FDA Notifications

Entecavir revision made by FDA and BMS

The Food and Drug Administration (FDA) and Bristol-Myers Squibb are notifying healthcare professionals of revisions to the microbiology/Antiviral Activity and indications and usage/Description of Clinical Studies/Special Populations sections of the prescribing information for entecavir (Baraclude), a nucleoside analog used in the treatment of chronic hepatitis B virus (HBV).

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

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

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

You can read the manufacturer's Dear Healthcare Provider Letter at: www.fda.gov.

FDA tentatively approves 3-drug tablet in India

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

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

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

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

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

Enfuvirtide has new instructions

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

1. The following section was added under PRECAUTIONS:

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

2. The following bullet was added under PRECAUTIONS, Information for Patients: section:

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

3. The following paragraph was added under ADVERSE REACTIONS, Local Injection Site Reactions section: Biojector 2000 Needle-Free Device:

Adverse events associated with the use of the Biojector 2000 needle-free device for administration of enfuvirtide have included: nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas.

4. The following section under DOSAGE AND ADMINISTRATION changed to:

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

5. The second to last paragraph under Subcutaneous Administration now reads:

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

6. The following was added under the HOW SUPPLIED section:

Biojector is a trademark of Bioject Medical Technologies, Inc. Patient Package Insert (compared to S-007 final printed labeling)

7. The following bullet under How should I use FUZEON? Section was changed to:

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

8. The following section was added under What are the possible side effects of enfuvirtide?

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

9. The following sentence was added under the Changes since the last version of this leaflet section:

Clarification of appropriate injection sites for enfuvirtide and addition of side effects when injecting with Biojector 2000 needle-free device.

10. The following statement was added to the last page:

Biojector is a trademark of Bioject Medical Technologies, Inc.

You can access the complete, revised label on the Daily Med site, at http://dailymed.nlm.nih.gov

Fuzeon is a distributed by Roche Pharmaceuticals.

Sustiva packaging instructions updated

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

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

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

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

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