FDA Notifications

Entecavir (Baraclude®) labeling changed

The Food and Drug Administration (FDA) approved changes to the labeling for entecavir (Baraclude®) to provide a dosing regimen for adult patients with chronic hepatitis B (HBV) and decompensated liver disease, based on efficacy data through Week 48 and cumulative safety data from one trial.

Here are some of the label changes:

• Section 1 INDICATIONS AND USAGE was updated to include the following bullet point in this subsection:

— The following points should be considered when initiating therapy with entecavir: Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

• Section 2 DOSAGE AND ADMINISTRATION includes dosing for decompensated liver disease as follows:

— 2.1 Recommend Dosage, Decompensated Liver Disease: The recommended dose of entecavir for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.

• Section 6 ADVERSE REACTIONS was updated as follows:

— Decompensated Liver Disease: Study AI463048 was a randomized, open-label study of entecavir 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1)]. Among the 102 subjects receiving entecavir, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites [accumulation of fluid in the abdomen] (15%), pyrexia [fever] (14%), hepatic encephalopathy [brain malfunction] (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 2 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).

Eighteen of 102 (18%) subjects treated with entecavir and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the entecavir group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with entecavir and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.

No subject in either treatment arm experienced an on-treatment hepatic flare (ALT > 2 X baseline and > 10 X ULN) through Week 48. Eleven of 102 (11%) subjects treated with entecavir and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.

The complete revised labeling will be available soon on the FDA website at www.fda.gov.

FDA tentatively approves fixed-dose lamivudine/zidovudine

On Oct. 18, 2010, the FDA granted tentative approval to fixed dose combination lamivudine/zidovudine tablets, 150mg/300mg, indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. The product is manufactured by Strides Arcolab Limited of Bangalore, India. The application was reviewed under expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR).

Combination products such as this one can decrease pill burden and may result in improved dosing compliance for HIV infected individuals.

"Tentative approval" means that FDA has concluded that a drug product meets all required quality, safety and efficacy standards, but is not presently eligible for final approval for marketing in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for purchase and use outside the United States under PEPFAR.

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

This is a generic formulation of Combivir Tablets, 150 mg/300 mg, a product of VIIV Healthcare Company, which is subject to patent protection in the United States.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA website.

New risk information added to label of antiviral saquinavir

The Food and Drug Administration is notifying the public that new risk information has been added to the label of the antiviral drug saquinavir (Invirase®), describing a potential change in the electrical activity of the heart when saquinavir is used in combination with ritonavir (Norvir®). Changes in the electrical activity of the heart may lead to abnormal heart rhythms.

In February 2010, the FDA announced it was reviewing clinical trial data about a potentially serious effect on the heart from the use of saquinavir in combination with ritonavir.

This new risk information has been added to the Warnings and Precautions, Contraindications, and Clinical Pharmacology sections of the Invirase label. The FDA is also requiring a medication guide for patients using Invirase that will describe the potential risk of abnormal heart rhythms.

The medications saquinavir and ritonavir are given together to treat HIV infection. Ritonavir is given at a low dose with saquinavir to increase the level of saquinavir in the body. This process, known as 'boosting,' lowers the daily number of Invirase capsules or tablets that a patient needs to take.

The potential changes to the electrical activity of the heart associated with saquinavir/ritonavir, known as prolonged QT or PR intervals, can be seen on an electrocardiogram (EKG). This new information was derived from a clinical study designed to study a drug's impact on the electrical activity of the heart. A prolonged QT interval can lead to a serious abnormal rhythm called torsades de pointes, which can be fatal. Torsades de pointes has been reported in patients taking saquinavir/ritonavir. A prolonged PR interval can lead to a serious abnormal rhythm called complete heart block. Complete heart block has been reported in patients taking the combination.

Patients with underlying heart conditions or those who have existing heart rate or rhythm problems are at particular risk.

The revised Invirase label can be viewed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020628s033,021785s010lbl.pdf.