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The Food and Drug Administration (FDA), on December 27, 2005, granted tentative approval, through an expedited procedure, to generic Nevirapine Oral Suspension, 50 mg/5 mL, manufactured by Aurobindo Pharma LTD., of Hyderabad, India. This product is a generic version of the approved product, Viramune Oral Suspension, 50 mg/5 mL, manufactured by Boehringer Ingelheim Pharmaceuticals. It is indicated for use in pediatric patients with HIV.
Nevirapine is active against the human immunodeficiency virus (HIV) that causes AIDS. It is in the class of drugs called nonnucleoside reverse transcriptase inhibitors (NNRTIs), which helps keep the AIDS virus from reproducing. It is used in combination with other antiretroviral agents for the treatment of HIV-1 infection.
FDA tentative approval means that although existing patents and/or exclusivity prevent marketing of this product in the U.S., it meets all of FDA's manufacturing quality and clinical safety and efficacy standards required for marketing in the U.S. As with all generic application assessments, 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 assess the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.
Tentative approval by FDA means that this product will now be available for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Food and Drug Administration (FDA) granted, on December 21, 2005, tentative approval to generic stavudine for Oral Solution, 1 mg/mL manufactured by Aurobindo Pharma LTD., of Hyderabad, India. This product is the first 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.
Stavudine (d4T) is active against the human immunodeficiency virus (HIV) that causes AIDS. It is in the class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which helps keep the AIDS virus from reproducing, and is used in combination with other antiretroviral agents for the treatment of HIV-1 infection.
FDA tentative approval means that although existing patents and/or exclusivity prevent marketing of this product in the U.S., it meets all of FDA's manufacturing quality and clinical safety and efficacy standards required for marketing in the U.S. As with all generic application assessments, 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 assess the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.
Tentative approval by FDA means that this product will now be available for
consideration for purchase under the President's Emergency Plan for AIDS Relief.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
On December 16th, 2005, The Centers for Disease Control and Prevention (CDC) issued an MMWR Dispatch regarding recent reports of a higher than expected number of false positive test results in certain geographic areas using the oral fluid rapid test for HIV. The Dispatch is available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm54d1216a1.htm
The following information is intended to address questions related to the reports of false positive results reported in the MMWR Dispatch:
· CDC, in cooperation with FDA, reminds users of rapid HIV tests that all preliminary positive test results must be confirmed with additional more specific tests in a manner consistent with previously published guidance. (see http://www.cdc.gov/hiv/rapid_testing/materials/qa_guidlines_oraquick.pdf)
· FDA is aware of recent reports of an unexpected increase in false positive results for the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test with oral fluid specimens mainly at testing sites in New York City and San Francisco.
· When whole blood specimens were used for testing, there was no observed increase in the false positive rate of this test at these test sites.
· Some false positive test results are expected with any HIV screening test. For this reason additional testing is always needed to confirm true positive results.
· The OraQuick ADVANCE Rapid HIV-1/2 Antibody Test for use with oral fluid specimens was approved in June 2004 with a reported sensitivity of 99.6% and a specificity of 99.8% based on clinical studies.
· A specificity of 99.8% means that users should expect approximately 2 false positive results out of every 1,000 tests. However, the reported rate of false positive test results has been as high as 9 per thousand in recent months at some locations.
· FDA believes that use of a rapid HIV test on oral fluid can continue as long as test subjects are properly informed about the need for additional testing to confirm or reject preliminary positive results on the rapid screening test.
· FDA is working closely with the manufacturer of OraQuick (OraSure Technologies, Bethlehem Pennsylvania), the Centers for Disease Control and Prevention (CDC), and local departments of public health to determine the nature and cause of these findings and will take further actions if needed.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
This week marks the tenth anniversary of the approval of the first protease inhibitor. In December of 1995, a then new class of drug for the treatment of HIV/AIDS in combination with other antiretroviral drugs represented an historical landmark in the treatment of HIV/AIDS. Protease inhibitors helped establish a new treatment standard of triple combination therapy, significantly improving the lives and health of people living with HIV in the United States and around the world.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Return to index
After reviewing the current CCR5 antagonist development issue, the FDA CCR5 Antagonist Review Group and the Forum for Collaborative HIV Research have decided to postpone the meeting to discuss the long-term follow up of patients enrolled in CCR5 antagonist clinical trials until February or March of 2006.
The original January 18th date was chosen to address the long-term follow up issues in as timely a manner as possible. However, because additional clinical trial data is accumulating, waiting until as much information as possible is available will ensure that the public discussion is as effective as possible.
An announcement will be sent once the exact meeting date is established.
We still encourage input from the patient and advocacy communities and academia to ensure your suggestions and concerns are taken into consideration as we prepare for this important meeting.
Please use the website at http://www.hivforum.org/CCR5/index.html to provide input. Please provide your comments by January 15, 2006.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
December 1 is World AIDS Day.
From the first, isolated reports in 1981, AIDS has grown into a global pandemic. Despite efforts in every nation, the epidemic continues to grow. While HIV/AIDS seems to have faded somewhat into the background in the United States, rarely making front page headlines as it has in years past, the epidemic is still present in this country. There are more than a million people living with HIV and AIDS in the United States today, and an estimated 38 million worldwide.
AIDS and HIV infection have become part of the American narrative over the past twenty four years. It is a now part of the fabric of our nation, and that of nations around the world.
FDA has played a strong role in addressing treatment and prevention from the beginning of the epidemic. FDA has made significant contributions to the development and availability of potent antiviral drugs that have dramatically helped people with HIV and AIDS live longer, healthier lives.
The agency has played an important role in improving medical treatments, providing access to promising investigational products, helping to prevent the transmission of HIV through regulation of barrier products, protection of the blood supply, and oversight of the development of vaccines (both preventive and therapeutic) and microbicides.
World AIDS Day commemorates those that have died from AIDS. It also serves as an opportunity to think about how we can help support the individuals, families, and communities affected by HIV and AIDS, and renew our commitment to preventing the spread of the disease, developing and delivering more effective treatments, and finding a cure.
You can find a comprehensive chronology of significant events in FDA's involvement in the fight against HIV on the FDA website at
http://www.fda.gov/oashi/aids/miles.html
1981-1990: This decade saw the first report of AIDS and its identification as a retrovirus, approval of the first immunoassay test, approval of the first drug to treat AIDS (AZT), the first drugs for treatment and prevention of certain opportunistic infections, and a mechanism for expanded access to promising therapies prior to approval.
1991-1994: These years saw the creation of the National Task Force on AIDS Drug Development, large-scale expanded access to pre-approved HIV therapies, and approval of a number of new drugs. Accelerated approval permitted earlier approval of therapies based on surrogate marker activity. The first non blood-based collection system was approved to test for HIV, and a female condom was approved, providing women with a barrier product that didn't rely on a woman's partner to use.
1995-1999: The final years of the century saw approval of the first protease inhibitor, a new class of drugs for treating HIV, the first home-use AIDS test kit, the first antigen test kit to screen blood donors for HIV-1, and the first viral load test.
2000-present: In the first years of the 21st century, new formulations and combinations of medications were approved to reduce pill burden. Other approvals: HIV genotyping to help improve treatment outcome, the first nucleic acid test for plasma screening, the first rapid HIV test for use in outreach settings, the first fusion inhibitor for treating HIV/AIDS, and the first generic formulations of drugs to treat HIV/AIDS.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Forum for Collaborative HIV Research and the FDA's Division of Antiviral Products are preparing to convene a joint open public meeting on January 18, 2006. The purpose of the meeting is to discuss issues regarding the development of CCR5 co-receptor antagonists for the treatment of HIV infection, specifically mechanisms for long-term follow-up of patients enrolled in CCR5 antagonist clinical trials, potential consequences of tropism changes, and characterization of resistance to these investigational agents.
A special website has been established to permit public input, and for meeting registration.
A subsequent posting will provide additional details regarding the venue and other details regarding the meeting.
FDA would like to encourage input from the patient and advocacy communities and academia to ensure your suggestions and concerns are taken into consideration as we prepare for this important meeting.
In preparing for this meeting, we are soliciting suggestions, experiences, and lessons learned from other long-term (>48 weeks) follow-up studies in HIV-infected subjects, as well as experiences from other therapeutic areas and innovative suggestions for collection of long-term safety data, to help formulate issues for presentation and discussion at the meeting.
In order to prepare for this meeting, we are requesting the following:
1. Detailed summaries regarding your experiences and lessons learned from long-term follow-up studies (for the treatment of HIV infection or relevant experiences from other therapeutic areas) through the conduct of controlled clinical trials, open-label safety studies, observational cohorts or registries
2. Final or draft protocol(s) under consideration, or proposed outlines for long-term safety follow-up
3. Comments regarding any protocol design elements for long-term follow-up trials that were found unacceptable by the HIV community (patients and investigators)
4. Comments on the topics and questions listed below :
1. Tropism and Safety Issues:
2. Long-term Monitoring Plan:
Currently the FDA is requesting five years of follow-up for patients who experience virologic failure in phase II and III CCR5 co-receptor antagonist studies. We recommend that sponsors evaluate patients two-three times a year for CD4+ cell counts, viral load, viral tropism, and occurrence of AIDS-defining illnesses and death.
3. Resistance/Tropism Issues:
4. Other:
During the meeting we intend to differentiate between information needed at the time of approval versus post-approval, and between academic/investigator-initiated studies. Please keep this distinction in mind as you prepare your responses.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The Food and Drug Administration (FDA) recently published information about proposed changes in the way condoms are to be regulated, and draft guidelines for condom labeling.
FDA sets regulatory controls on medical devices. The least restrictive level is general controls. General controls can include good manufacturing practices/quality system regulation, registration and listing, adverse event reporting, and the prohibitions on adulteration and misbranding.
Another level of control is known as special controls. The way a device is labeled can be considered part of special controls.
FDA believes that special controls (in this case special labeling), when combined with general controls, will be sufficient to provide a reasonable assurance of the safety and effectiveness of latex condoms, with or without spermicidal lubricant.
FDA is proposing to amend the classification regulations to designate a special control for natural rubber latex (latex) condoms, with and without spermicidal lubricant. New guidelines (below) specify the kind of labeling that will be considered sufficient and appropriate for the products.
Three separate documents were published on November 14, 2005 to support these proposed changes:
1. Proposed Rule - Obstetrical and Gynecological Devices; Designation of Special Control for Condom and Condom With Spermicidal Lubricant
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-22611.htm
This document explains the regulatory structure for devices of this class.
2. Class II Special Controls Guidance Document: Labeling for Male Condoms Made
of Natural Rubber Latex
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-22610.htm
A Notice of Availability of the Guidance, which includes a very good overview
of the regulatory history of condoms.
3. Draft Guidance - Class II Special Controls Guidance Document: Labeling for Male Condoms Made of Natural Rubber Latex
http://www.fda.gov/cdrh/comp/guidance/1548.html
The draft guidance, which explains the specific labeling requirements considered
to be special controls, including labeling recommendations intended to help
address issues related to nonoxynol-9 (N-9), used as a spermicide in the lubricant
of some latex condoms.
The labeling recommendations in the draft guidance reflect an extensive review by FDA, in consultation with the National Institutes for Health (NIH) and the Centers for Disease Control and Prevention (CDC), of the available medical literature on the safety and effectiveness of condoms intended to prevent pregnancy and provide protection against sexually transmitted diseases (STDs). In addition, the Agency considered other relevant information related to the barrier properties of latex condoms and the various routes of transmission of STDs.
Interested parties are encouraged to comment on the proposals. Instructions for submitting comments are provided within the linked documents.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The "Public Health Service Task Force 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" have been revised to include:
Updates to Clinical Scenario #3. The new information discusses a 3 to 7 day "tail" of postpartum maternal ZDV/3TC following single dose maternal/infant nevirapine; this "tail" may reduce the risk of nevirapine resistance.
Updated information on the role of cesarean delivery in preventing mother-to-child
transmission of HIV.
An updated Supplement: Safety and Toxicity of Individual Antiretroviral Agents
in Pregnancy, including a new section on tipranavir.
A Perinatal Antiretroviral Guidelines Working Group Conflict of Interest Disclosure
(Appendix).
Updated information appears highlighted in yellow.
You can download the updated guidelines, or request to receive them by e-mail or hard copy from the AIDSinfo Web site: www.aidsinfo.nih.gov.
The AIDSinfo website is also a useful source of other information related to HIV/AIDS, including other treatment and prevention guidelines, downloadable databases for PDAs (Personal Digital Assistants), fact sheets, and HIV/AIDS-related clinical trials information.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection"
has been updated. The new version includes:
1. Information about the recently approved protease inhibitor tipranavir and
information about new formulations of emtricitabine and lopinavir/ritonavir
2. A fully revised and updated Supplement I: Characteristics of Available Antiretroviral Drugs
3. Updated information on hepatotoxicity in Supplement III: Adverse Drug Effects
4. A Pediatric Antiretroviral Guidelines Working Group Conflict of Interest Disclosure (Appendix B).
The updated guidelines documents are available in the PEDIATRIC GUIDELINES section of the GUIDELINES page on the AIDSinfo Web site: www.aidsinfo.nih.gov.
All new information in the main document, Appendix A, and Supplement III is highlighted.
Appendix B is new and Supplement I has been entirely rewritten, so these sections
are highlighted in title only.
You can download the guidelines or can request to receive them by e-mail or
hard copy on the AIDSinfo Web site.
The AIDSinfo website is also a useful
source of other information related to HIV/AIDS, including other treatment and
prevention guidelines, downloadable databases for PDAs (Personal Digital Assistants),
and HIV/AIDS-related clinical trials information.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The Food and Drug Administration (FDA) today (November4, 2005) announced the tentative approval of Lamivudine Oral Solution, 10 mg/mL manufactured by Aurobindo Pharma LTD. of Hyderabad , India. Lamivudine Oral Solution is the first generic version of the already approved Epivir Oral Solution, 10 mg/mL, manufactured by GlaxoSmithKline. This child-friendly-product is indicated for use in pediatric patients with HIV from three months to 16 years.
Lamivudine is in the class of drugs called 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.
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 meet all of FDA's safety, efficacy, and manufacturing quality standards
required for marketing in the U.S. and it will now be available for consideration
for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Today (October 28, 2005) the Food and Drug Administration approved a new formulation of Kaletra. Kaletra (lopinavir/ritonavir) is now available as a film coated tablet (200mg/50mg) that provides advantages over the currently marketed capsule formulation for HIV-1 infected patients. Specifically, the tablet formulation:
The following additions and revisions were made to the package insert.
1. The CLINICAL PHARMACOLOGY section contains the following additions:
Pharmacokinetics
Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.
Effects of Food on Oral Absorption
KALETRA tablets
No clinically significant changes in Cmax and AUC were observed following administration of Kaletra tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 – 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9%, but not Cmax. Therefore, Kaletra tablets may be taken with or without food.
Drug-drug Interactions
Tables 2 and 3 were updated to clarify which formulations of Kaletra (capsule, oral solution or tablets) were used in the drug-drug interaction studies. Results of the drug-drug interaction study between efavirenz and Kaletra tablets were included.
2. The following text was added and/or revised in the PRECAUTION: Information for patients section:
KALETRA tablets can be taken at the same time as didanosine without food. Patients taking didanosine should take didanosine one hour before or two hours after KALETRA oral solution.
KALETRA tablets may be taken with or without food. KALETA oral solution should be taken with food to enhance absorption.
3. In the PRECAUTION section, Table 10: Established and Other Potentially Significant Drug Interactions, was revised to include the following:
4. The DOSAGE AND ADMINISTRATION section was revised to include the following information regarding the new tablet formulation:
KALETRA tablets may be taken with or without food.
KALETRA oral solution must be taken with food.
KALETRA tablets should be swallowed whole and not chewed, broken, or crushed.
The recommended oral dose of KALETRA is as follows: (Please refer also to INDICATIONS AND USAGE and ADVERSE REACTIONS)
Adults
Therapy-Naïve Patients
Therapy-Experienced Patients
Once-daily administration of KALETRA is not recommended in therapy-experienced patients.
Concomitant therapy: Efavirenz, nevirapine, fosamprenavir or nelfinavir
Increasing the dose of KALETRA tablets to 600/150 mg (3 tablets) twice-daily coadministered with efavirenz significantly increased the lopinavir plasma concentrations approximately 35% and ritonavir concentrations approximately 56% to 92% compared to KALETRA tablets 400/100 mg twice-daily without efavirenz (see CLINICAL PHARMACOLOGY– Drug-drug Interactions Table 2 and/or PRECAUTIONS – Table 10).
KALETRA tablets and oral solution should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
5. The HOW SUPPLIED section was revised to include storage information for the Kaletra tablets as follows:
Recommended storage: Store KALETRA film-coated tablets at 20°- 25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F) [see USP controlled room temperature]. Dispense in original container. For patient use: exposure of this product to high humidity outside the original container for longer than 2 weeks is not recommended.
The capsule formulation will be phased out over time by the company.
Kaletra is a product of 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
The Food and Drug Administration (FDA) is announcing a meeting of its Blood Products Advisory Committee (BPAC) to discuss important issues that include an approach for home-use rapid HIV test kits. The Committee will hear a proposal by OraSure Technologies, Inc. for over-the-counter (OTC) availability of the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test for use with oral fluid specimens, including:
The BPAC will also hear presentations addressing the role of rapid HIV tests in CDC's Advancing HIV Prevention initiative and CDC's current HIV test counseling recommendations, the role of quality systems in diagnostic testing, psychological and social issues associated with HIV testing, and prior experience with approved home-use test kits.
In addition, the committee will hear updates on the following topics: (1) West Nile Virus; (2) draft guidance on nucleic acid testing (NAT) for human immunodeficiency virus (HIV)-1 and hepatitis C virus (HCV): Testing, product disposition, and donor deferral and re-entry; (3) summary of the Department of Health and Human Services Advisory Committee on Blood Safety and Availability held on September 19 and 20, 2005; and (4) re-entry of donors deferred based on hepatitis B core antigen (anti-HBc) test results.
The meeting is scheduled for November 3, 2005, from 8:00 a.m. to 5:30 p.m. at:
Holiday Inn Gaithersburg
2 Montgomery Village Ave.
Gaithersburg, MD
The meeting is open to the public, and no registration is required. Please contact the hotel directly at 301.948.8900 for directions or information about accommodations.
Background materials for this meeting are posted on the FDA website at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4190b1.htm
A draft agenda is available at http://www.fda.gov/ohrms/dockets/ac/05/agenda/2005-4190A1_draft.htm
Interested persons may present data, information, or views - orally or in writing - on issues pending before the committee during the open public hearing. Written submissions may be made by October 25, 2005 to Donald W. Jehn or Pearline K. Muckelvene, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0314.
Those desiring to make formal oral presentations should, by October 25, 2005, 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 to Donald W. Jehn or Pearline K. Muckelvene, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0314.
Oral presentations from the public will be scheduled on November 3, 2005, between approximately 2 p.m. and 3:45 p.m. Time allotted for each presentation may be limited, depending on the number of requests to speak.
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 Donald W. Jehn or Pearline K. Muckelvene at least 7 days in advance of the meeting.
Advisory Committee Telephone Information Line:
Please call the Information Line for up-to-date information on this meeting,
1-800-741-8138 (301-443-0572 in the Washington, DC area), code 3014519516.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
On October 6, 2006, The Food and Drug Administration approved dosing recommendations for NORVIR (ritonavir) in pediatric patients one month to two years of age. The major revisions to the package insert include the following:
CLINICAL PHARMACOLOGY
This section was modified to include pharmacokinetic data in children 1 month
to 2 years of age. The new Clinical Pharmacology section for Pediatric Patients
reads as follows:
Pediatric Patients
Steady-state pharmacokinetics were evaluated in 37 HIV infected patients ages 2 to 14 years receiving doses ranging from 250 mg/m2 twice-daily to 400 mg/m2 twice daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses 350 and 450 mg/m2 twice daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m2 twice daily in pediatric patients > 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m2) twice daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg/m2 twice daily in children < 2 years of age. Higher ritonavir exposures were not evident with 450 mg/m2 twice daily compared to the 350 mg/m2 twice daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice daily. The area under the ritonavir plasma concentration-time curve and trough concentrations obtained after administration with 350 or 450 mg/m2 twice daily were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.
PRECAUTIONS
The following information was added under the section of Pediatric Use subsection:
Pediatric Use
In HIV-infected patients age > 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.
ADVERSE REACTIONS
The following information was added under the section of Pediatric Use subsection.
Of note, the treatment-emergent adverse events and laboratory abnormalities
shown in the label reflect the summary of the adverse events and laboratory
abnormalities observed in pediatric studies M95-310, PACTG 366, and PACTG 345.
Pediatrics
Treatment-Emergent Adverse Events
NORVIR has been studied in 265 pediatric patients > 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.
Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in = 2% of pediatric patients enrolled in NORVIR clinical trials.
Laboratory Abnormalities
The following Grade 3-4 laboratory abnormalities occurred in = 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).
DOSAGE AND ADMINISTRATION
The section of Pediatric Patients has been modified to include dosing recommendations
for children > 1 month to 2 years of age. The new Dosage and Administration
section for Pediatric Patients is:
Pediatric Patients
Ritonavir should be used in combination with other antiretroviral agents (see General Dosing Guidelines). The recommended dosage of ritonavir in children > 1 month is 350 to 400 mg/m2 twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and increased at 2 to 3 day intervals by 50 mg/m2 twice daily. If patients do not tolerate 400 mg/m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. When possible, dose should be administered using a calibrated dosing syringe.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" document has been revised to include the following changes:
What Not to Use as Initial Therapy (Table 8)
* The Panel recommends that a regimen containing "NNRTI + didanosine + tenofovir" should not be used as an initial regimen in antiretroviral treatment-naïve patients due to reports of early virologic failure and rapid emergence of resistant mutations to NNRTIs, tenofovir, and/or didanosine.(DII)
* The Panel does not recommend the use of ritonavir-boosted tipranavir in treatment-naïve patients due to the lack of clinical trial data in this setting.(DIII)
Management of Treatment Experienced Patients
* This section has been updated to redefine the goal of antiretroviral therapy in the management of treatment-experienced patients with virologic failure and to review the role of more potent ritonavir-boosted protease inhibitors such as tipranavir with or without enfuvirtide in these patients.
* Tables 23-25 have been updated to be consistent with the revised text.
The Following Tables Have Been Updated:
* Table 7 - Treatment outcome data of once daily abacavir-lamivudine and lopinavir-ritonavir have been added to this table.
* Tables 12 & 13 - These tables have been updated with information on once daily lopinavir-ritonavir dosing and new information on characteristics of tipranavir.
* Tables 16-21b - These tables have been updated to include information relating to tipranavir-associated adverse events and drug interactions.
* Tables 23-25 - These tables are updated to be consistent with the revised text on the management of treatment-experienced patients.
* Table 26 - Suggested minimum target trough concentration for atazanavir has been added to this table.
* Tables 28 & 29 - These tables are adapted from the USPHS perinatal antiretroviral guidelines with information on tipranavir use during pregnancy.
* Table 30 - This table has been updated with information for TMC-114 Expanded Access Program. Information regarding tipranavir expanded access program has been removed.
The updated guidelines document is available AIDSinfo
web site. Changes to the to the April 7, 2005 version of the guideline document
are highlighted in yellow.
You can view, order hard copies of the guidelines, or request them by email
at the web site.
The AIDSinfo website is also a useful source of other information related to HIV/AIDS, including other treatment and prevention guidelines, downloadable databases for PDAs (Personal Digital Assistants), and HIV/AIDS-related clinical trials information.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
On September 28, 2005, The Food and Drug Administration approved EMTRIVA (emtricitabine) Oral Solution 10 mg/mL. The approval of this Oral Solution formulation allows for dosing recommendations in pediatric patients. EMTRIVA is now indicated in combination with other antiretroviral agents, for the treatment of HIV-1 infection in patients over three months of age.
In addition the following changes to the label were made:
CLINICAL PHARMACOLOGY Section
Pharmacokinetic data in pediatrics, renal impairment information and results
from a drug-drug interaction study with zidovudine were included.
INDICATIONS AND USAGE
The indication was expanded to include patients over three months of age.
PRECAUTIONS
Addition of zidovudine to the drug interactions section, addition of the immune
reconstitution syndrome section, updated carcinogenicity data and pediatric
use statements were included.
ADVERSE REACTIONS
This section was updated to include data in pediatric patients.
DOSAGE AND ADMINISTRATION
This section was revised to include dosing information in pediatric patients
with the oral solution and capsule formulations. In addition, dosing information
for the oral solution for adult patients was included. A new table was added
to include dose adjustment information in adults with renal impairment for the
capsule and oral solution formulations.
HOW SUPPLIED
Data on storage conditions for the Oral Solution were included.
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
Some HIV-infected patients may have interrupted their antiretroviral therapy and other medications due to the recent hurricane disasters. The following link provides some guidance to the general practitioners attending to the medical needs of displaced HIV-infected adult or pediatric patients who have not yet secured HIV care in the local area.
Management of antiretroviral therapy is complex and should best be done with the assistance of specialized clinicians.
To see the recommendations go to: www.aidsinfo.nih.gov
Medical consultation may also be available at specific local or regional HIV clinics or via the 24-hour NIH Medical Consultation Services at 1-866-887-2842 or the National HIV Telephone Consultation Service: at 1-800-933-3413.
The recommendations were prepared by:
The Panel on Clinical Practices for Treatment of HIV Infection (Adult and Adolescent
HIV Treatment Guidelines Panel)
The Perinatal HIV Guidelines Working Group
The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected
Children
USPHS/IDSA Prevention and Treatment of Opportunistic Infections Working Groups
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
On September 19, 2005, FDA approved several generic formulations of Zidovudine for the U.S. market.
Previously, the products had been only tentatively approved and were not available
in the United States because patent or market exclusivity blocked their approval
for domestic marketing. With the expiration of those patents, the following
products have received full marketing authorization for the United States:
(1) zidovudine tablets, 300 mg , manufactured by Ranbaxy Laboratories Limited
of Guragon, India;
(2) zidovudine tablets, 300 mg and oral solution, 50 mg/5mL, manufactured by
Aurobindo Pharma LTD. Hyderabad, India; and
(3) zidovudine tablets, 300 mg, manufactured by Roxane Laboratories of Columbus,
Ohio, U.S.A.
These are the first generic versions of the already-approved Retrovir brand manufactured by GlaxoSmithKline to be approved for marketing in the U.S. FDA previously determined, as part of a tentative approval action, that these products meet all U.S. manufacturing quality and clinical safety and efficacy standards.
Zidovudine is in the class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing. This antiretroviral drug is intended to be used with other antiretroviral agents for the treatment of HIV infection.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Food and Drug Administration (FDA), on September 7, 2005, announced the tentative approval of zidovudine oral solution manufactured by Aurobindo Pharma LTD. Hyderabad, India. This product is the first tentatively approved generic version of Retrovir brand of the zidovudine oral solution (manufactured by GlaxoSmithKline). This oral dosage form of the drug is the first pediatric-friendly oral solution available for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
Zidovudine is in the class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing. It is intended to be used with other antiretroviral agents for the treatment of HIV-1 infection. This product contains 50 mg/5mL of zidovudine in an oral solution.
Tentative approval means that although existing patents and/or exclusivity prevent marketing of this product in the United States, it meets all of FDA's quality, safety and efficacy standards for U.S. marketing.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Food and Drug Administration, on August 25, 2005, granted tentative approval to zidovudine 300 mg tablets manufactured by Aurobindo Pharma LTD., Hyderabad, India. Tentative approval means that although existing patents and/or exclusivity prevent marketing of this product in the United States, it meets the quality, safety and efficacy standards for U.S. marketing.
The tablets are a generic version of the already-approved Retrovir brand of the product manufactured by GlaxoSmithKline.
The tentative approval by FDA makes Aurobindo Pharma's generic zidovudine eligible for purchase and use outside the United States under the President's Emergency Plan for AIDS Relief (PEPFAR).
On July 13, 2005, FDA granted tentative approval to a generic combination drug product manufactured by Aurobindo consisting of lamivudine and zidovudine. Another generic version of zidovudine tablets, manufactured by Ranbaxy Laboratories Limited of Guragon, India received tentative approval on July 13, 2005.
Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTIs), intended to be used 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
Return to index
FDA, in collaboration with The University of Medicine and Dentistry of New Jersey, The National Institute of Mental Health, The National Institute on Drug Abuse, and The Centers for Disease Control and Prevention is announcing a consensus conference, PDE-5 Inhibition and HIV Risk: Current Concepts and Controversies. The objective of the conference is to bring together and review data related to the use of Phosphodiesterase type-5 inhibitors (PDE-5's) for the treatment of male erectile dysfunction, such as sildenafil, tadalafil, and vardenafil, and their relationship to HIV transmission in high risk men and their sexual partners.
The conference will address:
· PDE-5 use and sexual behavior among at-risk populations
· PDE-5 use in combination with drugs of abuse
· Risks and benefits of PDE-5 treatment in at-risk populations
Evidence-based guidelines will be developed for prevention, education and research on causes and consequences of high-risk sexual behavior.
The conference will take place September 26 and 27, 2005, at the Bolger Conference Center in Potomac, MD. Registration is required, and there is a registration fee for this conference (see link below).
PDE-5 INHIBITION IN HIV+ AND HIV- MEN: BIOMEDICAL, BEHAVIORAL AND SOCIETAL PERSPECTIVES
Phosphodiesterase type-5 inhibitors (PDE-5's) are highly effective and well-tolerated oral drugs for treatment of male erectile dysfunction (ED), a medical condition which affects about 180 million men, worldwide. Three specific drugs in this class (sildenafil, tadalafil, vardenafil) have been approved and are currently used by approximately 20-25 million men. Recent reports of potential use of these agents as "recreational drugs" by selected groups of men has raised concerns about a variety of health risks: primarily, the association of these drugs with high risk sexual risk behavior, as well as the increasing co-use with known drugs of abuse (e.g. crystal methamphetamines).
This conference will aim to bring together existing data on use of PDE5 inhibitors (with or without drugs of abuse) in men and women at risk sexually, or being treated for HIV, the potential impact on physical and mental health in users, and the possible threat of increased risk for HIV spread. A major goal of the proposed conference is to critically evaluate the available evidence of increased use of these drugs by high risk individuals, and their potential contribution to further high-risk sexual behavior in HIV+ or HIV- men. What are the epidemiological implications, if any, of these trends, and what steps should be taken in regard to prevention or education?
A related goal is to critically evaluate the state of knowledge regarding biobehavioral effects of PDE-5 inhibition on sexual behavior generally, and the potential pharmacological interactions with other prescription or non-prescription drugs. Both pharmacological and behavioral aspects of this association will be addressed.
A third major area of focus for the proposed conference will be on the treatment of sexual dysfunction in men with HIV/AIDS, and the potential risks and benefits of PDE-5 use in this group. Clinical management guidelines will be developed in this regard.
Finally, the conference will address legal, ethical and social policy aspects of PDE-5 use in high risk or HIV+ individuals. Potential initiatives for education and prevention, particularly those which involve collaboration of industry, academia and government will be explored.
Additional details and registration information can be found at http://ccoe.umdnj.edu/rwjms/PDE5/index.htm.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Food and Drug Administration, on July 13, 2005, announced the tentative approval of zidovudine tablets manufactured by Ranbaxy Laboratories Limited of Guragon, India. The product contains 300 mg of zidovudine in each tablet. It is a generic version of the already-approved Retrovir brand of the product manufactured by GlaxoSmithKline.
Tentative approval means that although existing patents and/or exclusivity prevent marketing of this product in the United States, it meets the quality, safety and efficacy standards for U.S. marketing.
Tentative approval by FDA makes this Ranbaxy generic product eligible for purchase and use outside the United States under the President's Emergency Plan for AIDS Relief.
Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTIs), intended to be used with other antiretroviral agents for the treatment of HIV-1 infection.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The Food and Drug Administration (FDA), on July 7, 2005, announced the tentative approval of a generic combination drug product consisting of lamivudine and zidovudine, manufactured by Aurobindo Pharma LTD. Hyderabad, India.
FDA tentative approval means that the product meets all of FDA’s quality, safety and efficacy standards, but existing patents and/or exclusivity prevent marketing of the product in the U.S. Tentative approval by FDA, however, makes this Aurobindo generic product available for consideration for purchase and use outside the United States under the President’s Emergency Plan for AIDS Relief (PEPFAR).
The Aurobindo lamivudine/zidovudine combination product is a generic version of the U.S. approved Combivir lamivudine/zidovudine combination manufactured by GlaxoSmithKline.
Lamivudine and Zidovudine are both nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing. This combination antiretroviral drug is intended to be used with other antiretroviral agents in the treatment of HIV-1 infection.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The Food and Drug Administration (FDA), on July 1, 2005, announced the tentative approval of stavudine capsules manufactured by Aurobindo Pharma LTD., Hyderabad, India. This formulation of stavudine is the first generic version of the approved drug, Zerit, manufactured by Bristol-Myers Squibb to receive tentative approval. Tentative approval allows the product to be considered for purchase under the President’s Emergency Plan for AIDS Relief (PEPFAR).
Stavudine is in the class of drugs called Nucleoside Reverse Transcripts Inhibitors (NRTIs) which helps keep the AIDS virus from reproducing. This antiretroviral drug is used in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The agency’s tentative approval means that although existing patents and/or exclusivity prevent marketing of these products in the U.S., they meet all of FDA’s quality, safety and efficacy standards.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
The Food and Drug Administration (FDA), on June 24, 2005, granted tentative approval for efavirenz tablets manufactured by Aurobindo Pharma LTD. of Hyderabad, India. This product is the first tentatively approved generic version of Sustiva tablets (manufactured by Bristol-Myers Squibb).
Generic efavirenz will now be available for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
The agency's tentative approval means that although existing patents and/or exclusivity prevent marketing of a particular product in the United States, it meets all of FDA's quality, safety and efficacy standards required for marketing in the United States.
Efavirenz is a member of the non-nucleoside reverse transcriptase inhibitors
(NNRTIs) class of drugs, which helps keep the AIDS virus from reproducing in
cells. This antiretroviral drug is used in combination with other antiretroviral
agents for the treatment of HIV-1 infection.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
On June 22, 2005, the US Food and Drug Administration (FDA) granted accelerated approval of APTIVUS (tipranavir), a protease inhibitor. APTIVUS, co-administered with 200 mg of ritonavir, is indicated for use as part of combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.
FDA reviewed and approved APTIVUS within a six month time frame.
Clinical Study Results
The approval of APTIVUS/ritonavir is based on analyses of plasma HIV-1 RNA levels
in two controlled phase III studies of APTIVUS/ritonavir of 24 weeks duration.
Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI,
NNRTI, PI) treatment-experienced adults with evidence of HIV1 replication
despite ongoing antiretroviral therapy. The results of the two phase III studies
showed a statistically significant greater percentage of HIV-positive patients
taking APTIVUS/ritonavir achieved treatment response versus the comparator group
(40% vs. 18%). Treatment response was defined as a confirmed 1 log10 or greater
decrease in HIV RNA from baseline.
Dosage and Administration
The approved dose of APTIVUS is 500 mg taken with 200 mg of ritonavir, twice
daily with food. APTIVUS must be co-administered with 200 mg of ritonavir to
exert its therapeutic effect. Failure to correctly co-administer APTIVUS with
ritonavir will result in reduced plasma levels of tipranavir that will be insufficient
to achieve the desired antiviral effect. Taking the drug with food improves
absorption.
Usage Information:
The following points should be considered when initiating therapy with APTIVUS/ritonavir:
· The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response.
· Genotypic or phenotypic resistance testing and/or treatment history should guide the use of APTIVUS/ritonavir. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir.
· Because APTIVUS can cause serious liver toxicity, liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment
· Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, Hepatitis B or C co-infection, or other underlying hepatic (liver) impairment
· APTIVUS used with low-dose ritonavir has many drug interactions. Therefore, patients should report to their health care provider the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort. Certain medicines such as antiarrhythmics (medicines that treat irregular heart beats), antihistamines, ergot derivatives (found in some medicines to treat migraine headaches), medicines that speed up the digestive tract, herbal products, some medicines that lower cholesterol levels, and medicines to treat mental problems should never be given with APTIVUS plus ritonavir because serious side effects could occur.
Patients receiving estrogen-based birth control pills or patches should be instructed that additional or alternative forms of birth control should be used when taking APTIVUS.
The extensive drug-drug interaction potential of APTIVUS/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use.
· The risk-benefit of APTIVUS/ritonavir has not been established in treatment-naïve adult patients or pediatric patients.
· There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.
Safety Information:
The most commonly (> 3%) reported adverse reactions were diarrhea, nausea,
fatigue, headache and vomiting. The most commonly reported laboratory abnormalities
were elevated liver enzymes, cholesterol and triglycerides.
Hepatotoxicity
The APTIVUS label includes a Black Box warning regarding hepatoxicity. Specifically,
APTIVUS co-administered with low dose ritonavir has been associated with reports
of clinical hepatitis and hepatic decompensation, including some fatalities.
Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis
C co-infection, as these patients have an increased risk of hepatotoxicity.
All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment.
In addition, APTIVUS is contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency.
Sulfa Allergy
APTIVUS should be used with caution in patients with a known sulfonamide allergy.
Tipranavir contains a sulfonamide component. The potential for cross-sensitivity
between drugs in the sulfonamide class and tipranavir is unknown.
Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and possible
photosensitivity have been reported in subjects receiving APTIVUS/ritonavir.
In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of
males receiving APTIVUS/ritonavir. Additionally, in one drug interaction trial
in healthy female volunteers given a single dose of ethinyl estradiol (a hormonal
contraceptive) followed by APTIVUS/ritonavir, 33% of subjects developed a rash.
Rash accompanied by joint pain or stiffness, throat tightness, or generalized
pruritus (itching) has been reported in both men and women receiving APTIVUS/ritonavir.
Ongoing Clinical Trials
Boehringer Ingelheim agreed to continue to evaluate the safety and efficacy
of APTIVUS in the following patient populations:
· Pediatric patients
· Treatment-naïve adults
· HIV-positive women
· Hepatitis co-infected patients
Additional drug-drug interaction studies are planned.
Currently there are seven other protease inhibitors approved by FDA for the treatment of HIV infection. These medications work at the final stages of viral replication and attempt to prevent HIV from making new copies of itself by interfering with the HIV protease enzyme. As a result, the new copies of HIV are not able to infect new cells
The manufacturer of APTIVUS is Boehringer Ingelheim Pharmaceuticals.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The Food and Drug Administration (FDA) announced, on June 20, 2005, the Tentative Approval of two applications for nevirapine tablets manufactured by Ranbaxy Laboratories Limited, Guragon, India and Aurobindo Pharma Limited, Hyderabad, India. These are the first generic versions of Viramune (nevirapine) tablets manufactured by Boehringer Ingelheim. These products will now be available for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR).
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTIs) used in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The use of single dose nevirapine for the prevention of mother to child transmission of HIV is permitted under PEPFAR.
The FDA's tentative approval means that although existing patents and/or exclusivity prevent the marketing of Aurobindo's and Ranbaxy's products in the United States, these products meet all of the agency's quality, safety and efficacy standards required for marketing in the United States. Therefore, they are eligible to be considered for purchase and use outside the United States under the PEPFAR program.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
On June 15, 2005, FDA granted a tentative approval for generic Lamivudine Tablets, 150 mg and 300 mg, manufactured by Aurobindo Pharma Ltd., Hyderabad, India. Lamivudine Tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-l infection.
A Tentative Approval means that FDA has concluded that a drug product has met all of the required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. due to existing patents and/or exclusivity. It does, however, make the product eligible for use under the President's Emergency Plan for AIDS Relief (PEPFAR) program outside the United States.
This is the second application for Lamivudine Tablets for which FDA granted tentative approval granted under the PEPFAR expedited review program. On May 27, 2005, FDA granted tentative approval to Ranbaxy Laboratories Limited, for Lamivudine Tablets, 150 mg.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
FDA issued an approval on May 31, 2005 for a generic formulation of foscarnet sodium injection, 24 mg/mL, 250 mL and 500 mL single-dose containers, manufactured by Pharmaforce, Inc., of Columbus, Ohio. The product is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS), making a generic alternative formulation available in the United States.
The product is a generic version of Foscavir (foscarnet sodium Injection) 24 mg/mL, 250 mL and 500 mL single-dose containers, manufactured by Astra Zeneca, originally approved in 1991.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
FDA granted a tentative approval for a generic formulation of lamivudine tablets, 150 mg, manufactured by Ranbaxy Laboratories Limited (India), for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults. The tentative approval was issued May 27, 2005.
A Tentative Approval means that FDA has concluded that a drug product has met all of the required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. due to existing patents and/or exclusivity. It does, however, make the product eligible for use under the President's Emergency Plan for AIDS Relief (PEPFAR) program outside the United States.
The lamivudine tablets are a generic version of Epivir (lamivudine) Tablets, 150 mg, manufactured by Glaxo Smith Kline.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Roche Pharmaceuticals, of Nutley, New Jersey, has issued a Dear Health Care Provider letter to inform the clinical community that commercial distribution of Fortovase, the 200-mg soft-gel formulation of saquinavir, will be discontinued by February 15, 2006.
The letter cites decreased demand for Fortovase as the reason for the product's discontinuation.
Invirase, another formulation of saquinavir manufactured by Roche Pharmaceuticals, will continue to be available in 200-mg and 500-mg formulations.
Roche suggests that physicians refrain from starting Fortovase treatment in their HIV-positive Patients at this time, and encourages prescribing health care providers to discuss appropriate alternative treatment regimens with patients currently receiving Fortovase.
The complete text of the Dear Health Care Provider letter is reproduced below:
May 2005
Dear Health Care Professional:
Roche Pharmaceuticals would like to inform you that the sale and distribution
of Fortovase --
the 200-mg soft-gel formulation of saquinavir -- will be discontinued by February
15, 2006.
Roche has taken this action because the clinical demand for Fortovase has declined
significantly;
this is not the result of any safety or efficacy issues regarding the product.
Invirase, which is the preferred formulation of saquinavir, will continue to
be available in 200-mg and
500-mg formulations. Invirase offers patients key advantages over Fortovase,
including:
At this time, we encourage physicians to refrain from starting Fortovase treatment in their HIV-positive patients. If you are aware of a patient receiving Fortovase, please notify the prescribing health care provider (if someone other than yourself) and the patient regarding this announcement. We encourage you or the prescribing health care provider to discuss appropriate alternative treatment regimens with your patients currently receiving Fortovase.
Enclosed you will find the complete Product Information for Invirase (saquinavir mesylate). If you have any questions regarding the discontinuation of Fortovase, please call 1-800-526-6367.
Please see important safety information at close of letter.
Sincerely,
Lars E. Birgerson, MD, PhD
Vice President, Medical Affairs
References:
1. Kurowski M, Sternfeld T, Sawyer A, et al. Pharmacokinetic and tolerability
profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft
gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med. 2003;4(2):94-100.
2. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults
and Adolescents. Panel on Clinical Practices for Treatment of HIV Infection,
United States Department of Health and Human Services; October 29, 2004.
Indication
INVIRASE in combination with ritonavir and other antiretroviral agents is indicated
for the treatment of HIV infection. The twice-daily administration of INVIRASE
in combination with ritonavir is supported by safety data from the MaxCMin 1
study and pharmacokinetic data. The efficacy of INVIRASE with ritonavir or FORTOVASE
(with or without ritonavir coadministration) has not been compared against the
efficacy of antiretroviral regimens currently considered standard of care.
FORTOVASE is indicated for use in combination with other antiretroviral agents
for the treatment of HIV infection. This indication is based on studies that
showed increased saquinavir concentrations and improved antiviral activity for
FORTOVASE 1200 mg tid compared to INVIRASE 600 mg tid. In treatment-naive and
treatment-experienced patients, the efficacy of FORTOVASE (with or without ritonavir
coadministration) has not been compared against the efficacy of antiretroviral
regimens currently considered standard of care.
Important Safety Information
WARNING:
INVIRASE® (saquinavir mesylate) capsules and tablets and FORTOVASE®
(saquinavir) soft gelatin capsules are not bioequivalent and cannot be used
interchangeably. INVIRASE may be used only if it is combined with ritonavir,
which significantly inhibits saquinavir's metabolism to provide plasma saquinavir
levels at least equal to those achieved with FORTOVASE. When using saquinavir
as the sole protease inhibitor in an antiviral regimen, FORTOVASE is the recommended
formulation.
INVIRASE and FORTOVASE are contraindicated in patients with clinically significant
hypersensitivity to saquinavir or to any of the components contained in the
capsule. FORTOVASE and INVIRASE/ritonavir should not be administered concurrently
with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot
derivatives. Inhibition of CYP3A4 by saquinavir could result in elevated plasma
concentrations of these drugs, potentially causing serious or life-threatening
reactions, such as cardiac arrhythmias or prolonged sedation.
FORTOVASE and INVIRASE, when administered with ritonavir, are contraindicated
in patients with severe hepatic impairment. Saquinavir drug pharmacokinetics/pharmacodynamics
have not been studied in patients with hepatic impairment and caution should
be exercised when prescribing saquinavir in this population. Concomitant use
of INVIRASE or FORTOVASE with lovastatin or simvastatin is not recommended.
Caution should be exercised if HIV protease inhibitors, including INVIRASE or
FORTOVASE, are used concurrently with other HMG-CoA reductase inhibitors that
are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Concomitant use
of INVIRASE or FORTOVASE and St. John’s wort (hypericum perforatum) or
products containing St. John’s wort is not recommended. Garlic capsules
should not be used while taking unboosted saquinavir, due to the risk of decreased
saquinavir plasma concentrations. For a complete list of drugs that should not
be taken with saquinavir, please see TABLE 5 in the summary of complete product
information.
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and
hyperglycemia have been reported during postmarketing surveillance in HIV-infected
patients receiving protease-inhibitor therapy. No initial dose adjustment is
necessary for patients with renal impairment. However, patients with severe
renal impairment have not been studied, and caution should be exercised when
prescribing saquinavir in this population.
There have been reports of spontaneous bleeding in patients with hemophilia
A and B treated with protease inhibitors.
Elevated cholesterol and/or triglyceride levels have been observed in some patients
taking twice daily saquinavir in combination with ritonavir. Redistribution/accumulation
of body fat has been observed in patients receiving ART. A causal relationship
between protease-inhibitor therapy and these events has not been established,
and the long-term consequences are currently unknown.
Varying degrees of cross-resistance among protease inhibitors have been observed.
In clinical trials with saquinavir (1000 mg) in combination with ritonavir (100
mg) and other antiretrovirals, the grade 2, 3 and 4 adverse events occurring
in = 2% of 148 patients (considered at least possibly related to study drug
or of unknown relationship): abdominal pain (6.1%), back pain (2%), bronchitis
(2.7%), constipation (2%), diarrhea (8.1%), diabetes mellitus/hyperglycemia
(2.7%), dry lips/skin (2%), eczema (2%), fatigue (6.1%), fever (3.4%), influenza
(2.7%), lipodystrophy (5.4%), nausea (10.8%), pneumonia (5.4%), pruritus (3.4%),
rash (3.4%), sinusitis (2.7%) and vomiting (7.4%).
INVIRASE and FORTOVASE are not cures for HIV infection or AIDS. INVIRASE and
FORTOVASE do not prevent the transmission of HIV.
_____________________________ 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
The Food and Drug Administration (FDA) is issuing draft guidance to assist
product sponsors in the development of antiviral drug products and to serve
as a starting point for understanding the nonclinical and clinical virology
data important to support clinical trials of antiviral agents. This guidance
focuses on nonclinical and clinical virology reports, which are essential components
in the review of investigational antiviral drugs.
Topics in the guidance include studies defining the mechanism of action, establishing
specific antiviral activity of the investigative drug, submitting data on the
development of viral resistance to the investigational drug, and providing data
identifying cross-resistance to approved drugs having the same target.
The recommendations in the guidance are based on the review experience with antiviral drugs of the FDA Division of Antiviral Drug Products (DAVDP) and input from pharmaceutical sponsors and the scientific community. Because of the experience, history, and lessons learned with HIV-1 studies, the guidance focuses on studies commonly used to evaluate HIV-1 drugs and uses them as a model for future studies of drugs to treat other viruses. Since the field of virology is dynamic and continually evolving, this guidance will be revised as new information accumulates and as circumstances warrant.
The Federal Register document, including instructions for submitting comments to the agency, is available at http://www.fda.gov/OHRMS/DOCKETS/98fr/05-10431.htm
The draft guidance is available at http://www.fda.gov/cder/guidance/6568dft.htm
Guidances on the overall organization of investigational new drug (IND) applications and new drug applications (NDAs) can be found at http://www.fda.gov/cder/regulatory/applications/default.htm. Sponsors are encouraged to contact the Agency early in the development of an investigational antiviral drug to facilitate the review and approval process. To assist prospective sponsors, the Agency accepts informal submissions in an abbreviated IND format (i.e., pre-INDs) for review and comment. Pre-INDs are especially useful in instances where applicants are unfamiliar with the process for evaluating investigational drug products in humans. Information about submitting pre-INDs can be found at http://www.fda.gov/cder/ode4/preind/getting.htm
FDA guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On May 12, 2005, the FDA approved a new 30-count bottle for Norvir (ritonavir) Soft Gelatin Capsules, 100 mg. Previously only 120-count bottles were available. The new 30-count bottle is more convenient for pharmacy dispensing, and for patients who use Norvir 100 mg once or twice daily in combination with other protease inhibitors.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On May 12, 2005, FDA approved new labeling for Viread (tenofovir disoproxil fumarate). The label was updated to include results from Study 903, specifically, the 144 week efficacy and safety data in treatment-naïve patients. Study 903 fulfills part of the requirement for traditional approval by confirming long-term efficacy in treatment-naïve patients and by providing long-term safety information with respect to bone effects.
The following changes were made to the package insert:
Description of Clinical Studies:
The 144-week efficacy data from Study 903 was added. Sixty-eight percent of patients who received Viread in combination with Epivir (lamivudine) and Sustiva (efavirenz) achieved and maintained confirmed HIV RNA < 400 copies/mL at Week 144 compared to 62% of patients who received Zerit (stavudine) in combination with Epivir (lamivudine) and Sustiva (efavirenz).
New text describing the genotypic analysis performed during Study 903 was added as follows:
"Genotypic analyses of patients with virologic failure showed development of efavirenz-associated and lamivudine-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8 patients on the Viread arm and in 2 patients on the Stavudine arm. Of the 8 patients who developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at week 96. Other mutations resulting in resistance to VIREAD were not identified in this study."
PRECAUTIONS:
The Bone Effects subsection was updated with Study 903 data through 144 weeks of dosing as follows:
"In study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz (-2.2% ±3.9) compared with patients receiving stavudine + lamivudine + efavirenz (-1.0% ±4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ±3.5 in the VIREAD group vs. -2.4% ±4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the study and was sustained through Week 144. Twenty-eight percent of VIREAD-treated patients vs. 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the VIREAD group and 8 patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained."
A new paragraph, "Immune Reconstitution Syndrome," was added. This paragraph is being incorporated into the labels of all antiretroviral drugs.
"Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment."
ADVERSE REACTIONS:
· Text and tables displaying Selected Treatment-Emergent Adverse Events (Grades 2-4) and Grade 3/4 Laboratory Abnormalities in Study 903 was updated with data through 144 weeks of dosing.
· In the Post Marketing Experience section, increased amylase, increased liver enzymes, hepatitis, and nephrogenic diabetes insipidis were added to the list of reported disorders.
Viread is a product of Gilead Science, Inc.
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
FDA approved, on April 29, 2005, the use of KALETRA 800/200mg once-daily administration for the treatment of HIV-infection in therapy-naïve adult patients, based on review and analysis of two clinical trials comparing safety and efficacy of lopinavir (LPV)/ritonavir (RTV) 800/200 mg once daily (qd) and LPV/RTV 400/100 mg twice daily (bid), for a duration of at least 48 weeks in antiretroviral-naïve HIV-1 infected subjects.
At this time, once daily Kaletra is not approved for treatment experienced patients because trough concentrations of lopinavir are approximately 60% lower than that observed in the twice daily regimen and because there are no clinical studies comparing the two dosing schedules in treatment-experienced individuals.
The following is a summary of the labeling changes:
CLINICAL PHARMACOLOGY:
Pharmacokinetic data for Kaletra given as 800/200 mg once daily in HIV-1 infected antiretroviral naïve adult subjects were added. Specifically, the following text was included.
The pharmacokinetics of once daily KALETRA have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg KALETRA QD for 4 weeks with food (n=24) produced a mean + SD lopinavir peak plasma concentration (Cmax) of 11.8 + 3.7 µg/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 3.2 + 2.1 µg/mL and minimum concentration within a dosing interval was 1.7 + 1.6 µg/mL. Lopinavir Area Under the Curve (AUC) over a 24 hour dosing interval averaged 154.1 + 361.4 µg ·h/mL
A statement that KALETRA once daily has not been evaluated in pediatric patients was included.
INDICATIONS AND USAGE:
The following information was added:
Once-daily administration of KALETRA is not recommended in therapy-experienced patients.
When initiating treatment with KALETRA in therapy-naïve patients, it should be noted that the incidence of diarrhea was greater for KALETRA once daily compared to KALETRA twice daily in Study 418 (57% vs 35% - events of all grades and probably or possibly related to drug: 16% vs 5% - events of at least moderate severity and probably or possibly related to drug).
Description of Clinical Studies
Results from study M02-418 were included as follows.
Study 418: KALETRA QD + tenofovir DF + emtricitabine compared to KALTERA BID + tenofovir DF + emtricitabine
Study 418 is an ongoing, randomized, open-label, multicenter trial comparing
treatment with KALETRA 800/200 mg QD plus tenofovir DF and emtricitabine versus
KALETRA 400/100 mg BID plus tenofovir DF and emtricitabine in 190 antiretroviral
treatment naïve patients. Patients had a mean age of 39 years (range: 19
to 75), 54% were Caucasian and 78% were male. Mean baseline CD4 cell count was
260 cells/mm3 (range 3 to 1006 cells/mm3) and mean baseline plasma HIV RNA was
4.8 log10 copies/mL (range: 2.6 to 6.4 log10 copies/mL).
| KALETRA QD + TDF+FTC (N=115) | Kaletra BID + TDF+FTC (N=75) | |
|---|---|---|
| Outcome | ||
| Responder | 71% | 65% |
| Virologic failure | 10% | 9% |
| Rebound | 6% | 5% |
| Never suppressed through Week 48 | 3% | 4% |
| Death | 0% | 1% |
| Discontinued due to adverse event | 12% | 7% |
| Discontinued for other reasons | 9% | 19% |
PRECAUTIONS
In this section, Table 10: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction was revised to include information that KALETRA should not be administered once daily in combination with efavirenz, nevirapine, amprenavir, nelfinavir, carbamazepine, phenobarbital, or phenytoin. In addition, statements that KALETRA once daily has not been studied in combination with indinavir or saquinavir was included.
ADVERSE REACTIONS:
The adverse reaction profile and laboratory abnormalities observed in the Kaletra
once daily study were included in this section.
DOSAGE AND ADMINISTRATION
This section was modified to include dosing instructions for therapy-naïve
and therapy-experienced patients as follows:
Adults:
Therapy-Naïve Patients
~ KALETRA 400/100 mg (3 capsules or 5.0 mL) twice daily taken with food
~ KALETRA 800/200 mg (6 capsules or 10 mL) once daily taken with food
Therapy-Experienced Patients
~ KALETRA 400/100 mg (3 capsules or 5.0 mL) twice daily taken with food
Once-daily administration of KALETRA is not recommended in therapy-experienced patients
In addition, the following statements were added:
KALETRA should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
KALETRA once daily has not been evaluated in pediatric patients.
KALTERA is manufactured by Abbott Laboratories, North Chicago, IL.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" has been revised to include up-to-date drug information, including updated information on nevirapine hepatotoxicity risks, the interaction between rifampin and ritonavir-boosted saquinavir, new pregnancy data for efavirenz, and new contraindications and warnings for ritonavir and lopinavir/ritonavir use. Also included in the updated document is a new table, Table 30, providing information on the tipranavir expanded access program.
All changes to the document are highlighted in yellow.
The updated guidelines document is available AIDSinfo
Web site.
You can view, order hard copies of the guidelines, or request them by email
at the web site.
The AIDSinfo website is also a useful source of other information related to HIV/AIDS, including other treatment and prevention guidelines, downloadable databases for PDAs (Personal Digital Assistants), and HIV/AIDS-related clinical trials information.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The Food and Drug Administration (FDA) is announcing a meeting of its Antiviral Drugs Advisory Committee.
May 19, 2005
8:00 am to 5:00 pm
Hilton Washington DC/North
Salons A, B, and C
620 Perry Pkwy.
Gaithersburg, MD
If you need directions or hotel accommodations, please contact the hotel at 301-977-8900
Agenda:
The committee will discuss new drug application (NDA) 21-814, proposed trade
name APTIVUS (Tipranavir) 250 milligram capsules, Boehringer Ingelheim Pharmaceuticals,
Inc., indicated for the treatment of patients with human immunodeficiency virus,
HIV.
Background material and meeting information will become available on the FDA website no later than one business day before the meeting. (You will need to select the appropriate committee link. Please not that the information is not posted at this time.)
Procedure:
Interested persons may present data, information, or views - orally or in writing
- on issues pending before the committee.
Written submissions should be submitted to the contact person (below) by May 6, 2005.
Oral presentations from the public will be scheduled between approximately 1 p.m. and 2 p.m. at the meeting. Time allotted for each presentation may be limited. Those desiring to make formal oral presentations should notify the contact person (below) before May 6, 2005, 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.
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. No registration is required.
If you require special accommodations due to a disability, please contact Angie Whitacre at 301-827-7001, at least 7 days in advance of the meeting.
Persons attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.
Contact Person:
Anuja Patel, 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: patela@cder.fda.gov.
Please call the FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC area), and enter code 3014512531 for up-to-date information on this meeting.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Bristol-Myers Squibb Company has issued a Dear Health Care Provider Letter highlighting important information about Sustiva and pregnancy.
The contents of the letter are reproduced below.
March 2005
Re: Important Change in SUSTIVA (efavirenz) Package Insert —
Change from Pregnancy Category C to D
Dear Health Care Provider,
Bristol-Myers Squibb Company would like to make clinicians who are caring for
HIV-1-infected patients aware of important new information in the SUSTIVA Package
Insert regarding pregnancy. The pregnancy category for SUSTIVA has been changed
from Category C (Risk of Fetal Harm Cannot Be Ruled Out) to Category D (Positive
Evidence of Fetal Risk). This change is a result of four retrospective reports
of neural tube defects in infants born to women with first trimester exposure
to SUSTIVA including three cases of meningomyelocele and one Dandy Walker Syndrome.
As SUSTIVA may cause fetal harm when administered during the first trimester
to a pregnant woman, pregnancy should be avoided in women receiving SUSTIVA.
Women of childbearing potential should undergo pregnancy testing before initiation of SUSTIVA. If SUSTIVA is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Though there are no adequate, well-controlled studies in pregnant women, SUSTIVA should be used during the first trimester of pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. Barrier contraception should always be used in combination with other contraceptive methods.
During the development of SUSTIVA, animal studies were performed to assess the potential for birth defects. Malformations were observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20-150) with efavirenz 60 mg/kg daily, a dose resulting in plasma drug concentrations similar to those in humans given 600 mg/day of SUSTIVA. Anencephaly and unilateral anophthalmia were observed in one monkey fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. An increase in fetal resorptions was observed in rats given efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of SUSTIVA. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of SUSTIVA.
Limited data are available regarding birth defects occurring after intrauterine exposure to SUSTIVA. The outcomes of pregnancy have been reviewed for 206 women (207 fetuses) after being exposed to efavirenz-containing regimens, most of which were first-trimester exposures. Birth defects occurred in 5 of 188 live births with first-trimester exposure and in 0 of 13 live births with second- or third-trimester exposure. None of these prospectively reported defects were neural tube defects. However, there have been 4 retrospective reports (i.e., after the results of the pregnancy were known) of findings consistent with neural tube defects, including 3 cases of meningomyelocele. All 4 mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of SUSTIVA has not been established, similar defects have been observed in preclinical studies of efavirenz.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to SUSTIVA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
Please refer to the accompanying Important Information about SUSTIVA and the enclosed SUSTIVA Full Prescribing Information.
If you have any questions about this new information or require additional medical information, please contact the Virology Medical Services Department at Bristol-Myers Squibb Company at 1-800-426-7644 (select Option 3).
Sincerely,
Freda C. Lewis-Hall, MD
Senior Vice President, Medical Affairs
Bristol-Myers Squibb Company
SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma Company.
Enclosure: SUSTIVA (efavirenz) Package Insert
REFERENCE
1. SUSTIVA Package Insert, Bristol-Myers Squibb Co., Princeton, New Jersey.
Important Information About SUSTIVA (efavirenz) Capsules and Tablets
INDICATION:
SUSTIVA (efavirenz) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on two clinical trials of at least one year duration that demonstrated prolonged suppression of HIV RNA.
IMPORTANT SAFETY INFORMATION:
· Coadministration with astemizole, cisapride, midazolam, triazolam,
ergot derivatives, or voriconazole is contraindicated. Concomitant use of SUSTIVA
and St. John's wort (Hypericum perforatum) or St. John's wort-containing products
is not recommended. This list of medications is not complete.
· Serious psychiatric adverse experiences, including severe depression
(2.4%), have been reported in patients treated with SUSTIVA. In addition to
SUSTIVA, factors identified in a clinical study that were associated with an
increase in psychiatric symptoms included history of injection drug use, psychiatric
history, and use of psychiatric medication. There have been occasional reports
of suicide, delusions, and psychosis-like behavior, but it could not be determined
if SUSTIVA was the cause. Patients with serious psychiatric adverse experiences
should be evaluated immediately to determine whether the risks of continued
therapy outweigh the benefits.
· Fifty-three percent of patients reported nervous system symptoms when
taking SUSTIVA compared to 25% of patients receiving control regimens. These
symptoms usually begin during Days 1-2 of therapy and generally resolve after
the first 2-4 weeks of therapy.
Nervous system symptoms are not predictive of less frequent serious psychiatric
symptoms.
· SUSTIVA may cause fetal harm when administered to a pregnant woman.
Women should not become pregnant or breastfeed while taking SUSTIVA. Barrier
contraception must always be used in combination with other methods of contraception
(e.g., oral or other hormonal contraceptives). If a woman becomes pregnant while
taking SUSTIVA during the first trimester of pregnancy, she should be apprised
of the potential harm to the fetus.
· Mild to moderate rash is a common side effect of SUSTIVA. In controlled
clinical trials, 26% of patients treated with SUSTIVA experienced new-onset
skin rash compared with 17% of patients treated in control groups. SUSTIVA should
be discontinued in patients developing severe rash associated with blistering,
desquamation, mucosal involvement, or fever. Rash is more common and often more
severe in pediatric patients.
· Liver enzymes should be monitored in patients with known or suspected
hepatitis B or C and when SUSTIVA is administered with ritonavir.
· Use SUSTIVA with caution in patients with a history of seizures.
· Redistribution and/or accumulation of body fat have been seen in patients
receiving antiretroviral therapy. A causal relationship has not been established.
· Immune reconstitution syndrome has been reported in patients treated
with combination antiretroviral therapy, including SUSTIVA.
· It is recommended that SUSTIVA be taken on an empty stomach, preferably
at bedtime. The increased concentrations following administration of SUSTIVA
with food may lead to an increase in frequency of adverse events. Dosing at
bedtime may improve the tolerability of nervous system symptoms.
The Norvir (ritonavir) and Kaletra (lopinavir/ritonavir) package inserts (product labeling) were recently updated to include information regarding interactions with fluticasone (a synthetic corticosteroid, the active component of Flonase nasal Spray) and trazodone (Desyrel, a non-tricyclic antidepressant). In addition, alfuzosin (an alpha-blocker used to increase the flow of urine in people with benign prostatic hypertrophy (BPH)) was added to the Contraindications section of the Norvir package insert.
Listed below are labeling revisions for the Norvir and Kaletra package inserts.
Summary of Label Changes
NORVIR
Clinical Pharmacology:
Results of the drug interaction studies with NORVIR and fluticasone propionate aqueous nasal spray and trazodone were included:
NORVIR increased fluticasone AUC and Cmax by approximately 350-fold and 25-fold respectively. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.
NORVIR increased trazodone AUC and Cmax by 2.4 fold and 34%, respectively.
CONTRAINDICATIONS:
The Alpha1-adrenoreceptor antagonist drug, alfuzosin HCL, was added to the contraindicated list.
WARNINGS:
The following Warning regarding fluticasone was included:
A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. (see PRECAUTIONS: Drug Interactions)
PRECAUTIONS:
In the PRECAUTIONS section, the following clinical comment was included regarding
the fluticasone interaction:
Concomitant use of fluticasone propionate and NORVIR increases plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS)
The following clinical comments were included regarding the trazodone interaction:
Concomitant use of trazadone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
KALETRA
WARNINGS:
A drug interaction study in healthy subjects has shown that ritonavir significantly
increases plasma fluticasone propionate exposures, resulting in significantly
decreased serum cortisol concentrations. Concomitant use of KALETRA and fluticasone
propionate is expected to produce the same effects. Systemic corticosteroid
effects including Cushing's syndrome and adrenal suppression have been reported
during postmarketing use in patients receiving ritonavir and inhaled or intranasally
administered fluticasone propionate. Therefore, coadministration of fluticasone
propionate and KALETRA is not recommended unless the potential benefit to the
patient outweighs the risk of systemic corticosteroid side effects. (see PRECAUTIONS:
Drug Interactions)
PRECAUTIONS:
In the PRECAUTIONS section, the following clinical comment was included regarding
the fluticasone interaction:
Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS).
The following clinical comments were included regarding the trazodone interaction:
Concomitant use of trazodone and KALETRA may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On March 29, 2005, FDA approved Baraclude (entecavir) 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.
This indication is based on histologic, virologic, biochemical, and serologic responses after one year of treatment in nucleoside-treatment-naive and lamivudine-resistant adult patients with HBeAg*-positive, or HBeAg-negative chronic HBV infection with compensated liver disease, and on more limited data in adult patients with HIV/HBV coinfection who have received prior lamivudine therapy. *(hepatitis B e antigen)
Limited data about Baraclude in patients with HIV/HBV co-infection who received prior lamivudine therapy are presented in the label. Please refer to the attached label (pdf 303 KB) and the Special Population section under Description of Clinical Studies for information on HIV/HBV co-infected patients.
In summary, Study AI463038 was a randomized, double-blind, placebo-controlled study of Baraclude versus placebo in 68 patients co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral therapy (HAART) regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 patients) or placebo (17 patients) for 24 weeks followed by an open-label (non-blinded) phase for an additional 24 weeks where all patients received BARACLUDE.
At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log10 copies/mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy.
The proportion of HIV/HBV co-infected patients with HBV DNA < 300 copies/mL was 6% for the BARACLUDE 1 mg group versus 0% for the placebo group. The mean change from baseline for HBV DNA was -3.65 log10 copies/mL for the BARACLUDE 1 mg group versus +0.11 log10 copies/mL for the placebo group. Thirty-four percent of patients in the Baraclude 1 mg group had ALT normalization (< 1 x ULN) compared to 8% of patients in the placebo group.
There are no data for patients with HIV/HBV co-infection who have not received
prior lamivudine therapy.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been updated, March 24, 2005. Please note that the Appendix, Characteristics of Available Antiretroviral Drugs, has been extensively modified to include up-to-date drug information, including updated information about pediatric dosing and new drug formulations. The updated Appendix also includes a matrix based on Table 16 in the Adult Guidelines (adverse drug reactions) and three matrices based on Tables 19-21 in the Adult Guidelines (drug interactions between antiretrovirals and other drugs).
The Pediatric Guidelines are developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, which reviews new data on an ongoing basis and provides regular updates to the guidelines.
The updated guidelines document is available in the Pediatric Guidelines section of the Guidelines page on the AIDSinfo Web site.
The AIDSinfo website (AIDSinfo@nih.gov) is also a valuable source of other information related to HIV/AIDS, including other treatment and prevention guidelines, downloadable databases for PDAs (Personal Digital Assistants), and HIV/AIDS-related clinical trials information.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
FDA approved, on February 25, 2005, efficacy supplements for Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), making them the first approved therapies for treatment of Hepatitis C in patients coinfected with HIV. The approvals expand the therapeutic indications to include Peginteferon alone, or in combination with ribavirn, for the treatment of adult chronic hepatitis C in patients coinfected with HIV, who have clinically stable HIV disease (patients either on stable HIV antiretroviral therapy, or those who have not met the criteria to begin therapy).
Note that patients receiving Pegasys/Copegus and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) should be closely monitored for treatment-associated toxicities.
Revised labeling for Pegasys and Copegus is attached in pdf format.
Descriptive information about the clinical trial to support the supplement are contained in respective product labeling. (See Study 6.)
Pegasys and Copegus are manufactured by Hoffmann-La Roche Inc., Nutley, NJ
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Return to index
Roche Laboratories Inc. has issued a "Dear Health Care Provider" letter to communicate an important drug interaction warning for saquinavir/ritonavir, used as part of combination therapy for treatment of HIV infection:
DRUG-INDUCED HEPATITIS WITH MARKED TRANSAMINASE ELEVATIONS HAS BEEN OBSERVED IN HEALTHY VOLUNTEERS RECEIVING RIFAMPIN* 600 MG ONCE DAILY IN COMBINATION WITH RITONAVIR 100 MG/SAQUINAVIR 1000 MG TWICE DAILY (RITONAVIR BOOSTED SAQUINAVIR).
As a result of high incidence of hepatotoxicity in a Phase I, randomized, open-label, multiple-dose clinical pharmacology study in healthy volunteers, Roche now advises prescribers that:
Rifampin SHOULD NOT be administered to patients also receiving saquinavir/ritonavir (ritonavir boosted saquinavir) as part of combination antiretroviral therapy (ART) for HIV infection.
Roche is collaborating closely with the U.S. FDA (Food and Drug Administration) on this issue, and appropriate changes to the package insert will be made as soon as possible.
Health care professionals are encouraged to report any unexpected events associated with the use of saquinavir/ritonavir directly to Roche Laboratories at 1-800-526-6367 or to the FDA MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178 or by mail (MED WATCH, 5600 Fishers Lane, Rockville, MD 20852-9787).
*Rifampin is known as Rifampicin outside of the U.S.
The complete letter is attached in pdf format, which requires an Adobe Acrobat viewer. Acrobat is free and available directly from Adobe's Website with full installation instructions.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The Food and Drug Administration (FDA) is warning consumers not to use unapproved home-use diagnostic test kits that have been marketed nationwide via the Internet by Globus Media, Montreal, Canada. In fact, no home-use test kits intended for diagnosing HIV*, syphilis and dengue fever are approved for sale in the U.S. The use of these products could result in false results (though there is no confirmed evidence of false positives) that could lead to significant adverse health consequences. The illegal kits are labeled as:
FDA has not approved or evaluated the performance of any of Globus Media's products. As a result, consumers cannot know with any degree of certainty that test results are correct. For example, a person testing positive for HIV (human immunodeficiency virus, or the AIDS virus) using one of these tests may not be infected with HIV, or, worse, someone infected with HIV may test negative and not seek medical treatment, or spread the virus to others.
The tests were sold through websites and distributed throughout the U.S., usually
by overnight delivery services. They have been made available for sale
on several websites, including www.htkit.com <http://www.htkit.com> and
www.hstkits.com <http://www.hstkits.com>. The kits usually are contained
in a paper envelope with instructions inside the packaging. The envelope,
instructions and packaging may not accurately identify the manufacturer, packer
or distributor. The name of the kit appears on the instructions.
Consumers who have these products should not use them. Anyone who has
used one of these test kits should be retested using valid test methods.
The FDA has issued an import alert which alerts FDA field personnel to the possible
importation of these devices, provides guidance as to their detention and refusal
of admission into the U.S., and also advises U.S. Customs officials about these
products.
Other unapproved tests may also be available through the Internet. You
can find a list of FDA approved / licensed tests for HIV and Hepatitis on the
FDA website at http://www.fda.gov/cber/products/testkits.htm.
*Please not that one licensed/approved diagnostic home collection kit for HIV,
which is mailed to a laboratory for testing and confirmation, is commercially
available in the United States.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
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The Food and Drug Administration (FDA) today is announcing the tentative approval of a copackaged antiretroviral drug regimen, consisting of lamivudine/zidovudine fixed dose combination tablets and nevirapine tablets for the treatment of HIV-1 infection in adults. It is manufactured by Aspen Pharmacare of South Africa.
A Tentative Approval means that FDA has concluded that a drug product has met all of the required quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. due to existing patents and/or exclusivity. It does, however, make the product eligible for use under the President's Emergency Plan for AIDS Relief (PEPFAR) program.
The co-packaged drug products are a complete antiretroviral drug regimen that have met the FDA's quality, safety and efficacy standards, and will be available for potential procurement by PEPFAR for use in South Africa and developing nations. It is the first tentative approval of a product to treat HIV/AIDS under the new expedited FDA review process for PEPFAR, and the first tentative approval of an HIV drug regimen manufactured by a non-U.S.-based generic pharmaceutical company.
Aspen's lamivudine/zidovudine fixed dose combination tablets are a version of the already FDA approved Combivir tablets manufactured by GlaxoSmithKline and the nevirapine tablets are a version of Viramune tablets manufactured by Boehringer-Ingelheim. The new co-packaged product consists of both lamivudine/zidovudine fixed dose tablets and nevirapine tablets, one of each tablet to be taken twice daily, after the initial two week initiation phase of this nevirapine regimen.