FDA Notifications

FDA tentatively approves efavirenz cross-scored tablets

On Feb. 12, 2010, the Food and Drug Administration (FDA) granted tentative approval for efavirenz cross-scored tablets, 200 mg, manufactured by Strides Arcolab Limited of Bangalore, India. The cross-scored tablet can be broken into two 100 mg or four 50 mg doses to facilitate pediatric dosing.

FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the U.S., existing patents and/or proprietary issues currently prevent marketing of the product in the United States. Tentative approval, however, does qualify the product for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR) program.

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

Efavirenz is a generic version of Sustiva, a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), manufactured by Bristol Myers-Squibb.

A list of all approvals and tentative approvals under these provisions can be found at http://www.fda.gov/InternationalPrograms.

Potential serious effect of combination saquinavir-ritonavir

The Food and Drug Administration (FDA) is reviewing clinical trial data about a potentially serious effect on the heart from the use of saquinavir (Invirase®) in combination with ritonavir (Norvir®). The data suggest that together the two drugs may affect the electrical activity of the heart.

The changes to the electrical activity of the heart possibly associated with these drugs, known as prolonged QT or PR intervals, can be seen on an electrocardiogram (EKG). A prolonged QT interval can increase the risk for abnormal heart rhythms, including a serious abnormal rhythm called torsades de pointes. A prolonged PR interval can cause the electrical signal responsible for generating a heart beat to slow or even stop; this is known as heart block and can affect how fast the heart is able to beat.

Saquinavir and ritonavir are antiviral medications given together to treat HIV infection. Norvir is given at a low dose with Invirase in order to increase the level of Invirase in the body. This is a process known as "boosting."

FDA's analysis of these data is ongoing. However, healthcare professionals should be aware of this potential risk for changes to the electrical activity of the heart. Saquinavir and ritonavir should not be used in patients already taking medications known to cause QT interval prolongation such as Class IA (such as quinidine,) or Class III (such as amiodarone) antiarrhythmic drugs; or in patients with a history of QT interval prolongation.

Patients should not stop taking their prescribed antiviral medications. Patients who are concerned about possible risks associated with using Invirase and Norvir should talk to their healthcare professional.

This communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. The agency will update the public as soon as this review is complete.

Additional Information for Healthcare Professionals:

The FDA recommends that healthcare professionals do the following:

  • Not use saquinavir in patients with a history of QT interval prolongation, preexisting conduction system disease, ischemic heart disease, cardiomyopathy, or underlying structural heart disease.
  • Not use saquinavir in patients who are currently using Class IA (such as quinidine) or Class III (such as amiodarone) antiarrhythmic drugs or other drugs that may prolong the QT or PR interval.
  • Report any adverse events associated with the use of Invirase to FDA's MedWatch program at 1-800-332-1088, or MedWatch Online.

The study data were submitted by Roche, the manufacturer of Invirase, based on FDA's request that all manufacturers of protease inhibitors, including Invirase, conduct a thorough QT study to evaluate the effect these drugs have on the QT and PR intervals.

The preliminary data show that when saquinavir boosted with ritonavir (1000mg/100mg) was given to healthy patients, ages 18 to 55 years, there was a dose-dependent prolongation of the QT and PR intervals. The magnitude of the effect and clinical implications of QT and PR interval prolongation are still being reviewed by FDA.

These findings suggest that some patients using the combination may be at an increased risk for developing abnormal heart rhythms. In particular, this risk may be increased in patients using other medications known to cause QT interval prolongation such as Class IA and Class III antiarrhythmic drugs or in patients with a history of QT interval prolongation.

Rare complication with didanosine

The Food and Drug Administration (FDA) is alerting healthcare professionals and patients about a rare, but serious, complication in the liver known as non-cirrhotic portal hypertension in patients using didanosine (Videx®) or Videx EC. Didanosine is a medication used to treat human immunodeficiency virus (HIV) infection.

Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down. This slowed blood flow can lead to the development of severely enlarged esophageal veins (varices) in the gastrointestinal system. Because esophageal varices are thin and portal hypertension increases the pressure of blood flow in these veins, esophageal varices can break open. This can result in serious bleeding and, in some cases, death.

FDA became aware of cases of non-cirrhotic portal hypertension through adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the didanosine drug label to include information about non-cirrhotic portal hypertension to help ensure the safe use of this drug.

FDA believes the clinical benefits of didanosine for certain patients with HIV continue to outweigh its potential risks. The decision to use this drug, however, must be made on an individual basis between the treating physician and the patient.

Additional Information for Healthcare Professionals:

• Be aware that didanosine use has been associated with the development of non-cirrhotic portal hypertension.

• Discuss with patients the clinical benefits and potential risks, including the risk of non-cirrhotic portal hypertension, with the use of didanosine.

• Continue to monitor patients for the development of portal hypertension and esophageal varices.

• Be aware that didanosine already has a Boxed Warning for lactic acidosis and hepatomegaly with steatosis.

• Didanosine in combination with other antiretroviral agents as well as hydroxyurea or ribavirin has been associated with the development of liver toxicity.

The FDA's decision to revise the drug label for didanosine is based on post-marketing reports of patients developing non-cirrhotic portal hypertension while using didanosine. Other liver adverse events such as lactic acidosis, hepatomegaly with steatosis, and liver failure have been reported with the use of didanosine alone and in combination with other antiviral drugs.

Of the 42 post-marketing cases of non-cirrhotic portal hypertension in patients using didanosine:

• Twenty-six were males, 14 were females, and in two no gender was specified.

• The ages ranged from 10 years to 66 years.

• Duration of didanosine treatment ranged from months to years before development of non-cirrhotic portal hypertension.

• Definitive cases of non-cirrhotic portal hypertension were confirmed by biopsy and had no alternative etiology for the diagnosis.

• Medical interventions described in the reported cases included:

- Banding/ligation of esophageal varices in 8 patients.

- Transjugular intrahepatic portosystemic shunt (TIPSS) procedure in three patients.

- Liver transplantation in 3 patients.

- There were four deaths total in the 42 reported cases.

The cause of death in the four patients was due to:

- Hemorrhage from esophageal varices in two patients.

- Progressive liver failure in one patient.

- A combination of multi-organ failure, cerebral hemorrhage, sepsis, and lactic acidosis in one patient.

The only patients who have been reported as fully recovered are the three non-cirrhotic portal hypertension patients who received a liver transplant.

A causal association is difficult to determine from postmarketing reports alone. However, based on the number of well-documented cases and exclusion of other causes of portal hypertension such as alcohol-related cirrhosis or hepatitis C, FDA concludes there is an association between use of didanosine and development of non-cirrhotic portal hypertension. Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.

The Videx EC and Videx Pediatric Powder for Oral Solution were revised as follows:

• In Highlights section of the package insert under Warnings and Precautions, the following was added: Non-cirrhotic portal hypertension: Discontinue didanosine in patients with evidence of non-cirrhotic portal hypertension

• In section 5 Warnings and Precautions the following new subsection was added:

5.4 Non-cirrhotic Portal Hypertension - Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Patients receiving Videx should be monitored for early signs of portal hypertension (eg. Thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Videx should be discontinued in patients with evidence of non-cirrhotic portal hypertension

• In section 17 Patient Counseling Information the following was added: 17.5 Non-cirrhotic Portal Hypertension — Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking Videx, including cases leading to liver transplantation or death.

Videx and VidexEC are Nucleoside Reverse Transcriptase Inhibitors (NRTIs), products of Bristol Myers-Squibb.