Pfizer and FDA have agreed on interim and long term specifications of EMS in Viracept at levels substantially lower than those that prompted the Roche EU recall. Only product meeting the interim specifications will be released for patient use in the US. Pfizer is taking this step to balance the need to maintain the availability of Viracept as a therapeutic alternative for patients and prevent unexpected interruption of HIV-1 antiretroviral treatment with the need to minimize patient exposure to a potential carcinogen.

The agreed interim specification limits the theoretical lifetime increased cancer risk in adults to less than 17 cases per 100,000 exposed. The long term specification for levels of EMS limits the theoretical lifetime increased cancer risk in adults to less than 1 case per 100,000 exposed. Current estimates of the background incidence of cancer in the HIV population are about 20-30 cases per 1000 patient-years.

MANAGEMENT OF PEDIATRIC PATIENTS

While no data on the impact of high EMS levels in humans exist, toxicology experts generally agree that the/lifetime risk associated with exposure to a carcinogen is about 3-fold greater among pediatric patients between 2 and 16 years of age and even higher among pediatric patients younger than 2 years of age; this potentially greater risk was used to determine acceptable levels of EMS in formulations used in the pediatric population. For pediatric patients who are stable on Viracept-containing regimens, the FDA and Pfizer agree that the benefit-risk ratio remains favorable and those patients may continue to receive Viracept. Pediatric patients who need to begin HIV treatment should not start regimens containing Viracept until further notice.

We encourage you to refer to specific recommendations for the use of antiretroviral agents in pediatric HIV-1 infected patients from the United States Department of Health and Human Services (DHHS) guidelines.^[1]

MANAGEMENT OF PREGNANT WOMEN

We currently do not have information on the ability of EMS to cross the placenta nor enter breast milk. In the Antiretroviral Pregnancy Registry involving over 6000 HIV infected pregnant women, no significant difference in the prevalence of birth defects between women who used Viracept and those who used other antiretroviral therapy was observed. Nonetheless, FDA is recommending that pregnant women limit their exposure to EMS during pregnancy. Pregnant women who need to begin antiretroviral therapy should not be offered regimens containing Viracept until further notice. As a precautionary measure, pregnant women currently receiving Viracept should be switched to an alternative antiretroviral therapy while Pfizer and FDA work to implement the long term EMS specification for Viracept. We encourage you to refer to specific recommendations for the use of antiretroviral agents in pregnant HIV-1 infected patients from the United States Department of Health and Human Services (DHHS) guidelines^[2], in determining an alternative treatment option.

Maintaining the health of the mother and preventing transmission of HIV to the fetus are of paramount importance. For pregnant women with no alternative treatment options, FDA and Pfizer agree that the risk-benefit ratio remains favorable for the continued use of Viracept.

ALL OTHER PATIENTS

There is no change in the recommended use of Viracept for all other patients. Please see enclosed full prescribing information. In considering the best treatment for patients, please be aware that many HIV antiretroviral medications are carcinogenic in animal studies. In addition, some HIV antiretroviral medications are mutagenic or are teratogenic. Despite these findings, available information shows the benefits of HIV-1 antiretroviral treatment outweigh the risks of using these products or completely stopping HIV treatment. Please see individual product labeling for additional information.

Pfizer and FDA continue to work together to define a long-term, globally harmonized, plan which appropriately limits EMS levels within Viracept while still ensuring an uninterrupted supply of the medication to patients.

Sincerely,
Michael Berelowitz MB ChB, FACP, FCP(SA)

Safety Information

VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

Nelfinavir is principally metabolized by the liver; it can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be use in patients with either moderate or severe hepatic impairment.

Exercise caution when administering VIRACEPT with drugs that induce CYP3A, and with potentially toxic drugs that are metabolized by CYP3A, including those that prolong the QT interval.

In clinical studies (n>5000), the most common adverse event, diarrhea, was moderate to severe in 14% to 20% of patients.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRACEPT.

Redistribution/accumulation of body fat has been reported in patients receiving antiretroviral therapy. A causal relationship has not been established, and long-term consequences are not known at this time.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported with protease inhibitors.

There are no adequate and well-controlled studies in pregnant women taking VIRACEPT. VIRACEPT should be used in pregnancy only if clearly needed.

VIRACEPT use is contraindicated with amiodarone, quinidine, triazolam, midazolam, ergot derivatives, and pimozide. VIRACEPT should not be coadministered with St. John's wort, simvastatin, lovastatin, rifampin, and omeprazole. Rifabutin dose should be reduced by 50%. PDE5 inhibitors should be prescribed with caution.

Increased bleeding in patients with hemophilia type A or B has been reported with protease inhibitors.

1. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. October 26, 2006; 1-126. Available at http://www.aidsinfo.nih.gov

2. Public Health Service Taskforce: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. October 12, 2006; 1-65. Available at http://www.aidsinfo.nih.gov

- (end of letter) -

For additional information, see FDA’s Medwatch page titled Questions and Answers Regarding Health Concerns and Potential Shortage of Nelfinavir (marketed as Viracept) at http://www.fda.gov/cder/drug/infopage/nelfinavir/qa.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA, on August 13, 2007, granted tentative approval for a new fixed dose three-drug combination pill containing generic lamivudine, stavudine and nevirapine, to treat human immunodeficiency virus (HIV-1) infection in children outside the United States.  This is the first combination of its kind available to meet the needs of children less than 12 years of age, and represents a major advance in global AIDS treatment efforts.  The generic combination drug tablet is manufactured by Cipla Limited, of Mumbai, India.

The new combination constitutes a complete HIV regimen that is taken twice daily, once patients have tolerated 14 days of lead-in treatment with nevirapine taken once daily in combination with separate doses of lamivudine and stavudine. The combination tablet can be dissolved in water for children who cannot swallow tablets.

Each ingredient of this generic tablet is currently approved to treat HIV-1 in combination with other antiretroviral agents. The safety and effectiveness of the combination of lamivudine-stavudine-nevirapine in lowering viral load and increasing CD4+ cells has been demonstrated in previously conducted controlled studies of the individual ingredients used together.

The three drugs, combined in a single twice-a-day tablet is not only easier to administer to children, increasing access and adherence to therapy, but also facilitates storage and distribution.  This new combination represents a significant advance in the treatment of children infected with HIV in PEPFAR countries.

Tentative Approval means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards.  But because of existing patents and/or exclusivity rights, it may not be marketed in the U.S. The tentative approval, does however, make the product eligible for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR) program.

As with all generic applications, FDA conducts on-site inspections of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application, ensuring that antiretroviral drugs purchased by PEPFAR meet the same safety, efficacy, and manufacturing standards as drugs used in the United States.

This product was reviewed under guidance titled Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV developed by FDA to clarify what regulatory requirements apply to such applications, what issues might be of concern, how these issues should be addressed, and to encourage sponsors to submit applications for combination and co-packaged products to FDA.

The tentative approvals of nevirapine (notice sent yesterday) and this triple fixed dose combination tablet of lamivudine, stavudine and nevirapine represent the 50th and 51st approvals or tentative approvals, respectively, by FDA under the expedited review provisions developed for the President's Emergency Plan for AIDS Relief .  A list of all approvals and tentative approvals under these provisions can be found at http://www.fda.gov/oia/pepfar.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Abbott has sent out a Dear Healthcare Provider letter regarding KaIetra (lopinavir/ritonavir) oral solution and accidental overdose in children, highlighting important information about Kaletra dosing for children.

The Direct Healthcare Professional Communication indicated that Abbott was recently notified of an accidental overdose when an infant received a significantly large dose of Kaletra (lopinavir/ritonavir) Oral Solution. The infant subsequently died.

Abbott is reminding you that:

• Kaletra Oral Solution is highly concentrated, containing 80 mg lopinavir and 20 mg ritonavir per mL (not per bottle).
• Children dosages are calculated based on body weight. A child should receive less than 5 mL oral solution per dose unless they are also receiving certain concomitant antiretroviral medicines.

Further information on the safety concern:
The accidental overdose occurred in a 44-day-ld infant, born at 30 weeks gestation with HN, who was given approximately 6.5 mL of Katetra Oral Solution (this is about 10 times the calculated volume). The infant died nine days later of cardiogenic shock.

Special attention must be paid to accurate calculation of the dose, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors.

The FDA web site has a pediatric HIV drug page that provides additional information about pediatric dosing, at http://www.fda.gov/oashi/aids/pedlbl.html

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FDA , on August 13 , 2007, granted tentative approval for a generic formulation of nevirapine tablets, 200 mg , manufactured by Hetero Drugs Limited, Hyderabad, India, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts on-site inspections of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

This is a generic formulation of FDA-approved Viramune Tablets, 200 mg, made by Boehringer Ingelheim Pharmaceuticals, Inc., which is subject to existing patent and pediatric exclusivity protections .

Effective patent dates and additional marketing exclusivities can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book."

Nevirapine is a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) indicated for used in combination with other antiretroviral agents in the treatment of HIV infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA granted tentative approval on August 8, 2007 for a generic formulation of a combination product, lamivudine and zidovudine tablets,150 mg/300 mg, manufactured by Emcure Pharmaceuticals Inc. of Pune, India under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR)

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, the tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts on-site inspections of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

This is a generic formulation of Combivir Tablets, 150 mg/300 mg, marketed by GlaxoSmithKline, which is subject to patent and pediatric exclusivity protections.

Effective patent dates and additional marketing exclusivities can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

Lamivudine and zidovudine are both Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for used in combination with other antiretroviral agents in the treatment of HIV infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On August 6, 2007, the Food and Drug Administration (FDA) approved Selzentry (maraviroc) 150 mg and 300 mg tablets, a CCR-5 co-receptor antagonist used in combination with other antiretroviral products for the treatment of adults infected with CCR5-tropic HIV-1.

Maraviroc received a priority review by the FDA and is the first drug approved in the new class of anti-HIV medications called CCR-5 co-receptor antagonist.

Rather than fighting HIV inside white blood cells, like most antiretrovirals used to treat infection with HIV, maraviroc prevents the virus from entering uninfected cells by blocking the predominant route of entry, the CCR5 co-receptor, a protein on the surface of immune cells affected by HIV.  Among patients who have previously received HIV medications, approximately 50 percent to 60 percent have circulating CCR5-tropic HIV.

Maraviroc, in combination with other antiretroviral agents, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable virus, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. 

The approval of maraviroc is based on analyses of plasma HIV-1 RNA levels in two controlled studies each of 24 weeks duration with over 1000 clinical trial participants of which 840 received maraviroc. Both studies were conducted in clinically advanced, 3-class antiretroviral (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor, protease inhibitors or fusion inhibitor, specifically enfuvirtide) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

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

• Tropism testing and treatment history should guide the use of maraviroc.
• Use of maraviroc is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group.   
• The safety and efficacy of maraviroc have not been established in treatment-naïve adult patients or pediatric patients.

The recommended dose of maraviroc differs based on concomitant medications due to drug interactions.

Maraviroc can be taken with or without food.

The product label includes a boxed warning about liver toxicity (hepatoxicity) and a statement in the Warnings/Precautions section about the possibility of increased risk for cardiovascular events such as heart attack or symptomatic postural hypotension (dizziness upon quickly standing).  The most common adverse events reported with maraviroc were cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.

Maraviroc has not been tested or studied in pregnant women. The FDA recommends HIV positive women should not breast feed, whether or not they are on antiretroviral medications.

Maraviroc is distributed by Pfizer Inc., of New York and is available as 150 mg or 300 mg tablets.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA approved revised labeling on July 24, 2007 for BARACLUDE (entecavir) 0.5 mg and 1.0 mg Film-Coated Tablets, and BARACLUDE (entecavir) 0.05 mg/mL Oral Solution for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The amended label includes safety information related to the use of entecavir (ETV) in patients with human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection who are not receiving simultaneous highly active antiretroviral therapy (HAART).  Specifically, a recommendation against the use of BARACLUDE in HIV/HBV co-infected patients who are not also receiving adequate therapy for their HIV were added to the Boxed Warnings and the WARNINGS sections of the label. Corresponding changes were made to PRECAUTIONS: Information for Patients section, and in the Patient Information (also referred to as the Patient Package Insert).

Added to the Boxed Warning: Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). See WARNINGS: Co-infection with HIV.

Added to WARNINGS section/ Co-infection with HIV: BARCLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development to resistance HIV nucleoside reverse transcriptase inhibitors if BARCLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. (see MICROBIOLOGY: Antiviral Activity, Antiviral Activity against HIV). Therefore, therapy with BARCLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating BARCLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.

Added to PRECAUTIONS/Information for Patients: Patients should be offered HIV antibody testing before starting BARCLUDE therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARCLUDE may increase the chance of HIV resistance to HIV medication (see WARNINGS: Co-infection with HIV).

Added to Patient Information: If you have or get HIV (human immunodeficiency virus) infection be sure to discuss your treatment with your doctor. If you are taking BARCLUDE to treat chronic hepatitis B and are not taking medicines for your HIV at the same time, some HIV treatments that you take in the future may be less likely to work. You are advised to get an HIV test before you start taking BARCLUDE and anytime after that when there is a chance you were exposed to HIV. BARCLUDE will not help your HIV infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA is announcing a meeting of its Antiviral Drugs Advisory Committee on September 5, 2007, scheduled from 8 a.m. to 4 p.m. at the Hilton Washington DC/Silver Spring, The Ballrooms, 8727 Colesville Rd., Silver Spring, MD, 20910.

The purpose of the meeting is to discuss new drug application (NDA) 22-145 for the new drug raltegravir potassium, integrase inhibitor, 400 milligram tablets, Merck & Co., Inc., for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection, in combination with other antiretroviral agents, in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. Raltegravir works by blocking an HIV enzyme called integrase, which is one of the three enzymes necessary for HIV to replicate in the body. Raltegravir is the first drug of the new class called integrase inhibitors to be considered for approval.

Interested members of the public are encouraged to present data, information or views - orally or in writing – related to the application pending before the committee. Written submissions may be made to the contact person (see below) on or before August 21, 2007.

Oral presentations from the public will be scheduled between approximately 1 p.m. and 2 p.m. Those desiring to make formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before August 14, 2007.

Time allotted for each presentation may be limited, depending on the number of requests to speak. If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by August 13, 2007.

FDA intends to make background material available to the public at least 2 business days before the meeting at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm.

Click on the year 2007, and scroll down to the appropriate advisory committee link to find the information.

If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA's Web site after the meeting.

Contact Person: Cicely Reese, Center for Drug Evaluation and Research (HFD-21), Food and Drug Administration, 5600 Fishers Lane (for express delivery, 5630 Fishers Lane, rm. 1093), Rockville, MD 20857, 301-827-7001, FAX: 301-827-6776, e-mail: Cicely.Reese@fda.hhs.gov, or FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC area), code 3014512531.

Please call the Information Line for up-to-date information on this meeting. A notice in the Federal Register about last minute modifications that impact a previously announced advisory committee meeting cannot always be published quickly enough to provide timely notice. Therefore, you should always check the agency's Web site and call the appropriate advisory committee hot line/phone line to learn about possible modifications before coming to the meeting.

Those attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings. There is no registration and no fee required to attend.

FDA will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Cicely Reese at least 7 days in advance of the meeting.

For directions or lodging information, please contact the hotel directly at 301-589-5200.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA granted tentative approval on July 12, 2007 for a generic formulation of efavirenz tablets, 600 mg, manufactured by Matrix Laboratories Limited, of Hyderabad, India, under expedited review provisions developed for the President’s Emergency Plan for AIDS Relief (PEPFAR)

This is a generic formulation of already approved Sustiva tablets, 600 mg, made by Bristol Myers-Squibb, which is protected by existing patent rights. 

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but because of existing patents and/or exclusivity rights, it cannot yet be marketed in the United States. Effective patent dates are listed in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

Tentative approval does, however make the product eligible for consideration for purchase under the PEPFAR program for use outside the United States.

As with all generic applications submitted to the agency, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

Efavirenz is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) indicated for treatment of HIV infection in combination with other antiretroviral agents.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA granted tentative approval on July 10, 2007 for a generic formulation of nevirapine tablets, 200 mg, manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. of Zhejiang China, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

This is a generic formulation of the already approved Viramune tablets, 200 mg, made by Boehringer Ingelheim, which is protected by existing patent and pediatric exclusivity rights.  Effective patent dates are listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "OrangeBook"

Nevirapine is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) indicated for treatment of HIV infection in adults and adolescents in combination with other antiretroviral agents.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On June 14, 2007, the Food and Drug Administration approved a new formulation of Lexiva. Lexiva (fosamprenavir calcium) is now available as an oral suspension (50-mg/mL). The package insert was updated to include information on this new formulation and to provide dosing information for pediatric patients and patients with hepatic impairment as follows:

DOSAGE AND ADMINISTRATION:

Pediatric Patients (2 to 18 years of age)
The recommended dosage of LEXIVA in patients > 2 years of age should be calculated based on body weight (kg) and should not exceed the recommended adult dose. The data are insufficient to recommend: (1) once-daily dosing of LEXIVA alone or in combination with ritonavir, and (2) any dosing of LEXIVA in therapy-experienced patients 2 to 5 years of age.

Therapy-Naïve 2 to 5 Years of Age:

• LEXIVA Oral Suspension 30 mg/kg twice daily, not to exceed the adult dose of LEXIVA 1,400 mg twice daily.

Therapy-Naïve > 6 Years of Age:

• Either LEXIVA Oral Suspension 30mg/kg twice daily not to exceed the adult dose of LEXIVA 1,400 mg twice daily or LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg twice daily not to exceed the adult dose of LEXIVA 700 mg plus ritonavir 100 mg twice daily.

Therapy-Experienced > 6 Years of Age:

• LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of LEXIVA 700 mg plus ritonavir 100 mg twice daily.
• When administered without ritonavir, the adult regimen of LEXIVA Tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.
• When administered in combination with ritonavir, LEXIVA Tablets may be used of pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg.

Patients with Hepatic Impairment

Mild Hepatic Impairment (Child-Pugh score ranging from 5 to 6):
LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naïve) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naïve or PI-experienced)

Moderate Hepatic Impairment (Child-Pugh score ranging from 7 to 9):
LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily (therapy-naïve) without ritonavir, or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naïve or PI-experienced)

Severe Hepatic Impairment (Child-Pugh score ranging from 10 to 12):
LEXIVA should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naïve). There are no data on the use of LEXIVA in combination with ritonavir in patients with severe hepatic impairment

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On May 23, 2007, FDA approved the Procleix Ultrio Assay on the fully automated Procleix TIGRIS system manufactured by Gen-Probe Inc., of San Diego, California, and marketed by Chiron Corporation. This is a fully automated qualitative in vitro nucleic acid test (NAT) to screen for human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) RNA in donated blood from donors of whole blood, blood components, or source plasma. It is also licensed to screen individual organ donations from living donors, heart-beating organ donors, and cadaveric (non-heart-beating) organ donors. The capability of full automation will reduce human error and accelerate blood screening, enhancing blood safety.

On May 11/2007, FDA granted marketing approval to two HIV-1 PCR assays for use in managing the treatment HIV infection.

The Abbott RealTime HIV-1 Assay, made by ABBOTT Molecular, Inc., is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for the quantitation of Human Immunodeficiency Virus type 1 (HIV-1) on the automated m2000 System in human plasma from HIV-1 infected individuals over the range of 40 to 10,000,000 copies/mL. The Abbott RealTime HIV-1 assay is intended for use in conjunction with clinical presentation and other laboratory markers for disease prognosis and for use as an aid in assessing viral response to antiretroviral treatment as measured by changes in plasma HIV-1 RNA levels. (Product label)

The COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, made by Roche Diagnostics is an automated PCR test, indicated for the quantitation of Human Immunodeficiency Virus Type 1 (HIV-1) nucleic acid in human plasma (viral load) for use in conjunction with clinical presentation and other laboratory markers.  The test is intended for use in conjunction with clinical presentation and other laboratory markers of disease progress for the clinical management of HIV-1 infected patients. It can be used to assess patient prognosis by measuring the baseline HIV-1 RNA level or to monitor the effects of antiretroviral therapy by measuring changes in plasma HIV-1 RNA levels during the course of antiretroviral treatment.   (Product label)

Neither the Abbott RealTime nor the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 assay is intended to be used as a donor screening test for HIV-1 or as a diagnostic test to confirm the presence of HIV-1 infection.

Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration

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FDA granted approval, on May 23, 2007, to a generic formulation of zidovudine capsules, 100 mg, manufactured by Cipla Limited, of Mumbai, India.  The approval means that these generic zidovudine capsules can be marketed in the United States. 

Tablet and oral solution dosage forms of generic zidovudine were previously approved for sale in the United States as the patents on those dosage forms expired in September 2005.  An earlier generic version of the capsule formulation was approved for marketing in the United States in 2006, following the expiration of GlaxoSmithKline's patent on its Retrovir brand capsule.

A list of FDA approved generic antiretroviral drugs for the treatment of HIV is available on the web at http://www.fda.gov/oashi/aids/viralsgeneric.html

Zidovudine is in the class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing.  This anti-retroviral drug is intended to be used with other anti-retroviral agents for the treatment of HIV-1 infection.

The approval of generic zidovudine means that there are no existing patents and/or exclusivity preventing the approval of generic versions of this product to prevent marketing in the United States. 

As with all FDA-approved generics, this product must meet all of FDA's manufacturing quality, and clinical safety and effectiveness standards for U.S. marketing. 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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A supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (treatment guidelines) was added on April 30, 2007, discussing use of Entecavir in Hepatitis B/HIV Co-infected patients.

Based on preliminary findings from a recent case series of three patients, the Treatment Guidelines Panel now recommends that: For HBV/HIV co-infected patients, entecavir should not be used for the treatment of HBV infection without concomitant treatment for HIV.

The supplement is available from AIDSinfo at http://www.aidsinfo.nih.gov/contentfiles/EntecavirInHIV.pdf

The complete Adult and Adolescent Guidelines can be found on the AIDSinfo web site.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA granted tentative approval on April 23, 2007 for a generic formulation for stavudine capsules, 30 mg and 40 mg, manufactured by Matrix Laboratories Limited of Hyderabad, India, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

This is a generic formulation of the already approved Zerit brand capsules, 30 mg and 40 mg, made by Bristol Myers Squibb, which is protected by existing patent and pediatric exclusivity rights.  Effective patent dates are listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

Stavudine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for used in combination with other antiretroviral agents in the treatment of HIV infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Product labeling for KALETRA lopinavir/ritonavir)has been updated to reflect safety and efficacy data from study M97-720 in treatment-naïve patients out to 360 weeks. Kaletra is manufactured by Abbott Laboratories, North Chicago, IL.

The complete revised product labeling is available through Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Due to water damage caused by flooding over the weekend, FDA has been forced to change the location for the upcoming Antiviral Drugs Advisory Committee meeting on April 24, 2007 to discuss new drug application for maraviroc 300 milligram tablets.   Originally scheduled to be held at the FDA, Center for Drug Evaluation and Research Advisory Committee Conference Room, Room, 5630 Fishers Lane, in Rockville, MD, the meeting has been relocated to

Crown Plaza Hotel Silver Spring
Kennedy Ballroom
8777 Georgia Avenue, Silver Spring, MD 20910.

If you need to arrange accommodations or get directions, you can contact the hotel directly at 301-589-0800.  A map and local area information is available at the Silver Spring Downtown web site.

The committee will discuss new drug application (NDA) 022-128, maraviroc 300 milligram tablets, Pfizer, Inc., proposed for the treatment of antiretroviral-experienced patients with chemokine (c-c motif) receptor 5 (CCR5)--tropic human immunodeficiency virus (HIV).

Background material for this meeting will be available to the public no later than 1 business day before the meeting. Posted background material is available at http://www.fda.gov/ohrms/dockets/ac/cder07.htm#AntiviralDrugs. The Change in Meeting Location notice, and Federal Register Notice announcing the change will also be posted at this site.

The meeting is open to the public. There is no registration required, and no fees associated with attending FDA advisory committee meetings.  However, please be sure to have a photo ID to enter this government building.

Contact Person: Cicely Reese, Center for Drug Evaluation and Research (HFD-21), Food and Drug Administration, 5600 Fishers Lane (for express delivery, 5630 Fishers Lane, rm. 1093) Rockville, MD 20857, 301-827-7001, FAX: 301-827-6776, e-mail: cicely.reese@fda.hhs.gov

Please call the FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC area), code 3014512531 for further, up-to-date information about this meeting.

Persons attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings and will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Cicely Reese 7 days in advance of the meeting.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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GlaxoSmithKline recently issued a "Dear Pharmacy Professional" letter to raise awareness of an isolated, but potentially serious, apparent tampering incident involving Ziagen and Combivir tablets for treatment of HIV.  The complete text of the letter follows...

Dear Pharmacy Professional,

We would like to call to your attention an apparent third-party tampering that caused misbranding of Ziagen® (abacavir sulfate) Tablets as Combivir® (lamivudine and zidovudine) Tablets and employed counterfeit labels for Combivir Tablets.  Both Combivir and Ziagen are medicines used as part of combination regimens to treat HIV infection.

These incidents appear to be isolated and limited in scope to one pharmacy in California; to date, there have been no reports of similar incidents in other cities or in other states.  No injuries or adverse reactions have been reported.  Company tests have shown no problems with the medicine itself; both Ziagen and Combivir are authentic drug product.  GlaxoSmithKline is working with the U.S. Food and Drug Administration to investigate.

Involved in the misbranding cases were two 60-count bottles of Combivir Tablets.  Combivir Tablets (in a legitimate bottle) contain 150 milligrams of lamivudine and 300 milligrams of zidovudine; however, the misbranded bottles of Combivir contained 300 milligram tablets of Ziagen.  The counterfeit labels identified Lot No. 6ZP9760 with expiration dates of April 2010 and April 2009. 

If you have bottles of Combivir Tablets in your pharmacy, you should immediately examine the contents of each bottle of Combivir to confirm that it does indeed contain tablets of Combivir.  You may choose to counsel patients who have recently received Combivir.  The Combivir and Ziagen tablets are easily distinguishable.  Combivir is a white capsule-shaped tablet engraved with "GX FC3" on one side; the other side of the tablet is plain.  Ziagen is a yellow capsule-shaped tablet engraved with "GX 623" on one face; the other side is plain.  Please see the enclosed photos of Combivir and Ziagen.

If you discover a bottle of Combivir that contains anything but Combivir tablets, please notify the GSK Response Center at 1-888-825-5249 (toll free) between 8:00 a.m. and 8:00 p.m. ET, Monday through Friday.

The risk to patients is primarily due to the fact that approximately 8% of individuals who receive abacavir sulfate in Ziagen Tablets, Trizivir (abacavir sulfate, lamivudine and zidovudine) Tablets or Epzicom™ (abacavir sulfate and lamivudine) Tablets have developed a potentially life-threatening hypersensitivity reaction.  Symptoms generally resolve after discontinuing the medication; however, patients who have had a hypersensitivity reaction to abacavir-containing products are advised to never take the medication again.  Patients taking Combivir would not have been advised about the hypersensitivity reaction and how to take abacavir-containing products safely because Combivir does not contain abacavir sulfate (abacavir).  Patients, who have had a hypersensitivity reaction to abacavir and take Ziagen, Trizivir or Epzicom again, experience more severe symptoms within hours that may include life-threatening hypotension and death. 

In addition, the replacement of Combivir, which contains two antiviral drugs, with Ziagen, a single antiviral, may decrease the effectiveness of a patient's treatment regimen.

At GlaxoSmithKline, patient safety is our first priority.  We appreciate your help as we try to resolve this matter as quickly as possible.  GSK is taking all possible steps to protect the quality and integrity of our products.  If you or your patients have any additional questions, please contact the GSK Response Center at 1-888-825-5249 between 8:00 a.m. and 8:00 p.m. ET, Monday through Friday.  Full product information is available on the GlaxoSmithKline Web site, www.gsk.com.

For additional helpful information on how to avoid unsafe medicines and vendors, see the following Web site sponsored by The Partnership for Safe Medicines:  www.safemedicines.org/
(end of letter)_________________________________________________

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Food and Drug Administration, on April 5, 2007, granted tentative approval for abacavir sulfate tablets, 300 mg, manufactured by Matrix Laboratories, Inc., of Hyderabad, India, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).

This is a generic version of the already-approved Ziagen brand of the product manufactured by GlaxoSmithKline, which is protected under patent and pediatric exclusivity, which are listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

Abacavir sulfate is a member of the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing. This antiretroviral drug is intended to be used in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 26, 2007, FDA granted tentative approval for a generic drug formulation of efavirenz tablets (600 mg), manufactured by Strides Acrolab Ltd., Bangalore, India, under the expedited review provisions created by FDA for the President's Emergency Plan for AIDS Relief (PEPFAR).

The tentatively approved product is a generic version of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Sustiva Tablets, 600 mg, for use in combination with other antiretroviral agents in the treatment of HIV infection.  Sustiva, manufactured by Bristol Myers Squibb Co., is currently subject to patent protection.

FDA's tentative approval of this product means that although existing patents and/or exclusivities prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under the PEPFAR program for use in qualifying countries.

A complete list of approved and tentatively approved antiretroviral drugs associated with PEPFAR is available at www.fda.gov/oia/pepfar.htm.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA granted tentative approval on March 19, 2007 for lamivudine tablets (150 mg), manufactured by Matrix Laboratories, Inc., of Hyderabad, India,  under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).  Final approval cannot be granted because the reference drug product, Epivir® Tablets, a product of GlaxoSmithKline, is currently subject to patent protection.

Lamivudine is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.

FDA's tentative approval of this product means that although existing patents and/or exclusivity prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under the PEPFAR program for use in PEPFAR listed countries.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 13, 2007, FDA granted tentative approval for two applications for antiretroviral drugs products made by Strides Acrolab Ltd., Bangalore, India, under the expedited review provisions created by FDA for the President's Emergency Plan for AIDS Relief (PEPFAR).

The first is a fixed dose combination of stavudine/lamivudine (40mg/150mg) tablets, co-packaged with nevirapine tablets  (200mg) for use in HIV-1 treatment  of HIV-1.

The second is a fixed dose combination of Stavudine/Lamivudine (40mg/150mg) Tablets for use in HIV-1 treatment in combination with other antiretroviral drugs. These products represent drug combinations which can significantly decrease pill burden and could result in improved compliance for HIV infected individuals.

FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the U.S., existing patents and/or exclusivity currently prevent marketing of the product in the United States.  Tentative approval, however, qualifies the product for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 9, 2007, FDA issued a public health advisory outlining new safety information, including revised product labeling about erythropoiesis-stimulating agents (ESAs), widely-used drugs for the treatment of anemia in a variety of conditions, anemia due to zidovudine therapy in HIV patients.

The drugs affected by the safety update are darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit). (ESAs are genetically engineered forms of the naturally occurring human protein, erythropoietin. Natural erythropoietin is made by the kidney and increases the number of red blood cells).

FDA and the manufacturer of these products have agreed on revised product labeling that includes updated warnings, a new black box warning, and modifications to the dosing instructions. The new black box warning advises physicians to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions. Physicians and patients should carefully weigh the risks of ESAs against transfusion risks.

Recently completed studies describe an increased risk of death, blood clots, strokes, and heart attacks in patients with chronic kidney failure when ESAs were given at higher than recommended doses. In other studies, more rapid tumor growth occurred in patients with head and neck cancer who received these higher doses.

In studies where ESAs were given at recommended doses, an increased risk of death was reported in patients with cancer who were not receiving chemotherapy and an increased risk of blood clots was observed in patients following orthopedic surgery.

"The agency is in the process of re-evaluating the safety of Aranesp, Epogen, and Procrit on the basis of the results of recent clinical studies," said Steven Galson, M.D. director of FDA's Center for Drug Evaluation and Research. "The new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting."

Safety concerns from earlier ESA studies were discussed during a 2004 meeting of the ODAC. Product labeling was previously revised in 1997, 2004, and 2005 to reflect new safety information.

The three drugs are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy. Epogen and Procrit are approved for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia due to zidovudine therapy in HIV patients. ESAs are not approved to treat the symptoms of anemia – including fatigue – in cancer patients, surgical patients, or those with HIV.

All three drugs are manufactured by Amgen Inc. of Thousand Oaks, California. Procrit is marketed and distributed by Ortho Biotech LP, a subsidiary of Johnson & Johnson.

The FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs)

Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)

Recent reports of studies with erythropoiesis-stimulating agents (ESAs) have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents.  ESAs stimulate the bone marrow to make more red blood cells and are FDA approved for use in reducing the need for blood transfusions in patients with chronic kidney failure, patients with cancer on chemotherapy, patients scheduled for major surgery (except heart surgery) and patients with HIV that are using AZT.  Because all ESAs work the same way, the findings from these studies apply to all ESAs; the FDA is re-evaluating the safe use of this drug class.

Patients currently using or considering the use of an ESA should know the following:

• A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.   
• A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs.
• ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV. 
• If you have any questions you should talk with your health care provider.

Important study results include the following:

• Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
• Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.
• Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
• Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA.

Physicians who prescribe ESAs should consider the important study results above and:

• Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for transfusions;
• Monitor patients' hemoglobin levels to ensure they do not exceed 12 g/dL;
• Understand that ESAs are given to decrease the chances of receiving transfusions;
• Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor shrinkage, delay in tumor growth or longer time for survival);
• Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA; and
• Understand that ESAs should not be given to treat the symptoms of anemia, including shortness of breath, dizziness, fatigue, low energy, or poor quality of life.

FDA and Amgen, the manufacturer of these products, and Ortho Biotech Products, L.P, a Johnson & Johnson Pharmaceuticals Research and Development subsidiary, the distributor of Procrit, have agreed to change the labeling for Aranesp, Epogen, and Procrit to reflect the new safety information and to provide additional instructions for their use. 

FDA-approved uses of ESAs are: for the treatment of anemia in chronic kidney failure patients, in patients with cancer whose anemia is caused by chemotherapy, in patients with HIV whose anemia is caused by AZT (zidovudine), and to reduce the number of transfusions in patients scheduled for major surgery (except heart surgery).

You can find more details about  the use of ESAs in FDA's Information for Healthcare Professional.

The FDA asks health care professionals and patients to report serious side effects after using ESAs to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at  http://www.fda.gov/medwatch

A Questions and Answers on Erythropoiesis-stimulating Agents (ESAs)  page has been added to the FDA website at http://www.fda.gov/cder/drug/infopage/RHE/qa.htm to address questions and likely further explain the issue.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 8, 2007, FDA granted approval for generic didanosine for oral solution (Pediatric Powder), 10 mg/mL, packaged in 2 gram and 4 gram containers, manufactured by Aurobindo Pharma Limited, of Hyderabad, India, allowing marketing in United States.

This is a generic version of the already FDA approved Videx Pediatric Powder for Oral Solution, 10 mg/mL, manufactured by Bristol Myers Squibb.

FDA granted tentative approval for this product on October 5, 2006, permitting purchase of this generic formulation of didanosine by the President's Emergency Plan for AIDS Relief, or PEPFAR. A tentative approval means that a drug product has met FDA's safety, efficacy and quality standards, but is ineligible for marketing in the U.S. until patent and/or exclusivity restrictions expire.

However, because patents and exclusivity for Videx For Oral Solution have expired (see FDA's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"), the generic formulation can be granted approval, allowing it to be marketed in the United States.

Didanosine for Oral Solution is approved for use in combination with other antiretroviral agents in the treatment of HIV infection.

This seems like an excellent example to illustrate the relationship of FDA to the President's Emergency Program for AIDS Relief. The PEPFAR program was created to provide government funding to treat, and reduce transmission of HIV in 15 focus countries, mostly in Sub-Saharan Africa, but including Haiti, Guyana, and Vietnam.

Because drugs that do not conform to standards of potency, purity, stability, or good manufacturing procedures may pose a threat by increasing chance of substandard performance, treatment failure, and emergence of resistant virus, PEPFAR limits funding to acquire only products that have undergone stringent regulatory review. 

While FDA does not approve drugs for use in other countries, the agency has expedited review procedures in place (and conducts inspections of the manufacture and testing sites) to determine whether the drug products meet FDA safety, efficacy, and manufacturing quality standards, thus making them eligible for purchase using PEPFAR funds.

When the determination is made that a product meets the required criteria and standards, FDA may issue a "tentative approval," even though the product cannot yet be marketed in the U.S. because of legal restrictions related to existing exclusivity rights held by the original drug manufacturer.  Once marketing exclusivities expire, FDA can grant marketing approval of the generic formulation in the U.S. market.

Since the time didanosine for oral solution received a tentative approval in October 2006, allowing it to be purchased through PEPFAR (for use in PEPFAR-affected countries), expiration of patents has resulted in an approval that now allows marketing of this generic formulation of didanosine for oral solution in the United States.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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3/7/2007

FDA has issued final guidance, entitled "Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)," to assist establishments making donor eligibility determinations to comply with the requirements for determining donor-eligibility, including donor screening and testing for donors of human cells, tissues, and cellular and tissue-based products. (for background, see http://www.fda.gov/oashi/aids/listserve/listserve2004.html#screen)

The guidance applies to cells and tissues procured on or after the effective date of the regulations contained in 21 CFR part 1271, subpart C (effective date May 25, 2005). It does not replace the guidance concerning 21 CFR part 1270, entitled "Guidance for Industry: Screening and Testing of Donors of Human Tissue Intended for Transplantation," which remains applicable to tissues recovered before May 25, 2005, and subject to 21 CFR part 1270.

The document provides guidance on donor-eligibility determination, donor screenings, donor testing requirements (including HIV), additional screening and testing requirements for reproductive cells and tissues, and exceptions from the requirements for determining donor-eligibility, and special circumstances.

You can find the complete guidance document on the FDA web site at http://www.fda.gov/cber/gdlns/tissdonor.htm

Richard Klein
HIV/AIDS Program Director
Food and Drug Administration

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3/6/2007

The Food and Drug Administration granted tentative approval on March 2, 2007 for a fixed dose tablet containing lamivudine/zidovudine(150 mg/300 mg) tablets, co-packaged with Nevirapine(200 mg tablets for the treatment of HIV-1 infection, manufactured by Strides Arcolab Ltd, Bangalore, India.

The lamivudine/zidovudine combination is a generic formulation of the FDA approved combination product, Combivir, manufactured by GlaxoSmithKline, which combines the two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in a single tablet. Nevirapine, which is a Nucleoside Reverse Transcriptase Inhibitor (NNRTI), is a generic formulation of the approved product, Viramune, manufactured by Boehringer Ingelheim.

The application was reviewed under expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR).

Tentative Approval means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, though it may not be marketed in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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2/26/2007

FDA and Bristol-Myers Squibb are notifying healthcare professionals of revisions to the MICROBIOLOGY/Antiviral Activity and INDICATIONS AND USAGE/Description of Clinical Studies/Special Populations sections of the prescribing information for Baraclude (entecavir), a nucleoside analog used in the treatment of chronic hepatitis B virus (HBV).

The revised labeling is the result of a case report in which a human immunodeficiency virus (HIV) variant containing the M184V resistance substitution was documented during Baraclude treatment for HBV infection in an HIV/HBV co-infected patient who was not simultaneously receiving highly active antiretroviral therapy (HAART).

Current treatment guidelines recommend Baraclude as an option for treatment of HBV in the HIV/HBV co-infected adult patient who does not qualif for HAART.

Healthcare professionals are advised that when considering therapy with Baraclude in an HIV/HBV co-infected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information.

You can read the manufacturer's Dear Healthcare Provider Letter at: http://www.fda.gov/medwatch/safety/2007/Baraclude_DHCP_02-2007.pdf

The revised labeling can be found at: http://www.fda.gov/medwatch/safety/2007/Baraclude_PI.pdf

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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2/9/2007

The Food and Drug Administration (FDA) will hold a meeting of its Antiviral Drugs Advisory Committee on April 24, 2007, from 8 a.m. to 4 p.m. at the Food and Drug Administration, Center for Drug Evaluation and Research Advisory Committee Conference Room, Room 1066, 5630 Fishers Lane, Rockville, MD.

The committee will discuss new drug application (NDA) 022-128, maraviroc 300 milligram tablets, Pfizer, Inc., proposed for the treatment of antiretroviral-experienced patients with chemokine (c-c motif) receptor 5 (CCR5)--tropic human immunodeficiency virus (HIV).

Background material for this meeting will be available to the public no later than 1 business day before the meeting. Posted background material is available at http://www.fda.gov/ohrms/dockets/ac/cder07.htm#AntiviralDrugs

The meeting is open to the public. There is no registration required, and no fees associated with attending FDA advisory committee meetings.  However, please be sure to have a photo ID to enter this government building.

Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.

Written submissions may be made to the contact person (see below) on or before April 3, 2007

Oral presentations from the public will be scheduled between approximately 1 p.m. and 2 p.m. Those desiring to make formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before March 26, 2007. Time allotted for each presentation may be limited, depending on the number of people who wish to speak.

If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by March 27, 2007.

Contact Person: Cicely Reese, Center for Drug Evaluation and Research (HFD-21), Food and Drug Administration, 5600 Fishers Lane (for express delivery, 5630 Fishers Lane, rm. 1093) Rockville, MD 20857, 301-827-7001, FAX: 301-827-6776, e-mail: cicely.reese@fda.hhs.gov

Please call the FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC area), code 3014512531 for further, up-to-date information about this meeting.

Persons attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings and will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Cicely Reese at least 7 days in advance of the meeting.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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2/6/2007

The Food and Drug Administration (FDA), on January 31, 2007, granted tentative approval for a fixed-dose, three-drug tablet for use as a complete anti-viral treatment of human immunodeficiency virus (HIV-1) infection in adults. The tablet contains lamivudine-zidovudine-nevirapine, the active ingredients in the widely used antiretroviral drugs Epivir (lamivudine), Retrovir (zidovudine) and Viramune (nevirapine). The new combination tablet is manufactured by Cipla Limited, of Mumbai, India.

The recommended regimen for the lamivudine-zidovudine-nevirapine tablet is one pill twice a day following an initial two week treatment with the individual components taken individually. Each ingredient of this generic tablet is currently approved to treat HIV-1 infected adults in combination with other antiretroviral agents. The safety and effectiveness of the combination of lamivudine-zidovudine-nevirapine in lowering the viral load and increasing the CD4+ cell has been demonstrated in previously conducted adequate and well controlled studies of the individual ingredients being used together for treatment.

The labeling of the combination drug includes a medication guide and a boxed warning that the drug's use can cause liver failure, severe rash, and lactic acidosis (buildup of an acid in the blood).

A similar Fixed Dose Combination product, containing the same constituent drugs, was given tentative approval by FDA on 6/30/2006.

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, though it may not be marketed in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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1/31/2007

Important additions have been made to the Fuzeon (enfuvirtide) for injection product label to include a description of nerve bundle pain, hematoma, and cautionary wording regarding Biojector use in patients with coagulopathy. The changes add language to the Precautions, Adverse Reactions, and Dosage and Administration sections of the Physician's Insert (PI), as well as corresponding changes to the Patient's Package Insert (PPI), to provide additional safety information regarding the use of the Biojector 2000 to administer Fuzeon as follows:

1. The following section was added under PRECAUTIONS:
Administration with Biojector(r) 2000
Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas (see ADVERSE REACTIONS) have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of postinjection bleeding.

2. The following bullet was added under PRECAUTIONS, Information for Patients section:
*Patients and caregivers should be instructed on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites.

3. The following paragraph was added under ADVERSE REACTIONS, Local Injection Site Reactions section:
Biojector 2000 Needle-Free Device
Adverse events associated with the use of the Biojector 2000 needle-free device for administration of FUZEON have included: nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas (see Error! Reference source not found.)

4. The following section under DOSAGE AND ADMINISTRATION changed from:
Adults
The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.

to:
Adults
The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.

5. The second to last paragraph under Subcutaneous Administration now reads:
The reconstituted solution should be injected subcutaneously in the upper arm, abdomen or anterior thigh. The injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction. Also, do not inject near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises or near the navel, surgical scars, tattoos or burn sites. A vial is suitable for single use only; unused portions must be discarded (see FUZEON Injection Instructions).

6. The following was added under the HOW SUPPLIED section:
Biojector is a trademark of Bioject Medical Technologies, Inc. Patient Package Insert (compared to S-007 final printed labeling)

7. The following bullet under How should I use FUZEON? Section was changed from:
*Do not inject FUZEON in the same area as you did the time before. Do not inject FUZEON into the following areas: around the navel (belly button), scar tissue, a bruise or a mole, and where there is an injection site reaction.

To:
* Do not inject FUZEON in the same area as you did the time before. Do not inject FUZEON into the following areas: near the elbow, knee, groin, the lower or inner buttocks, directly over a blood vessel, around the navel (belly button), scar tissue, a bruise, a mole, a surgical scar, tattoo or burn site, or where there is an injection site reaction.

8. The following section was added under What are the possible side effects of FUZEON?
Injection using Biojector(r) 2000
Shooting nerve pain and tingling lasting up to 6 months from injecting close to large nerves or near joints, and bruising and/or collections of blood under the skin have been reported with use of the Biojector 2000 needle-free device to inject FUZEON. If you are taking any blood thinners, or have hemophilia or any other bleeding disorder, you may be at higher risk of bruising or bleeding after using the Biojector.

9. The following sentence was added under the Changes since the last version of this leaflet section:
Clarification of appropriate injection sites for FUZEON and addition of side effects when injecting with Biojector 2000 needle-free device.

10. The following statement was added to the last page:
Biojector is a trademark of Bioject Medical Technologies, Inc.

You can access the complete, revised label on the Daily Med site, at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2705#nlm42232-9

Fuzeon is a distributed by Roche Pharmaceuticals.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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1/31/2007

The Sustiva (efavirenz) package insert was updated to include drug-drug interaction information regarding coadministration of efavirenz with rifampin, diltiazem, itraconazole, voriconazole, atorvastatin, pravastatin, simvastatin, pimozide and bepredil. 

The Clinical Pharmacology section Tables 1 and 2 were revised to include the results of drug-drug interactions studies with diltiazem, itraconazole, voriconazole, atorvastatin, pravastatin, and simvastatin.

The CONTRAINIDCATION section was revised to state Sustiva should not be administered concurrently with bepridil, pimozide and standard doses of voriconazole.

The PRECAUTION: Drug Interaction section (Tables 5 and 6) were updated to include information regarding coadministration of efavirenz with rifampin, diltiazem (and other calcium channel blockers), itraconazole, ketoconazole, voriconazole, pimozide and bepredil.

The Dosing and Administration section was updated to include dosing information for the co administration of efavirenz and voriconazole. Specifically, if Sustiva is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (three 100-mg capsules or one 200-mg and one 100-mg capsule). SUSTIVA tablets should not be broken.

Please refer to the detailed summary below for the revised changes to the package insert.

Table 1: Effect of Efavirenz on Coadministered Drug Plasma Cmax, AUC, and Cmin

* Indicates no change or a mean increase or decrease of <10%.
h  90% CI not available.
i   Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
NA = not available.

Table 2: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin

* Indicates no change or a mean increase or decrease of <10%.
e   90% CI not available.
f   Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).

NA = not available.

CONTRAINDICATIONS

SUSTIVA should not be administered concurrently with astemizole, bepridil, cisapride, midazolam, pimozide, triazolam, or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression).  SUSTIVA should not be administered concurrently with standard doses of voriconazole because SUSTIVA significantly decreases voriconazole plasma concentrations. Adjusted doses of voriconazole and efavirenz may be administered concomitantly (see CLINICAL PHARMACOLOGY, Tables 1 and 2; PRECAUTIONS: Drug Interactions, Table 5; and DOSAGE AND ADMINISTRATION: Dosage Adjustment).
PRECAUTIONS: Drug Interactions

Table 5: Drugs That Are Contraindicated or Not Recommended for Use With SUSTIVA

Table 6: Establisheda and Other Potentially Significantb Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

1. DOSAGE AND ADMINISTRATION
2. Adults

Dosage Adjustment: If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (three 100-mg capsules or one 200-mg and one 100-mg capsule). SUSTIVA tablets should not be broken. (See CLINICAL PHARMACOLOGY, Tables 1 and 2; CONTRAINDICATIONS; and PRECAUTIONS: Drug Interactions).

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1/22/2007

On January 20, 2007, the Food and Drug Administration (FDA) granted tentative approval for a new fixed drug combination of lamivudine/stavudine (150mg/ 30mg or 150mg/40mg) tablets manufactured by Cipla Limited, of Mumbai, India. This product was reviewed under expedited procedures for the President's Emergency Plan for AIDS Relief (PEPFAR) program.

Lamivudine and stavudine, are anti-viral drugs for the treatment of HIV-1 infection. This product represents a new combination which can decrease pill burden and could result in improved compliance for HIV infected individuals.

FDA's tentative approval of this product means that although existing patents and/or exclusivity prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under PEPFAR.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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