 |
|
 |
FDA Home Page | Search
FDA Site | FDA A-Z Index | Contact
FDA
Human Immunodeficiency Virus and
Acquired Immunodeficiency Syndrome
 |
FDA HIV/AIDS List Serve Archive
|
|
The Food and Drug Administration (FDA) has approved a marketing application (PMA) for the Multispot HIV-1/HIV-2 Rapid Test. This device is indicated for the detection and differentiation of circulating antibodies associated with HIV-1 and HIV-2 in human plasma and serum, as an aid in the diagnosis of infection with HIV-1 and/or HIV-2.
The test is manufactured by Bio-Rad Laboratories, Redmond, WA.
Additional information about this approval is available on the FDA website:
Letter - (Text)
Summary of Safety and Effectiveness - (PDF)
Label - (PDF)
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The Clinical Pharmacology section of the Crixivan (indinavir) label has been revised to include pharmacokinetic data from a study (PACTG 358) in HIV-infected pregnant women. Results from this study show substantially reduced indinavir concentrations in women at weeks 30-32 weeks gestation compared to postpartum. Based on these data, the Precautions Sections now states that indinavir is not recommended in HIV-infected pregnant patients.
Revisions to the Package Insert
1. The following was added to the CLINICAL PHARMACOLOGY: Pharmacokinetics: Pregnant Patients section:
"Pregnant Patients: The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). The mean indinavir plasma AUC0-8hr at weeks 30-32 of gestation (n=11) was 9231 nM*hr, which is 74% (95% CI: 50%, 86%) lower than that observed 6 weeks postpartum. Six of these 11 (55%) patients had mean indinavir plasma concentrations 8 hours post-dose (Cmin) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in another study (see PRECAUTIONS, Pregnancy)."
2. The following was added to the PRECAUTIONS: Pregnancy: Pregnancy Category C section:
"A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients (see CLINICAL PHARMACOLOGY, Pregnant Patients)."
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Jeffrey Murray
Division of Antiviral Drug Products
Food and Drug Administration
Bristol-Meyers Squibb has issued a Dear Healthcare Provider letter regarding important new pharmacokinetic data concerning the coadministration of REYATAZ (atazanavir) and Norvir (ritonavir) with Prilosec (omeprazole). Omeprazole is a proton-pump inhibitor (PPI) for the treatment of acid-related diseases that works by suppressing gastric acid secretion.
The following observations were made from a randomized, open-label, multiple-dose drug interaction study.
A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) were observed when REYATAZ/ritonavir 300/100 mg was coadministered with omeprazole 40 mg.
Based on the study results:
* DO NOT COADMINISTER REYATAZ OR REYATAZ/ritonavir with omeprazole due to the reduction in atazanavir exposure levels. This recommendation is consistent with the current REYATAZ U.S. Package Insert.
* It is not known whether the over-the-counter dose of omeprazole (20 mg once daily) would produce similar results; therefore, coadministration is not recommended.
* Increasing the REYATAZ/ritonavir dose to 400/100 mg in combination with omeprazole DID NOT result in REYATAZ exposures comparable to those observed with a regimen of REYATAZ/ritonavir 300/100 mg without omeprazole.
* Simultaneous administration of 8 ounces of cola given in an effort to decrease (acidify) gastric pH did not appear to affect this reduction.
Investigations regarding the potential drug interaction between REYATAZ (atazanavir sulfate) and H2-Receptor antagonists (another type of gastric medication) when coadministered are ongoing. Until data are available, clinicians should note the following statements from the REYATAZ Package Insert: "Reduced plasma concentrations of atazanavir are expected if H2-receptor antagonists are administered with REYATAZ (atazanavir sulfate). This may result in loss of therapeutic effect and development of resistance. To lessen the effect of H2 -receptor antagonists on atazanavir exposure, it is recommended that an H2-receptor antagonist and REYATAZ be administered as far apart as possible, preferably 12 hours apart."
Bristol-Meyers Squibb Dear
Healthcare Provider Letter (44 KB PDF)
Text version of the letter.
To view or print the document, you can use the free Adobe Acrobat, available directly from Adobe's Website with full installation instructions. http://www.adobe.com/products/acrobat/readstep2.html
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
FDA approved, on December 17, 2004, a new 500 mg tablet formulation of the HIV protease inhibitor, INVIRASE (saquinavir mesylate). The dosage and administration for INVIRASE in adults (over the age of 16 years) is 1000 mg twice a day (taken as either two 500 mg tablets or five 200 mg capsules) in combination with ritonavir 100 mg twice a day, after a meal. The new tablet formulation reduces the pill burden compared to the capsule formulation.
Below is the DOSAGE AND ADMINISTRATION section as it appears in the package insert.
DOSAGE AND ADMINISTRATION
INVIRASE (saquinavir mesylate) capsules 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, because it significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE at the recommended dose of 1200 mg tid. When using saquinavir as the sole protease inhibitor in an antiretroviral regimen, FORTOVASE is the recommended formulation (see CLINICAL PHARMACOLOGY: Drug Interactions).
Adults (Over the Age of 16 Years)
* INVIRASE 1000-mg bid (5 x 200-mg capsules or 2 x 500-mg tablets) in combination
with ritonavir 100-mg bid.
* Ritonavir should be taken at the same time as INVIRASE.
* INVIRASE and ritonavir should be taken within 2 hours after a meal
A pdf copy of the complete labeling is attached.
Invirase is a product of Roche Laboratories, Inc., of Nutley, New Jersey.
To view or print the document, you can use the free Adobe Acrobat, 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) today (December 3, 2004) approved a generic formulation of Didanosine (ddI) Delayed Release capsules, 200 mg, 250 mg, and 400 mg for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults. The product, manufactured by Barr Laboratories, Inc. of Pomona, NY will be available for use within the United States and foreign countries.
It is the first approval in the United States of a generic antiretroviral product to treat HIV/AIDS.
Didanosine (ddI) is the a generic version of the already approved Videx EC Delayed-Release Capsules manufactured by Bristol Myers Squibb. It is a delayed-release capsule, taken once daily.
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.
The Pediatric Guidelines, developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, now include Supplement II, titled "Managing Complications of HIV Infection in HIV-Infected Children on Antiretroviral Therapy, "and Supplement III, titled "Adverse Drug Effects." Also included in the new version are updates to the atazanavir, indinavir, and enfuvirtide sections in Supplement I, "Pediatric Antiretroviral Drug Information."
All new information is highlighted in yellow in the main document. Supplements II and III are new to the guidelines and are highlighted in title only.
The updated guidelines document is available in the Pediatric Guidelines section (http://aidsinfo.nih.gov/guidelines/default_db2.asp?id=51) of the Guidelines page on the AIDSinfo Web site.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Today is World AIDS Day.
From the first, isolated reports in 1981, AIDS has grown into a global pandemic. It affects every corner of the world. Despite efforts in every nation, the epidemic continues to grow.
Today the face of AIDS is increasingly young and female. Globally, women account for nearly half the adults living with HIV. The official theme of World AIDS Day this year is Women and Girls and HIV/AIDS, intending to help focus attention and resources on increasing access to prevention and treatment services for women.
In the United States and other industrialized nations, potent antiviral drugs have dramatically helped people with HIV and AIDS live longer, healthier lives.
FDA has played a strong role in addressing treatment and prevention from the beginning of the epidemic, including the approval of improved 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 to 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, and the first fusion inhibitor for treating HIV/AIDS.
_____________________________________________________________________
In addition, AIDSinfo Launches a New Web Site Design on World AIDS Day 2004
AIDSinfo is commemorating World AIDS Day 2004, and the web site's second anniversary, with a new web site design. The new design, which is live today, features a more intuitive layout and consistent navigation. The colorful design, along with improved search functions, makes the site more accessible and useful for health care providers, researchers, patients, families, and users. The site is also rich in resources because of the significantly increased number of materials available for viewing online, downloading onto Pocket PC/Palm PDAs, and printing from PDFs.
AIDSinfo provides a wealth of information and resources, including the most up-to-date versions of the HIV/AIDS treatment guidelines and HIV/AIDS-related clinical trial information at www.AIDSinfo.nih.gov
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
FDA is announcing the availability of a draft guidance for industry entitled "Role of HIV Drug Resistance Testing in Antiretroviral Drug Development." This draft guidance addresses the role of HIV resistance testing during antiretroviral drug development and postmarketing. The draft guidance is based on the following: (1) A 2-day session of the Antiviral Drug Product advisory committee convened November 2 and 3, 1999, to address issues relating to HIV resistance testing; (2) the DAVDP's experience with reviewing resistance data for antiretroviral drugs; and (3) input from pharmaceutical sponsors and the HIV community.
The draft guidance discusses the nonclinical studies (mechanism of action; antiviral activity in vitro; cytotoxicity/therapeutic index; and the effects of serum protein binding on antiviral activity) we recommend be completed prior to the initiation of phase 1 clinical studies in HIV-infected patients. In addition, the draft guidance addresses the use of resistance testing in the clinical phases of drug development and recommends the type of information that should be collected and the types of analyses that should be conducted to characterize an antiretroviral's resistance profile.
This draft guidance also reviews the role of resistance testing in initial activity and dose-finding, for study enrollment criteria, for background regimen selection, and to establish an indication. Included in the draft guidance are two appendices: (1) A template for submitting HIV resistance data and (2) information on the genetic threshold for resistance.
The draft guidance represents the agency's current thinking on the role of HIV resistance testing in antiretroviral drug development. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
You can read the draft guidance document on the FDA website at
http://www.fda.gov/cder/guidance/5879dft.htm (HTML version)
http://www.fda.gov/cder/guidance/5879dft.pdf (pdf version) or at
http://www.fda.gov/cder/guidance/5879dft.doc (Word version)
FDA encourages comments regarding this draft document. Comments and suggestions
should be submitted within 90 days of publication in the Federal Register of
the notice announcing the availability of the draft guidance (November 26, 2004).
Please submit comments to:
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, MD 20852.
All comments should be identified with the Docket No. 2004D-0484.
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) has issued final guidance on the "Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components (including Source Plasma and Source Leukocytes) to Adequately and Appropriately Reduce the Risk of Transmission of HIV-1 and HCV."
FDA's blood testing rules require establishments that collect blood and blood components (e.g. Whole Blood and Blood Components, including Source Plasma and Source Leukocytes), to test each donation of human blood or blood component intended for use in preparing a blood product for evidence of infection due to specific communicable disease agents. The purpose is to reduce the risk of transfusion-transmitted transmission of communicable disease.
The purpose of this guidance is to inform blood collecting and processing establishments that:
1. FDA has licensed nucleic acid tests (NAT) as tests to screen blood donors for HIV-1 ribonucleic acid (RNA), and HCV RNA; and
2. These licensed tests can detect evidence of infection at a significantly earlier stage than is possible under previously approved tests using antibody or antigen detection technology; including the HIV-1 p24 antigen test.
Nucleic Acid Testing, or NAT, is a nucleic acid amplification technology that includes polymer chain reaction, or PCR, to detect certain viral components. NAT enables the earliest and most sensitive detection of disease-causing human viruses in blood and plasma donations.
A recently infected person would have virus particles in the blood stream. Although the blood or plasma could be infectious, the infection may not be detected using current antibody tests because the person may not yet have developed antibodies. This time frame before measurable antibody production is called the " window period." Over time, the person would make enough antibodies for the antibody test to be effective. However, because NAT can detect RNA or DNA from a very small number of virus particles, it can reduce the window period by detecting the infection earlier.
This guidance combines and finalizes the draft guidance " Use of Nucleic Acid Tests on Pooled Samples from Source Plasma Donors to Adequately and Appropriately Reduce the Risk of Transmission of HIV-1 and HCV" (http://www.fda.gov/ohrms/dockets/98fr/01d-0584_gdl0001.pdf)dated December 2001 (January 31, 2002, 67 FR 4719) and the draft guidance " Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components for Transfusion to Adequately and Appropriately Reduce the Risk of Transmission of HIV-1 and HCV" (http://www.fda.gov/ohrms/dockets/98fr/040902c.pdf)dated March 2002 (April 9, 2002, 67 FR 17077).
The complete final guidance document can be found on the FDA website at http://www.fda.gov/cber/gdlns/hivhcvnatbld.htm
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Bristol-Myers Squibb (BMS) today is issuing a "Dear Healthcare Provider" letter regarding is important new clinical data regarding coadministration of Viread (tenofovir disoproxil fumarate [TDF]), Videx EC (didanosine delayed-release capsules enteric-coated beadlets [ddI EC]), and either Sustiva (efavirenz [EFV]) or Viramune (nevirapine [NVP]). Data for EFV + TDF + ddI EC are derived from an open-label randomized study (virologic failure in 6/14 patients) and a retrospective database analysis (virologic failure in 5/10 patients), while data for NVP + TDF + ddI EC are derived from a retrospective database analysis (virologic failure in 2/4 patients).
· Results from two recently conducted, investigator-sponsored trials have demonstrated a potential for early virologic failure associated with this antiretroviral regimen in treatment-naïve HIV patients with high baseline viral loads. The mechanism of early virologic failure in these patients is unclear.
· Early virologic failure appears to be limited to the specific combination of TDF + ddI EC + either EFV or NVP as there are data from registrational trials supporting the efficacy of EFV and TDF-based regimens as well as EFV and ddI EC-based regimens in treatment-naïve HIV patients. Additionally, a recent post-hoc analysis performed in treatment-experienced HIV patients with high baseline viral loads receiving a boosted protease inhibitor (PI) with two nucleoside reverse transcriptase inhibitors (NRTIs) demonstrated lower virologic failure rates in subjects receiving ddI EC and TDF than those receiving another nucleoside analogue in combination with TDF, though significance testing could not be performed due to a small number of patients (n=55).
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
Bristol-Myers Squibb (BMS) today is issuing a "Dear Healthcare Provider" letter regarding is important new clinical data regarding coadministration of Viread (tenofovir disoproxil fumarate [TDF]), Videx EC (didanosine delayed-release capsules enteric-coated beadlets [ddI EC]), and either Sustiva (efavirenz [EFV]) or Viramune (nevirapine [NVP]). Data for EFV + TDF + ddI EC are derived from an open-label randomized study (virologic failure in 6/14 patients) and a retrospective database analysis (virologic failure in 5/10 patients), while data for NVP + TDF + ddI EC are derived from a retrospective database analysis (virologic failure in 2/4 patients).
Results from two recently conducted, investigator-sponsored trials have demonstrated a potential for early virologic failure associated with this antiretroviral regimen in treatment-naïve HIV patients with high baseline viral loads. The mechanism of early virologic failure in these patients is unclear.
Early virologic failure appears to be limited to the specific combination of TDF + ddI EC + either EFV or NVP as there are data from registrational trials supporting the efficacy of EFV and TDF-based regimens as well as EFV and ddI EC-based regimens in treatment-naïve HIV patients. Additionally, a recent post-hoc analysis performed in treatment-experienced HIV patients with high baseline viral loads receiving a boosted protease inhibitor (PI) with two nucleoside reverse transcriptase inhibitors (NRTIs) demonstrated lower virologic failure rates in subjects receiving ddI EC and TDF than those receiving another nucleoside analogue in combination with TDF, though significance testing could not be performed due to a small number of patients (n=55).
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
Revised "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" become available today (October 29, 2004) on the AIDSinfo.nih.gov website.
What's New in the Document?
This guidelines revision represents a major rewriting of the document to improve
its organization and readability. The tables are updated with the most current
available information. The following major changes have been made to the March
28, 2004 version of the guidelines:
Changes in Recommendations:
Additions to the Guidelines Document:
Deletion from the Guidelines Document:
The most current version of this, and other national HIV-related guidelines are always available at http://aidsinfo.nih.gov/
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
FDA approved, on October 15, 2004, a supplemental new drug application for Fuzeon (enfuvirtide, also known as T-20) injection, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment experienced patients with ongoing viremia, granting " traditional approval."
FDA originally approved Fuzeon on March 13, 2003 under the regulations at 21 CFR 314, Subpart H, for accelerated approval of new drugs for serious or life-threatening illnesses. Approval of this supplement is based on fulfillment of research commitments made by the sponsor, Hoffmann-La Roche, Inc. of Nutley, NJ, under 21 CFR 314.510. The supplemental application submitted in support of traditional approval of enfuvirtide included 48 week safety and efficacy data from studies T20-301 and T20-302. These studies also provided the basis for the accelerated approval. In addition, safety data from clinical access studies, open label safety studies, the early access program, and pediatric studies were submitted in this supplemental application.
There was clear evidence of efficacy in the two randomized, controlled, 48 week trials in heavily pretreated HIV-infected subjects. In these studies, the primary efficacy endpoint was the maintenance or improvement of treatment effect from week 24 to week 48 as measured by the percentage of subjects with a HIV RNA level less than 50 copies/ml, HIV RNA less than 400 copies/ml, or a one log or more decrease in viral load. A greater proportion of subjects receiving enfuvirtide plus an optimized background (OB) antiretroviral regimen had a treatment response at 48 weeks compared to those receiving an OB regimen alone (p<0.001).
Review of the safety data submitted in this supplement did not identify any new or unexpected toxicities for enfuvirtide. As expected, injection site reactions (ISRs) were the most common adverse event and were reported by almost all subjects receiving enfuvirtide (98%). ISRs were common at the week one study visit (86%) and continued to occur throughout treatment. Most ISRs were associated with pain or discomfort, erythema, induration, and nodules or cysts. Infectious complications were rare (1.7%). ISRs and injection difficulties, such as inconvenience and injection fatigue, had a substantial impact on study participation and were the cause of early discontinuation in 7% of the study population. An increased incidence of pneumonia was observed in the first 24 weeks of the phase 3 studies and again in the second 24 weeks. There was no evidence of increasing risk over time, and no new risk factors or changes in severity of pneumonia were identified. Finally, episodes of systemic hypersensitivity, which were reported in less than 1% of subjects during the first 24 weeks of the phase 3 trials, were rare in the second 24 weeks of these studies and in the other studies included in this supplement. The observed toxicities did not outweigh the clear benefit of enfuvirtide as a treatment option for treatment experienced patients with measurable ongoing viremia.
The following changes were made to the package insert and patient package insert:
CLINICAL PHARMACOLOGY, Pediatric Patients
The pharmacokinetics of enfuvirtide (AUC, Cmax, Ctrough, and apparent clearance) were changed to reflect the results of additional subjects enrolled in studied T20-310. These results were similar to previous findings and did not change the dosing recommendation for pediatric patients.
INDICATIONS AND USAGE
This section was updated to provide the 48 week efficacy data from studies T20-301 and T20-302.
The outcome table (Table 3) was revised to provide clear information on the outcome for each subject in these studies.
Limited information on the efficacy of enfuvirtide in subgroup populations was added.
PRECAUTIONS, Pediatric Use
This section was revised to reflect the efficacy and safety results from additional subjects enrolled in study T20-310.
ADVERSE REACTIONS
Injection site reactions
The table summarizing individual signs and symptoms of injection site reactions was revised to decrease the number of footnotes and increase the comprehension of the results.
A brief description of the results of an Injection Site Reaction intervention study was added.
Other adverse events
Peripheral neuropathy, anxiety, lymphadenopathy, and suicide ideation were added to the list of other reported AEs. Peripheral neuropathy, anxiety and lymphadenopathy were common, but mild.
Because of the difference in rate of exposure, adverse event results for subjects receiving enfuvirtide were provided as percentages and as rates per 100 patient-years.
PATIENT PACKAGE INSERT
Similar revisions were made to the patient package insert to improve readability and patient comprehension.
Accelerated approval recognizes improvement in a surrogate marker which is reasonably likely to predict clinical benefit. The subsequent study under the commitments made under the Accelerated Approval requirements demonstrated durable viral suppression and safety for 48 weeks, upon which the traditional approval is based.
The complete revised label will be available soon on the "Drugs@FDA" website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
The Kaletra (lopinavir and ritonavir), Soft Gel Capsules and Oral Solution, labeling has been revised to include long-term (week 144-204) efficacy and safety results from two phase II trials. Specifically, the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included in the label. In addition, results of a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment and Week 104 mice and rat data were submitted to update the respective sections of the package insert.
The following changes appear in the revised labeling.
CLINCIAL PHARMACOLOGY:
Information from a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment was added. Specifically, the following text was included.
Multiple doses of KALETRA 400/100 mg bid to HIV and HCV co-infected subjects with mild to moderate hepatic impairment (n=12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-infected subjects with normal hepatic function (n=12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs 99.31%, respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment.
Results from drug-drug interaction studies with fosamprenavir (Lexiva) and tenofovir (Viread) were included.
INDICATIONS AND USAGE and Description of Clinical Studies:
These sections were updated to include long-term efficacy results from two uncontrolled dose-ranging studies. Specifically the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included as follows:
Through 204 weeks of treatment in study 720, the proportion of patients with HIV RNA <400 (<50) copies/mL was 71% (70%) [n=100], and the corresponding mean increase in CD4 cell count was 440 cells/mm3. Twenty-eight patients (28%) discontinued the study, including 9 (9%) discontinuations due to adverse events and 1 (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV RNA <400 (<50) copies/mL was 54% (50%) [n=70], and the corresponding mean increase in CD4 cell count was 212 cells/mm3. Twenty-seven patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths.
WARNINGS:
The erectile dysfunction drugs tadalafil (Cialis), and vardenafil (Levitra) were included with sildenafil (Viagra) under Pharmacokinetics: Drug-Drug Interactions, as follows:
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse events including hypotension, syncope, visual changes and prolonged erection (see PRECAUTIONS: Drug Interactions and the complete prescribing information for sildenafil tadalafil, and vardenafil.)
PRECAUTIONS:
The following statement regarding immune reconstitution syndrome was added.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including KALETRA. 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 carinii pneumonia,
or tuberculosis) which may necessitate further evaluation and treatment.
Drug Interactions
Carcinogenesis, Mutagenesis and Impairment of Fertility
ADVERSE REACTIONS:
The complete revised label will be available soon on the "Drugs@FDA website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
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 public workshop entitled " From Concept to Consumer: Center for Biologics Evaluation and Research (CBER) Working with Stakeholders on Scientific Opportunities for Facilitating Development of Vaccines, Blood and Blood Products, and Cellular, Tissue, and Gene Therapies."
The goal of the public workshop is to provide stakeholders a forum for the development of innovative scientific knowledge and tools to facilitate the development and availability of new biological products including vaccines, blood and blood products, and cellular, tissue, and gene therapies. The Center for Biologics Evaluation and Research (CBER) is seeking input from government and nongovernment research organizations, medical professional organizations, health care practitioners, patients, disease interest groups, pharmaceutical and biological product manufacturers and their industry organizations, and others with interests in facilitating development of the biological products that CBER regulates. The workshop will cover delineation of opportunities in key technologies and medical science knowledge needed to contribute to science based evaluation of the safety and efficacy of those biological products, and innovative development processes to manufacture them. FDA will discuss and welcomes input concerning all applicable areas of science including, but not limited to, bench laboratory investigations, clinical research and clinical trial design and execution, facility and manufacturing process research, statistical and epidemiological research, and computer science and computer modeling research. The workshop will not cover discussions of biological product discovery and invention, or regulatory policies. The workshop will include presentations by FDA speakers and breakout sessions with panels composed of both FDA staff and non-FDA stakeholders, with an opportunity for public questions and comments.
The workshop will be held on October 7, 2004 from 8:30 a.m. to 5:00 p.m., at the The Gaithersburg Marriott Washingtonian Center, 9751 Washingtonian Boulevard, Gaithersburg, MD 20878
If you are interested in attending this workshop, please register by contacting:
Melanie Whelan
Center for Biologics Evaluation and Research (HFM-43)
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448
301-827-3841 Fax 301-827-3079
Whelan@cber.fda.gov
by mail, fax or email, and provide your name, title, affiliation, address, telephone
and facsimile numbers by September 30, 2004.
There is no registration fee for the workshop. If you need special accommodations due to a disability, please contact Melanie Whelan at least 7 days in advance.
Regardless of attendance at the public workshop, interested persons may submit
written or electronic comments through September 23, 2004 to the:
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, MD 20852 .
Submit electronic comments to
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www/fda.gov/dockets/ecomments
Please submit a single copy of electronic comments or two copies of any mailed
comments, except that individuals may submit one paper copy. Comments are to
be identified with the docket Docket No. 2004N-0366
You can read the Federal Register Notice at http://www.fda.gov/cber/meetings/criticalpath100704fr.htm
__________________________________________________________________________________________
AGENDA
8:30 -
8:40 WELCOME
Kathryn M. Carbone, M.D., Associate Director for Research and Division of Manufacturers
Assistance and Training
Office of Communication, Training and Manufacturers Assistance, CBER
8:40 -
9:10 Introduction to Scientific Opportunities for Facilitating
the Development of Biological Products
Jesse L. Goodman, M.D., M.P.H.
Director, Center for Biologics Evaluation and Research
CBER Staff Presentations: Overview of Current and Future Scientific Opportunities
9:10 - 9:30 VACCINES Office of Vaccines Research and Review Speaker TBD
9:30 -
9:50 CELL, TISSUE AND GENE THERAPIES,
Office of Cellular, Tissue and Gene Therapies, Joyce Frey Vasconcells, Ph.D.,
Office Director (Acting),
9:50 -
10:10 BLOOD AND BLOOD PRODUCTS
Office of Blood Research and Review, Jay Epstein, M.D., Office Director
10:10 - 10:40 BREAK
10:40 -
11:00 STATISTICS, RISK MANAGEMENT AND CLINICAL TRIAL DESIGN
Office of Biostatistics and Epidemiology, Susan Ellenberg, Ph.D., Office Director
11:00 -
11:20 MANUFACTURING SCIENCE
Office of Compliance and Biologics Quality, James Cohen, JD, Office Director
(Acting)
11:20 - 12:00 Questions for morning speakers
12:00 - 1:00 Lunch (on your own)
1:00 -
3:30 Breakouts: Panel Sessions and Open Discussion
Vaccines (Moderator to be determined)
Panelists: Gary Overturf MD (University of New Mexico), John La Montagne PhD
(NIAID, NIH), Alan Shaw PhD (Merck), Robert Reinhard (AVAC), Laurie Norwood
(CBER/OCBQ)
Blood and Blood Products (Moderator: Hira Nakhasi, Ph.D., CBER/OBRR)
Mark Brecher MD (UNC-CH), Jonathan Goldsmith MD (IDF), Harvey Klein MD (NIH),
Chris Healey (PPTA), Gerald Schochetman PhD (Abbott Laboratories), Kay Gregory
(Invited) (AABB), Chiang Syin (CBER/OCBQ)
Cell/Gene Therapies (Moderator: Eda Bloom, Ph.D., CBER/OCTGT)
Katherine High MD (University of Pennsylvania), Alex Kuta PhD (Genzyme), Patrick
Terry (Genetic Alliance), Sonia Skarlatos PhD (NIH), Nick Obiri (CBER/OCBQ)
Tissues and Tissue Engineering (Moderator: Joyce Frey Vasconcells, Ph.D., CBER/OCTGT)
Michael Yaszemski MD PhD (Invited) (Mayo), Angela Hightwalker PhD (NIST), Sharon
Kiely MD MPM (West Penn Allegheny Health System), Nancy Parenteau PhD (Amaranth
Bio), Thomas Lynch JD PhD (Cryolife), Jerry Davis (CBER/OCBQ), Celia Whitten
(CDRH/FDA)
Statistics, Risk Management and Clinical Trial Design (Mary Foulkes, Ph.D.,
CBER/OBE)
Marie Griffin MD MPH (Vanderbuilt), M. Elizabeth Halloran MD PhD (Emory), June
S. Almenoff MD PhD (GSK), Dennis Dixon PhD (NIH), Pat Holobaugh (CBER/OCBQ)
3:30 - 3:45 BREAK
3:45 - 4:45 Reconvene for Panel Reports
4:45 -
5:00 Closing Comments/Summary
Jesse L. Goodman, M.D., M.P.H., Director, Center for Biologics Evaluation and
Research
More about The Challenge and Opportunity on the Critical Path to New Medical Products can be found at - www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
Richard Klein
HIV/AIDS Program Director
Food and Drug Administration
The Food and Drug Administration (FDA) will hold a meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) on September 23, 2004, from 9:00 a.m. to 12:15 p.m. at the Holiday Inn - Select, 8120 Wisconsin Avenue, Bethesda, MD 20814.
The purpose of the meeting is to update the Committee on the phase 3 Thai trial of ALVAC vCP 1521 [Aventis Pasteur, Inc.] with AIDSVAX B/E [VaxGen, Inc.] (HIV-1 Recombinant Canarypox-Vectored Vaccine with Recombinant gp 120 B/E) for the prevention of HIV-1 infection.
Please note, this meeting will be closed from 11 a.m. to 12:15 p.m. to permit discussion and review of trade secret and/or confidential information (5 U.S.C. 552b(c)(4)).
Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee during an open public hearing portion of the meeting, scheduled between approximately 10:15 and 10:45 a.m. Those wishing to speak or present data to the committee during the open public hearing should notify either Christine Walsh, R.N. (Walshc@cber.fda.gov), or Denise Royster (Royster@cber.fda.gov), Center for Biologics Evaluation and Research (HFM- 71), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD, 301-827-0314, of their intent to speak by September 16, 2004. Those who wish to present should 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. Time allotted for each presentation may be limited.
Background materials related to the September 23 meeting will be posted on the
FDA web site at least 24 hours prior to the meeting, at:
www.fda.gov/ohrms/dockets/ac/cber04.html#VaccinesandRelatedBiological
FDA welcomes the attendance of the public at its advisory committee meetings. No preregistration is necessary. FDA will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Christine Walsh or Denise Royster at least 7 days in advance of the meeting.
Those attending FDA advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.
If you need directions or accommodations, please contact the hotel directly at 301-652-2000.
Please call the FDA Advisory Committee Information Line, 1- 800- 741- 8138 (301- 443- 0572 in the Washington, DC area), code 3014512391, for up-to-date information on this meeting.
Richard Klein
HIV/AIDS Program Director
Food and Drug Administration
Sustiva labeling has been revised to include safety and efficacy data representing 168 weeks of treatment from Study 006 ( efavirenz + lamivudine + zidovudine vs indinavir + lamivudine + zidovudine vs efavirenz + indinavir) and other available data.
The following changes appear in the revised labeling:
The Microbiology section was updated to include resistance information from
clinical studies and cross-resistance data.
The Clinical Pharmacology section was updated to include pharmacokinetic data
on the interaction between efavirenz and atazanavir/ritonavir and efavirenz
and voriconazole
The Description of Clinical Studies section was updated to efficacy data through
168 weeks of therapy from study 006. Study 006 was a randomized, open-label
trial, compared SUSTIVA (600 mg once daily) + zidovudine (300 mg twice daily)
+ lamivudine (150 mg twice daily) vs indinavir (800 mg every 8 hours) + zidovudine
(300 mg twice daily) + lamivudine (150 mg twice daily) vs SUSTIVA (600 mg once
daily) + indinavir (1000 mg every 8 hours). At week 168, the proportion of subjects
who achieved and maintained HIV RNA < 400 copies/mL (and < 50 copies/mL)
was the following
SUSTIVA + zidovudine + lamivudine = 48% (43%)
Indinavir + zidovudine + lamivudine = 29% (23%)
SUSTIVA + indinavir = 40% (31%)
The Contraindications section was updated to include the following:
SUSTIVA should not be administered concurrently with voriconazole because SUSTIVA
significantly decreases voriconazole plasma concentrations
The Warnings - Psychiatric Symptoms and Nervous System subsections were updated
as follows:
Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported
in patients treated with SUSTIVA. In controlled trials of 1008 patients treated
with regimens containing SUSTIVA for a mean of 2.1 years and 635 patients treated
with control regimens for a mean of 1.5 years, the frequency of specific serious
psychiatric events among patients who received SUSTIVA or control regimens,
respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%,
0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%),
paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric
symptoms similar to those noted above were combined and evaluated as a group
in a multifactorial analysis of data from Study 006, treatment with efavirenz
was associated with an increase in the occurrence of these selected psychiatric
symptoms. Other factors associated with an increase in the occurrence of these
psychiatric symptoms were history of injection drug use, psychiatric history,
and receipt of psychiatric medication at study entry; similar associations were
observed in both the SUSTIVA and control treatment groups. In Study 006, onset
of new serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated
and control-treated patients. One percent of SUSTIVA-treated patients discontinued
or interrupted treatment because of one or more of these selected psychiatric
symptoms. There have also been occasional postmarketing reports of death by
suicide, delusions, and psychosis-like behavior, although a causal relationship
to the use of SUSTIVA cannot be determined from these reports. Patients with
serious psychiatric adverse experiences should seek immediate medical evaluation
to assess the possibility that the symptoms may be related to the use of SUSTIVA,
and if so, to determine whether the risks of continued therapy outweigh the
benefits.
Nervous System Symptoms: Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among SUSTIVA-treated patients were generally similar to those in the indinavir-containing control arm.
The Precautions section was updated to include information on Immune Reconstitution Syndrome and update Table 5: Drugs That Should Not Be Coadministered with SUSTIVA and the Established Drug Interaction Table as follows:
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SUSTIVA. 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 carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Voriconazole was added to Table 5: Drugs That Should Not Be Coadministered
with SUSTIVA
The Established Drug Interaction table includes the following information regarding
atazanavir
When coadministered with SUSTIVA in treatment-naive patients, the recommended
dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once
daily). Dosing recommendations for SUSTIVA and atazanavir in treatment-experienced
patients have not been established.
The Adverse Reactions section was updated to include the 168 week safety data
(adverse reactions and laboratory abnormalities) from study 006
Table 9: Selected Grade 3 and 4 laboratory abnormality table was also updated
to include triglyceride data > 751 mg/dL from studies 006 and ACTG 364
The Liver Enzymes and Lipids subsection were revised to include the following
information from study 006
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these co-infected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the SUSTIVA arms and 7% of patients in the control arm. Among co-infected patients, 3% of those treated with SUSTIVA-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders
Lipids: Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels > 240 mg/dL and > 300 mg/dL were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + zidovudine + lamivudine, 54% and 20%, respectively, of patients treated with SUSTIVA + indinavir, and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of SUSTIVA on triglycerides and LDL were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown.
The complete revised label will be available soon on the "Drugs@FDA" website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
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 today, August 3, 2004, approved Sculptra, an injectable filler to correct facial fat loss in people with human immunodeficiency virus (HIV).
Sculptra is the first such treatment approved for a condition known as lipoatrophy, or facial wasting, a sinking of the cheek, eye and temple areas of the face caused by the loss of fat tissue under the skin which can affect HIV patients. FDA expedited review of the product because of its importance in treating people living with AIDS.
Sculptra is an injectable form of poly-L-lactic acid, a biodegradable, biocompatible synthetic polymer from the alpha-hydroxy-acid family that has been widely used for many years in dissolvable stitches, bone screws and facial implants.
FDA approval of Sculptra was based on data from four studies, totaling 277 HIV-positive patients with severe facial lipoatrophy. The patients, who were all being treated with antiretroviral drugs, were primarily white males, mostly ages 41 to 45. Patients were given three to six injections of Sculptra at two-week intervals and were followed for two years.
Skin thickness measurements and serial photographs from clinical studies were assessed, as well as other data submitted by the manufacturer, Dermik Laboratories, of Berwyn, Pa. Analysis indicated that the product significantly improved facial appearance, and was safe for restoration and/or correction of shape and contour deficiencies resulting from facial fat loss in patients with HIV/AIDS. Sculptra was shown to produce significant increases in dermal thickness (up to 2 to 3 times baseline values), adding volume to facial tissue and restoring shape to areas of the face with fat loss.
After an initial treatment series, repeat treatments may be needed to maintain the correction.
Most adverse events were related to the injection itself and included nodules, redness, swelling and bruising in the injection area.
The studies also demonstrated significant improvement in quality of life, and measures of anxiety and depression, conditions which can be associated with lipoatrophy.
Sculptra should only be used in patients with HIV by health care providers
who are fully familiar with the product training materials provided by Dermik
and the entire product package insert. The use of the product for other indications,
such as to treat wrinkles, has not been approved by FDA.
Sculptra should not be used in anyone who is allergic to any of the product's
components.
As a condition of approval, Dermik has agreed to conduct an open-label registry study of 100 patients for five years to evaluate Sculptra's long-term safety. The study will include at least 30 females and 30 people with dark skin types.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
FDA announced approval today, August 2, 2004, of two fixed-dose combination (FDC) antiretroviral drug products for use with other antiretroviral agents for the treatment of HIV-1 infection. The FDCs are GlaxoSmithKline's EPZICOM(tm) (abacavir/lamivudine) and Gilead Sciences, Inc.'s TRUVADA(tm) (tenofovir disoproxil/emtricitabine)
These FDC approvals are important because they provide simplified dosing regimens - one pill, once daily, for the component of multi-drug therapy represented by these FDCs.
TRUVADA(tm) (tenofovir disoproxil/emtricitabine) - Gilead Sciences, Inc.
TRUVADA is a fixed-dose combination (FDC) of the antiretroviral drugs tenofovir disoproxil fumarate 300 mg (TDF) and emtricitabine 200 mg (FTC), both of which are approved individually under the brand names of VIREAD(tm) (tenofovir disoproxil fumarate) and EMTRIVA(tm) (emtricitabine).
The approval of TRUVADA is based on bioequivalence studies demonstrating similar pharmacokinetic parameters of the combination product and the individual products, safety and efficacy data that exist for both components individually, and efficacy results from studies using the combination of TDF and lamivudine (3TC), [lamivudine is an approved product with many similarities to FTC] are being extrapolated to support the use of the TDF/FTC combination.
TRUVADA should be considered as an alternative to TDF and 3TC for treatment
naïve patients who might benefit from a once-a-day regimen.
EPZICOM(tm) (abacavir/lamivudine) - GlaxoSmithKline
EPZICOM is a fixed dose combination (FDC) of the antiretroviral drugs abacavir sulfate 600 mg and lamivudine 300 mg, both of which are approved individually under the brand names of ZIAGEN(tm) (abacavir sulfate) and EPIVIR(tm) (lamivudine).
EPZICOM is being approved based on a large well-controlled clinical study which
showed that abacavir dosed once daily had similar antiviral effect as abacavir
dosed twice daily both in conjunction with lamivudine and efaviranz.
The important safety issue regarding abacavir-containing products, including
EPZICOM, is abacavir hypersensitivity reaction (a serious allergic reaction).
Previous clinical trials showed that there is a possibility of this hypersensitivity
reaction occurring in approximately 8% of the patients. EPZICOM should be discontinued
a soon as a hypersensitivity reaction is suspected. EPZICOM or other abacavir-containing
products must not be restarted following a hypersensitivity reaction because
more severe symptoms can occur within hours and may include life-threatening
hypotension and death. Information on this serious allergic reaction has been
updated in the EPZICOM package insert as well as the patient Medguide/Warning
Card.
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 has developed a web page to consolidate records of advisory committee meetings related to HIV/AIDS and associated conditions, making them easier to access.
The new page, which lists HIV/AIDS-related advisory committee meetings held since 1996, indexed by topic and by year, can be found at www.fda.gov/oashi/aids/advisorycom.html
The page is linked from the main HIV/AIDS page at www.fda.gov/oashi/aids/hiv.html
The page contains records of meeting held by advisory committees related to drugs, biologics, and medical devices, and will be updated to reflect availability of records of future meetings. Most records contain a variety of documents, such as the meeting announcement, committee rosters, briefing materials - which often contain background materials and slides, and transcripts of the meetings.
Topics include consideration of new drug applications, regulatory policy issues, and trial design topics.
The page also contains a link to the main FDA Advisory Committee page for other resources and topics related to FDA advisory committee meetings.
We hope you this new page useful.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On July 6, 2004, the Division of Antiviral Drug Products approved a new dosing regimen for REYATAZ. In antiretroviral-experienced patients the new recommended dose is
REYATAZ 300 mg (two 150 mg capsules) once daily plus ritonavir 100 mg once daily taken taken with food.
For antiretroviral-naïve patients the recommended dose remains as REYATAZ 400 mg (two 200 mg capsules) once daily with food.
The data to support the new dosing regimen came from study AI424-045, a study of patients who had failed at least two regimens containing medications from the three ARV drug classes available at the time of enrollment. This 48-week trial evaluated the efficacy and safety of REYATAZ 300 mg + ritonavir 100 mg once daily or REYATAZ 400 mg + saquinavir 1200 mg once daily compared to lopinavir/ritonavir 400/100 mg twice daily each with tenofovir and an nucleocide reverse transcriptase inhibitor (NRTI).
REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. The HIV RNA change from baseline was -1.58 log10 copies/mL for REYATAZ/ritonavir and -1.70 log10 copies/mL for lopinavir/ritonavir.
Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measures of proportion below the HIV RNA lower limit of detection. The proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 was 55% and 38% for REYATAZ/ritonavir and 57% and 45% for lopinavir/ritonavir, respectively.
The major revisions to the package insert are summarized below.
INDICATIONS AND USAGE:
Information that should be considered when initiating therapy with REYATAZ was added as follows. This data pertains to REYATAZ/ritonavir.
The following points should be considered when initiating therapy with REYATAZ:
In antiretroviral-experienced patients with prior virologic failure, coadministration of REYATAZ with ritonavir is recommended.
In Study AI424-045 REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. (See Description of Clinical Studies)
The number of baseline primary protease inhibitor mutations affects the virologic response of REYATAZ/ritonavir (See CLINICAL PHARMACOLOGY: Microbiology)
There are no data regarding the use of REYATAZ/ritonavir in therapy-naive patients.
CLINICAL PHARMACOLOGY
Microbiology
A table was included to provide information regarding HIV RNA response at week 48 by number and type of baseline protease inhibitor mutations and baseline phenotype in treatment-experienced subjects (study AI424-045). In summary, HIV RNA the response rate (< 400 copies/mL) was 75% for both REYATAZ/ritonavir (50/67) and lopinavir/ritonavir (50/67) in patients with 0-2 baseline primary protease inhibitor mutations. In patients with 3-4 baseline primary protease inhibitor mutations the response rates were 41% (14/34) and 43% (12/28) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations the response rates were 0% (0/9) and 23% (5/18) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively.
WARNINGS
PR Interval Prolongation
The following statement was added - There have been rare reports of second-degree
AV block and other conduction abnormalities and no reports of third-degree AV
block.
Information regarding reports of first-degree AV block from Study 045 was added.
PRECAUTIONS
A subsection regarding rash was included to state that the incidence of rash
in controlled clinical trials (n=1597) was 21% . The median time to onset of
rash was 8 weeks after initiation of REYATAZ and the median duration of rash
was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions.
Dosing with REYATAZ was often continued without interruption in patients who
developed rash. The discontinuation rate for rash in clinical studies was 0.4%.
REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson
syndrome and erythema multiforme have been reported in patients receiving REYATAZ.
Drug Interactions
A change to the clinical comment for the interaction between efavirenz and REYATAZ was made to distinguish the dose adjustment of REYATAZ/ritonavir/efavirenz 300/100/600 mg once daily applies to treatment-naïve subjects. Appropriate dosing recommendations for efavirenz and REYATAZ in treatment-experienced subjects have not been established.
Revised label can be found at Drugs@fda
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On July 1, 2004, the VIREAD (tenofovir disoproxil fumerate) label was updated to include the following information.
The Box Warning was updated to include the following:
VIREAD IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF VIREAD HAVE NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HBV AND HIV AND HAVE DISCONTINUED VIREAD. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE VIREAD AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).
The Warning section was also updated to include the following:
Patients Co-infected with HIV and Hepatitis B Virus
It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not indicated for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue VIREAD and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Additionally, the Clinical Pharmacology and Precaution sections were updated to include information regarding drug-drug interactions with atazanavir, adefovir and ribavirin.
No drug-drug interaction was seen between tenofovir and adefovir or tenofovir and ribavirin.
The following text was added to the Precaution section.
Higher tenofovir concentrations could potentiate VIREAD-associated adverse events,
including renal disorders.
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and VIREAD should be monitored for VIREAD- associated adverse events. VIREAD should be discontinued in patients who develop VIREAD-associated adverse events.
VIREAD decreases the Area Under the Curve (AUC) and Minimum Concentration (Cmin)
of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir
300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not
be coadministered with VIREAD.
The Carcinogenesis, Mutagenesis, Impairment of Fertility section was revised
to include results of the long-term carcinogenicity studies in mice and rats.
The following information was included in this section.
Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
FDA granted a CLIA (Clinical Laboratory Improvements Amendments of 1988] waiver
to the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test for use with oral fluid
on June 25, 2004.
The OraQuick ADVANCE Rapid HIV Test is a fast and non-invasive test approved
on March 26, 2004, to detect antibodies to HIV-1 in oral fluid. The oral fluid
indication was extended by FDA to include detection of antibodies to HIV-2 in
oral fluid on June 22, 2004.
Originally, use of OraQuick ADVANCE Rapid HIV test to detect antibodies to HIV in oral fluid had been limited to certified laboratories (high and moderate complexity laboratories under CLIA). However, as a result of the waiver from the requirements of CLIA, all clinical laboratories certified through CLIA (high, moderate, and waived) can now use this test. The CLIA waiver allows the test to be used under less stringent controls, which is expected to have a major impact on increased access to HIV testing.
The CLIA waiver will allow the rapid oral fluid test to be used in more health care settings, such as doctors' offices, clinics, and some mobile labs that can offer testing in high-risk areas. Through these venues, testing will be accessible to many more people, particularly to those individuals who are reluctant to be tested due to the need to draw blood.
The test is expected to help diagnose more people earlier, improving their treatment options, and reducing their chance of infecting others. It will also protect health care workers from infection by reducing their exposure to blood.
Manufacturers must submit a request for a CLIA waiver to FDA. To qualify for a waiver, a test must be simple, accurate and present no reasonable risk of harm.
FDA based its waiver decision for the OraQuick ADVANCE Rapid HIV Test on information submitted by the manufacturer, OraSure Technologies, Inc., Bethlehem, PA, demonstrating that the test is simple to run, is very robust under a wide range of environmental stresses, and generates highly accurate results in a wide variety of settings.
The OraQuick ADVANCE Rapid HIV-1/2 Antibody Test provides a highly accurate HIV test result from an easily collected oral fluid sample in as little as 20 minutes, without the need to draw blood. According to data submitted by OraSure and reviewed by the FDA, in limited clinical studies the OraQuick correctly identified at least 99.3% of specimens from HIV-infected persons and at least 99.8% of specimens from uninfected persons.
A reactive result using the OraQuick Rapid HIV-1/2 Antibody Test with oral fluid is considered a preliminary positive result and must be confirmed using an additional, more specific test, such as the Western Blot, just as for testing using blood samples.
Richard Klein
HIV/AIDS Program Director
Food and Drug Administration
FDA and Bristol-Myers Squibb recently notified healthcare professionals of revisions to the CLINICAL PHARMACOLOGY and PRECAUTIONS sections of the product labeling for DESYREL (trazodone hydrochloride) Tablets, indicated for the treatment of depression.
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir.
It is likely that CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered.
The following label changes include modifications to the CLINICAL PHARMACOLOGY section:
Metabolism
In vitro studies in human liver microsomes show that trazodone is
metabolized to an active metabolite, m-chlorophenylpiperazine (mCPP) by
cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be
involved in metabolism of trazodone have not been well characterized.
Elimination
In some patients DESYREL may accumulate in the plasma.
Drug-Drug Interactions
See also PRECAUTIONS: Drug Interactions. In vitro drug metabolism
studies reveal that trazodone is a substrate of the cytochrome P450 3A4
(CYP3A4) enzyme and trazodone metabolism can be inhibited by the
CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. The effect of short-term
administration of ritonavir (200 mg twice daily, 4 doses) on the
pharmacokinetics of a single dose of trazodone (50 mg) has been studied in
10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC
increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance
decreased by 52%. Adverse effects including nausea, hypotension, and
syncope were observed when ritonavir and trazodone were coadministered.
Additionally, the Drug Interactions sub-section within the
PRECAUTIONS section has been updated with the following information:
In vitro drug metabolism studies suggest that there is a potential for drug
interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a
potent CYP3A4 inhibitor, increased the Cmax, AUC, and elimination half-life,
and decreased clearance of trazodone after administration of ritonavir twice
daily for 2 days. Adverse effects including nausea, hypotension, and
syncope were observed when ritonavir and trazodone were coadministered.
It is likely that ketoconazole, indinavir, and other CYP3A4
inhibitors such as itraconazole or nefazodone may lead to substantial
increases in trazodone plasma concentrations with the potential for adverse
effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of
trazodone should be considered.
You can access the entire Dear Healthcare Provider Letter at
http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_DHCP.pdf
The complete product label is available at
http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_PI.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
FDA published on May 20, 2004 a new Final Rule on donor eligibility for human tissues and cells (Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products), and draft guidance (Guidance for Industry Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products) related to donor screening and eligibility. These documents include HIV, among a variety of conditions for which cell and tissue donor screening would be required.
The final rule establishes donor eligibility criteria for donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) to help prevent the transmission of communicable disease when these products are transplanted. This new rule is part of the Agency's plan to regulate tissues and related products with a comprehensive, risk-based approach. The requirements are comprehensive, yet adequately flexible, and they provide needed protections for patients without imposing unnecessary regulation.
Along with the potential for great benefit, products derived from the human body such as HCT/Ps may pose risks of transmitting communicable diseases, especially if donors are not properly screened and tested. For this reason, this final rule requires that, before the use of most HCT/Ps, the cell or tissue donor must be found eligible, based on the results of screening for risk factors and testing for relevant communicable diseases. In most cases, a donor who tests positive for a particular disease or who possesses clinical signs or risk factors for such a disease would be considered ineligible, and cells and tissues from that donor would not ordinarily be used.
The new rule on donor eligibility expands the types of human-derived products that come under FDA regulation in an effort to prevent the transmission of diseases through transplantation. Some 350,000 transplants were performed in 1990. Approximately one million are expected to be performed in 2004. The rule pertains to donors of traditional tissues such as musculoskeletal, skin and eye tissues that have been required since 1993 to be screened and tested for HIV, Hepatitis B virus (HBV) and Hepatitis C virus (HCV). Under this new rule, however, reproductive tissue (semen, ova, and embryos), hematopoietic stem cells derived from cord blood and peripheral blood sources (circulating blood sources as opposed to bone marrow), cellular therapies and other innovative products are also regulated.
In addition to including a broader range of tissues and cells, the new rule extends the scope of protection against additional communicable diseases that can be transmitted through transplanted tissues and cells. The new regulation adds requirements to screen for human transmissible spongiform encephalopathies, including Creutzfeldt-Jakob disease (CJD), and to screen and test for syphilis. Screening and testing for still other relevant communicable disease agents (human T-lymphotropic virus (HTLV) would be required for viable cells and tissue rich in leukocytes such as semen and hematopoietic stem cells. For reproductive tissues, Chlamydia trachomatis and Neisseria gonorrhoeae also pose potential risks and are included.
The new rule also provides a framework for identifying emerging diseases that may pose risks to recipients of transplanted HCT/Ps and for which appropriate screening measures or testing are available. Thus, this new regulation gives FDA the flexibility to rapidly address new disease threats as they appear, providing substantial new protections for patients receiving tissue transplants. Examples of such diseases include West Nile virus, Severe Acute Respiratory Syndrome (SARS) and sepsis.
The behavioral risk factors that are used to screen donors are consistent with 1994 Centers for Disease Control and Prevention (CDC) guidelines for preventing transmission of HIV through organ and tissue transplantation and with the scientific literature as reviewed by CDC in 2000. Professional groups, such as the American Association of Tissue Banks, have adopted the recommendations contained in the CDC guidelines.
The rule also contains requirements related to record-keeping, quarantine, storage and labeling of the HCT/Ps, all important to the prevention of disease transmission.
Certain exceptions from the requirements for donor eligibility testing and screening exist. These tissues and cells include:
Other cells and tissues are subject to donor testing and screening, but may be used with appropriate communication, labeling and documentation of the relevant results even if the donor is determined to be ineligible.
These are:
The new framework does not include whole organs or minimally-manipulated bone marrow, which are regulated by the Health Resources and Services Administration (HRSA), another agency of the Department of Health and Human Services. It also does not cover blood products for transfusion or products derived from animals, which FDA regulates under the biologics license requirements and other applicable regulations.
The final rule becomes effective on May 25, 2005.
The new Final Rule is accompanied by draft guidance that provides recommendations for complying with the requirements in the donor eligibility rule. Comments on the draft guidance will be accepted until August 23, 2004 (90 days from the publication date) for consideration in the final guidance.
The Notice of Final Rule, and the draft guidance document are available on FDA's website:
Federal Register Notice http://www.fda.gov/OHRMS/DOCKETS/98fr/97N-484S-nfr0001.pdf
Draft Guidance Document http://www.fda.gov/cber/gdlns/tissdonor.pdf
In addition, a "Questions and Answers" document has been prepared to address basic points about the Donor Eligibility Final Rule and the Draft Guidance.
Questions and Answers http://www.fda.gov/cber/rules/suitdonorq&a.htm
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
FDA announced, on May 17, 2004, issuance of a guidance document that describes a process to expedite approval of low cost, safe and effective co-packaged and fixed dose combination (FDC) HIV therapies so that high quality drugs can be made available in Africa and developing countries around the world under the President's Emergency Plan for AIDS Relief.
DETAILS OF FDA'S GUIDANCE
FDA's Guidance for Industry Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV provides simplified pathways for submitting clinical safety and efficacy data, virology, chemistry and bioavailability information for combination therapy products for HIV. The guidance states that applicants for co-packaged or FDC products may provide clinical efficacy (as measured by the drug's effect on viral load) and safety information by one of the following mechanisms:
The guidance describes how applicants can submit chemistry data to FDA to show that the drugs used in the combination, as well as any other ingredients, do not interact or cause other problems when used together, that the product is stable in the packaging that will be used, to establish specifications for the final drug product, and describe how a bioavailability study should be conducted to show that blood levels of the drugs, when used in combination, are the same as those needed to achieve efficacy when the drugs are used alone.
While a marketing application cannot be approved to permit sale in the United States until applicable patents or exclusivity protections expire, FDA can grant "tentative approval," showing that a product has met all FDA scientific standards for safety, efficacy, and quality. Such tentatively approved products would then be available for procurement under the President's Emergency Plan for AIDS Relief - a program that would provide $15 billion over five years - with the goal of preventing 7 million new infections, treating 2 million HIV infected people, and caring for 10 million HIV infected individuals and AIDS orphans.
Link to the Federal Register Notice, Availability of Guidance: http://www.fda.gov/OHRMS/DOCKETS/98fr/cd0466.pdf (PDF 25 KB)
Link to the draft Guidance Document: www.fda.gov/oc/initiatives/hiv/hivguidance.html
BACKGROUND ON TODAY'S ACTION
For What Drugs Does the Guidance apply?
It applies to proposed fixed dose combination (FDC) antiretroviral products
and proposed co-packaged antiretroviral products for which there is adequate
evidence of safety and efficacy for the treatment of HIV and is aimed primarily
at those combinations of individual drugs for which the combination has already
been evaluated and established.
This guidance does not specifically apply to FDCs or co-packaged products to treat diseases other than HIV/AIDS.
How many drugs are needed to treat HIV the virus that causes AIDS?
In general three antiretroviral drugs are required to treat HIV/AIDS when initiating
therapy. This is called combination antiretroviral therapy or HAART (highly
active antiretroviral therapy). Most of the time it consists of two drug from
one class of drugs (nucleoside reverse transcriptase inhibitors) and a third
drug from another class (either an HIV protease inhibitor or non-nucleoside
reverse transcriptase inhibitor) More than three drugs may be needed for HIV-infected
patients who have resistant virus or who have previously experienced loss of
virologic control on antiretroviral therapy
What is a FDC (fixed dose combination)?
A fixed-dose combination product is one in which two or more separate drug and/or
biological active ingredients are combined in a single dosage form.
What is a co-packaged product?
A co-packaged product consists of two or more separate drug and/or biological
products in their final dosage form, packaged together.
Why are FDCs or co-packaged drugs important for HIV treatment?
Such products may allow for easier distribution and help to simplify regimens,
leading to improved patient adherence, particularly in resource poor settings.
Combination antiretroviral therapy is essential to effectively treat HIV/AIDS,
and improved adherence to combination antiretroviral therapy may help to slow
the rate of development of drug resistant HIV.
What kind of combinations should be co-packaged or put in an FDC?
Proposed combination products should be relatively well tolerated and easy to
administer, while providing adequate potency and sufficient barrier to the emergence
of drug resistance. They should have proven safety and efficacy in patients
initiating HIV treatment.
Why does FDA have requirements for Fixed Dose Combinations and Co-Packaged
Drugs?
Combining drugs in one formulation (pill) can potentially change the amount
of drug the gets into the bloodstream (its bioavailability). When treating HIV
low blood levels of drugs could lead to drug resistance in people taking them
and could even lead to the spread of drug resistance. Changes in bioavailability
could be due to problems with manufacturing several drugs into one pill or could
be due to interactions between the drugs in the product. Even co-packaging drugs
into new containers or blister packs could change the potency of a drug when
stored over a period of time especially in severe climates (very hot or humid).
All of these factors are important because the amount of drug that eventually
gets into the bloodstream is very important for controlling HIV.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The following revisions were made to the Crixivan product label
1. The following changes were made to the CLINICAL PHARMACOLOGY section
• Text was revised in Delavirdine section and now reads:
"Delavirdine inhibits the metabolism of indinavir such that coadministration
of 400-mg or 600-mg
indinavir three times daily with 400-mg delavirdine three times daily alters
indinavir Area Under the Curve (AUC), Maximum Concentration (Cmax ) and Minimum
Concentration (Cmin). Indinavir had no effect on delavirdine pharmacokinetics
(see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Delavirdine), based on
a
comparison to historical delavirdine pharmacokinetic data."
• Text was revised in the Methadone section and now reads:
"Administration of indinavir (800 mg every 8 hours) with methadone (20
mg to 60 mg daily) for
one week in subjects on methadone maintenance resulted in no change in methadone
AUC.
Based on a comparison to historical data, there was little or no change in indinavir
AUC."
• Text was revised in Ritonavir section and now reads:
"Compared to historical data in patients who received indinavir 800 mg
every 8 hours alone,
twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir
with food for two
weeks resulted in an 2.7-fold increase of indinavir AUC24h, a 1.6-fold increase
in indinavir Cmax,
and an 11-fold increase in indinavir Cmin for a 100-mg ritonavir dose and a
3.6-fold increase of
indinavir AUC24h, a 1.8-fold increase in indinavir Cmax, and a 24-fold increase
in indinavir Cmin
for a 200-mg ritonavir dose. In the same study, twice-daily coadministration
of indinavir (800 mg)
and ritonavir (100 or 200 mg) resulted in ritonavir AUC24h increases versus
the same doses of
ritonavir alone (see Table 3)."
• Vardenafil text was added, and reads:
Vardenafil: Indinavir (800 mg every 8 hours) coadministered with a single 10-mg
dose of vardenafil resulted in a 16-fold increase in vardenafil AUC, a 7-fold
increase in vardenafil Cmax, and a 2-fold
increase in vardenafil half-life (see WARNINGS, Drug Interactions and PRECAUTIONS,
Drug Interactions).
2. In the WARNINGS: Drug Interactions section text was added to include references
to tadalafil,
sildenafil, and vardenafil.
3. In the PRECAUTIONS: Information for Patients section the following sentence
was revised to include
reference PDE5 inhibitors.
"Patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil,
tadalafil, or vardenafil)
should be advised that they may be at an increased risk of PDE5 inhibitor-associated
adverse
events including hypotension, visual changes, and priapism, and should promptly
report any
symptoms to their doctors."
4. In the PRECAUTIONS section, atazanavir was added to Table 8: "Drugs
that should not be
Coadministered with CRIXIVAN"
5. In the DOSAGE AND ADMINISTRATION section, text regarding efavirenz was deleted.
The following revisions were made to the Crixivan Patient Package Insert
• Seldane (terfenadine) was deleted and Cordarone (amiodarone) and D.H.E.
45,
Migranal, Ergotrate, and Methergine were added under "Medicines you should
not take
with CRIXIVAN" in the "Can CRIXIVAN be taken with other medications?"
section.
• The following sentence was added to "Medicines you should not
take with CRIXIVAN" in the
"Can CRIXIVAN be taken with other medications?" section:
"Taking CRIXIVAN with REYATAZ (atazanavir) is not recommended because
they can both
sometimes cause increased levels of bilirubin in the blood."
• A paragraph under the "Can CRIXIVAN be taken with other medications?" section was revised and now reads:
"Before you take VIAGRA (sildenafil), CIALIS (tadalafil), or LEVITRA (vardenafil)
with
CRIXIVAN, talk to your doctor about possible drug interactions and side effects.
If you take any
of these medicines together with CRIXIVAN, you may be at increased risk of side
effects such
as low blood pressure, visual changes, and penile erection lasting more than
4 hours, which have
been associated with sildenafil, tadalafil, and vardenafil. If an erection lasts
longer than 4 hours,
you should seek immediate medical assistance to avoid permanent damage to your
penis.
Your doctor can explain these symptoms to you."
• "CRESTOR (rosuvastatin)" was added to "Medicines you
can take with CRIXIVAN" in the "Can
CRIXIVAN be taken with other medications?" section.
• The following sentences were added to the "Can CRIXIVAN be taken with other medications?" section:
"Calcium Channel Blockers: Tell your doctor if you are taking calcium channel blockers (e.g., amlodipine, felodipine).
Antiarrhythmics: Tell your doctor if you are taking antiarrhythmics (e.g., quinidine).
Anticonvulsants: Tell your doctor if you are taking anticonvulsants (e.g., phenobarbital, phenytoin, or carbamazepine).
Steroids: Tell your doctor if you are taking steroids (e.g., dexamethasone)."
The complete revised label is available on the web at http://www.fda.gov/cder/foi/label/2004/20685slr046,047_crixivan_lbl.pdf
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Please note that the following changes have been made to the label for Voriconazole
(VFEND)
triazole antifungal agent, to include drug interaction information when coadministered
with efavirenz or ritonavir.
1. CLINICAL PHARMACOLOGY
2. CONTRAINDICATIONS
Coadministration of VFEND with ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with efavirenz is contraindicated because efavirenz significantly decreases voriconazole plasma concentrations while VFEND also significantly increases efavirenz plasma concentrations (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
3. PRECAUTIONS
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
On April 6, 2004, FDA approved two generic versions of the drug, ribavirin, Ribavirin Capsules, 200 mg, made by Geneva Pharmaceuticals, and Ribasphere Capsules, 200 mg, made by Three Rivers Pharmaceuticals, L.L.C., for the treatment of Chronic Hepatitis C.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
1. FDA APPROVES FIRST ORAL FLUID BASED RAPID HIV TEST KIT - OraQuick Rapid HIV-1 Antibody Test
FDA today (March 26, 2004) approved the use of oral fluid samples with a rapid HIV diagnostic test kit that correctly identified 99.3 of specimens from infected people (sensitivity) and 99.8% of specimens from uninfected people (specificity) in limited studies provided by the manufacturer in support of this approval. The test provides the result in approximately 20 minutes.
In addition to simplifying the testing process, precluding the need for a blood sample, use of the oral collection component reduces risk to healthcare workers performing the test by reducing exposure to blood and sharps.
The original version of this rapid test - the OraQuick Rapid HIV-1 Antibody Test, manufactured by OraSure Technologies, Inc., Bethlehem, PA - was approved November 7, 2002 for detection of antibody to HIV-1 in blood.
The test can quickly and reliably detect antibodies to HIV-1, can be stored at room temperature and requires no specialized equipment.
The device has an exposed absorbent pad at one end which is gently swabbed around the mouth between the teeth and the outer gums. It is then inserted into a vial containing a solution. In as little as 20 minutes, the test device will indicate whether HIV-1 antibodies are present in the solution by displaying either one bar (the control indicator, showing a negative HIV response) or two bars (the control plus reactive test indicator) in a small window on the device. Two bars indicate a presumptive positive result, requiring a Western Blot test to confirm HIV infection.
The rapid test is not approved or intended for home use and has not been approved to screen blood donors.
All new test systems are categorized under CLIA (Clinical Laboratory Improvements Amendments of 1988) as high complexity systems until they are submitted for categorization under CLIA. The product sponsor may apply for a waiver for this test. Without a CLIA waiver, tests can only be administered in CLIA-approved labs by CLIA-certified laboratory technicians or medical staff. CLIA waiver allows the test to be used in many more health care settings.
The OraQuick Rapid HIV-1 antibody test was granted a CLIA waiver in January, 2003 for use with whole blood specimens only.
2. HIV-1/2 IN PLASMA
Also on March 26, 2004, the OraQuick Rapid HIV-1 Antibody Test was approved for testing plasma for HIV-1 and HIV-2 (a variant of HIV that is prevalent in parts of Africa but rarely found in the United States).
3. HIV-2 IN WHOLE BLOOD
On March 19, 2004, FDA approved the OraSure rapid test for detection of HIV-2 when used with a whole blood sample. The rapid test kit is identical to the earlier approved version. However, subsequent data submitted to the agency has demonstrated its ability to detect HIV-2.
When used with oral fluid the test is approved only to detect antibodies only to HIV-1.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
The "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents," was updated today (March 23, 2004), and is available at AIDSinfo.nih.gov. The guidelines were developed, and are updated by the panel on Clinical Practices for Treatment of HIV Infection, convened by the Department of Health and Human Services (HHS). The changes in this update are outlined below.
1. "Table 12a -
Antiretroviral Regimens Recommended for Treatment
of HIV-1 Infection
in Antiretroviral Naïve Patients":
Additions:
Deletions:
2. New safety information regarding the risks of nevirapine-associated symptomatic
hepatic events has been added to the text of the guidelines (sections on "NNRTI-Based
Regimens" and "Hepatotoxicity") and the respective tables (Tables
12a, 12b, and 19).
3. Characteristics and drug interaction information for fosamprenavir have
been added to
the respective tables (Tables 17, 20, 21, 22a, 22b, 23, and 30).
4. A new table (Table 13) with "Antiretroviral Dosing Recommendations
for Patients with
Renal or Hepatic Dysfunction" has been created.
The complete, updated Adult and Adolescent Guidelines are available on AIDSinfo.nih.gov
Other HIV-related guidelines available on the site are:
Antiretroviral Treatment
Pediatric Guidelines
Maternal-Child Transmission
Perinatal Guidelines
Post-Exposure Prophylaxis
Health-Care Worker Exposure Guidelines
Nonoccupational Exposure Considerations
Management of HIV Complications
Tuberculosis Guidelines
Opportunistic Infections Guidelines
Incorporation of HIV Prevention
Testing
Revised Guidelines for Counseling, Testing, and Referral
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
Based on clinical and pharmacokinetic data from 5 pediatric studies, FDA has approved new dosing recommendations for VIRACEPT (nelfinavir) in patients 2 years of age or older.
In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established. Summary data from all pharmacokinetic (PK) studies submitted is included in the revised label for completeness. The major revisions made to the product label based on this review are described below:
1. Pediatric PK information is incorporated into the product label in a table summarizing the steady-state area under the concentration-time curve from 0 to 24 hours (AUC24) of nelfinavir observed in pediatric studies enrolling patients from birth to 13 years of age. Comments regarding the marked variability of drug exposure identified in pediatric patients are also included.
2. The basis for the pediatric indication with relevant age groups and brief descriptions of the major pediatric clinical trials available for review are incorporated. The following points are highlighted in the PEDIATRIC USE section of the label:
In pediatric patients 2 years of age and older receiving VIRACEPT as part of triple combination antiretroviral therapy in randomized studies, the proportion of patients achieving an HIV RNA level less than 400 copies/mL through 48 weeks ranged from 26% to 42%.
Response rates in children less than 2 years of age appeared to be poorer than those in patients 2 years of age and older in some studies.
Highly variable drug exposure remains a significant problem in the use of VIRACEPT in pediatric patients. Unpredictable drug exposure may be exacerbated in pediatric patients because of increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing.
3. An updated description of the pediatric safety data is included, highlighting the size of the safety database, the similarity of the safety profile in adults and children, and 2 of the most commonly reported toxicities (diarrhea and neutropenia).
4. The new dosing recommendations for children are included in the DOSAGE AND ADMINISTRATION section of the label. These recommendations include tables that provide dosing guidelines for pediatric patients of different weights taking either the 250 mg tablets or the oral powder. Instructions for mixing the powder remain unchanged.
The revised dose recommendations are as follows:
"In children 2 years of age and older, the recommended oral dose of VIRACEPT oral powder or 250 mg tablets is 45 to 55 mg/kg twice daily (BID) or 25 to 35 mg/kg three times daily (TID). All doses should be taken with a meal. Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children. For children unable to take tablets, VIRACEPT Oral Powder may be administered."
Viracept was originally approved for pediatric use in 1997. This supplement provides additional information, and new TID and BID dose recommendations.
A pdf file containing the revised VIRACEPT
label is attached. A free copy of Adobe Acrobat Reader 5.0 can be downloaded.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
New drug interaction information has led to the following changes in the CLINICAL PHARMACOLOGY section of the REYATAZ (atazanavir sulfate) label:
Table 2: Drug Interactions: Pharmacokinetic Parameters for Atazanaivr in the Presence of Coadministered Drugs and Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ were revised to include results from the tenofovir interaction studies.
The following information was added to the PRECAUTION: Drug Interaction section:
Table 9: Established and Other Potentially Significant Drug Interactions. Specifically the following statement was included
Tenofovir decreases the AUC (area under the curve) and Cmin (minimum concentration) of REYATAZ. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg is given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir.
REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events.
The following information was added to the DOSAGE AND ADMINISTRATION section:
When coadministered with tenofovir, it is recommended that REYATAZ 300 mg is given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir.
Further, information regarding PDE5 inhibitors (sildenafil [Viagra], tadalafil [Cialis] and vardenafil [Levitra]) was added to the WARNINGS and PRECAUTION sections. The information included is consistent with the recently approved Invirase and Fortovase label.
In addition, the patient package insert was revised to include information regarding tenofovir and PDE5 inhibitors (sildenafil, tadalafil, vardenafil).
A pdf file containing the revised label is attached. A free copy of Adobe Acrobat Reader 5.0 can be downloaded.
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) will hold a meeting of its General and Plastic Surgery Devices Panel on on March 25, 2004, from 8 a.m. to 5 p.m. at the Hilton Gaithersburg, 620 Perry Parkway, Salons A, B, C, and D, Gaithersburg , MD 20877
The meeting will be open to the public, and no preregistration is necessary to attend. If you need directions or accommodations, please contact the hotel directly at (301) 977-8900.
The committee will discuss, make recommendations, and vote on a premarket approval application (PMA) for an injectable device intended for use in the correction of lipoatrophy of the face in HIV (human immunodeficiency virus) positive patients. Background information for this PMA, including the agenda and questions for the committee, will be available to the public one business day before the meeting on the Internet. The material for this meeting will be posted on March 24, 2004 at www.fda.gov/cdrh/panelmtg.html.
Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.
Written submissions should be sent to David Krause, Center for Devices and Radiological Health (HFZ-410), Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850, 301-594-3090, ext. 141 by March 11, 2004.
On March 25, 2004, oral presentations from the public will be scheduled for approximately one hour at the beginning of committee deliberations and for approximately one hour near the end of the deliberations. Time allotted for oral public presentations may be limited depending on the number of people requesting time to speak.
Those desiring to make formal oral presentations should notify David Krause, Center for Devices and Radiological Health (HFZ-410), Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850, 301-594-3090, ext. 141, before March 11, 2004. Please 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. If you require special accommodations due to a disability, please contact Shirley Meeks, Conference Management Staff, at 301-594-1283, ext. 105, at least 7 days in advance of the meeting.
Up-to-date information about the meeting can be found on the FDA Advisory Committee page at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfAdvisory/details.cfm?mtg=508
Persons attending FDA's advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
FDA approved a labeling supplement on January 12, 2004 for Crixivan (Indinavir Sulfate) Capsules, resulting in the following changes:
Revisions to the Package Insert (Drug Label)
In the Precautions section:
"Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/high power field). Patients with asymptomatic severe leukocyturia should be followed closely and monitored frequently with urinalyses. Further diagnostic evaluation may be warranted, and discontinuation of CRIXIVAN should be considered in all patients with severe leukocyturia."
"Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including CRIXIVAN. During the initial phase of treatment, patients responding to antiretroviral therapy whose immune system responds to CART may develop an inflammatory response to indolent or residual opportunistic infections (such as MAI, CMV, PCP, or TB), which may necessitate further evaluation and treatment."
In the "Drug Interactions" subsection, the following information
was added about Reyataz (atazanavir):
"Both CRIXIVAN and atazanavir are associated with indirect (unconjugated)
hyperbilirubinemia. Combinations of these drugs have not been studied and coadministration
of CRIXIVAN and atazanavir is not recommended."
Revisions to the Patient Package Insert (PPI)
The following wording was added to the "What are the possible side effects of CRIXIVAN?" section of the PPI:
"In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from opportunistic infections may occur when combination antiretroviral treatment is started."
In the same section, under Marketing Experience, the words "and increased cholesterol" were added so that the revised text reads: "Other side effects reported since CRIXIVAN has been marketed include: allergic reactions; severe skin reactions; yellowing of the skin and/or eyes; heart problems including heart attack; stroke; abdominal swelling; indigestion; inflammation of the kidneys; inflammation of the pancreas; joint pain; depression; itching; hives; change in skin color; hair loss; ingrown toenails with or without infection; crystals in the urine; painful urination; numbness of the mouth and increased cholesterol."
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
FDA approved, on December 23, 2003, the Uni-Gold Recombigen(TM) HIV rapid HIV
test, a single use rapid test for the detection of antibodies to HIV-1 in plasma,
serum and whole blood (venipuncture). It is the first device to be FDA approved
for use with all three sample types. Uni-Gold Recombigen HIV is intended for
use in point of care settings as an aid in diagnosis of infection with HIV-1.
Use of Uni-Gold Recombigen HIV is restricted to clinical laboratory professionals
in facilities having an adequate quality assurance program. The test is not
approved to screen donors of blood, plasma, cells or tissues, or for home use.
Uni-Gold Recombigen HIV provides results in 10 minutes. It was approved by the FDA on the basis of clinical trial results demonstrating test sensitivity of 100% and specificity of over 99.7%.
Test subjects must receive the "Subject Information Leaflet" prior to specimen collection, and appropriate counseling when test results are provided.
Positive test results require confirmation. The test is suitable for use in appropriate multi-test algorithms designed for the statistical validation of rapid HIV test results.
Product labeling will be available in the coming weeks at www.fda.gov/cber/products/testkits.htm
The Uni-Gold Recombigen HIV test is made by Trinity Biotech plc of Bray, Ireland, and distributed in the U.S. by Trinity Biotech USA, Jamestown, NY.
Richard Klein
Office of Special Health Issues
Food and Drug Administration