FDA Announces Label Changes for Darunavir (Prezista), Didanosine (Videx), and Lopinavir/ritonavir (Kaletra)

		SUMMARY: The U.S. Food and Drug Administration (FDA) last week announced that product label information for 3 antiretroviral drugs has been updated to reflect new information. The product label for darunavir (Prezista) was updated to reflect 96 week data from the ARTEMIS (treatment-naive) and TITAN (treatment-experienced) trials, as well as additional information on drug interactions and side effects. The didanosine (ddI; Videx) label adds a warning about non-cirrhotic portal hypertension, a rare but life-threatening condition, based on post-marketing reports of 42 cases (including 4 deaths). The package insert for lopinavir/ritonavir (Kaletra) now includes information about drug interactions with the asthma medication salmeterol (Serevent, Advair) and with sildenafil (Revatio) for pulmonary arterial hypertension.

By Liz Highleyman

Below are edited excerpts from the 3 recent FDA announcements.

Prezista (darunavir) labeling changes reflect 96 week study data

On January 27, 2010, FDA approved revisions to the Prezista (darunavir) product labeling to include the 96 week data from two trials; one trial in treatment-experienced patients (TMC114-C214) and one trial in treatment-naive patients (TMC114-C211).

Section 6: Adverse Reactions and Section 14 Clinical Studies were updated to reflect the updated 96 week efficacy and safety data. The 96 week efficacy results are summarized briefly below. Study TMC114-C211 [ARTEMIS] is a randomized, controlled, open-label Phase 3 trial comparing Prezista/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naive HIV-1 infected adult subjects. All patients received a fixed background regimen consisting of tenofovir disoproxil fumarate (TDF) 300 mg once daily and emtricitabine 200 mg once daily (FTC). At Week 96, 78% of patients randomized to Prezista/ritonavir were virologic successes (HIV RNA < 50 copies/mL) compared to 74% of patients randomized to lopinavir/ritonavir. Study TMC114-C214 [TITAN] is a randomized, controlled, open-label Phase 3 trial comparing Prezista/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naive HIV-1 infected adult subjects. Both arms used an optimized background regimen consisting of at least 2 antiretrovirals (nucleoside reverse transcriptase inhibitors with or without non-nucleoside reverse transcriptase inhibitors). At Week 96, 58% of patients randomized to Prezista/ritonavir were virologic successes (HIV RNA < 50 copies/mL) compared to 52% of patients randomized to lopinavir/ritonavir.

Additional revisions were made to the label and include the following: The Contraindications section (Section 4) is updated for alfuzosin (Table 2) in order to maintain consistency with the list of contraindicated medications in the ritonavir label: In Section 6.1 Clinical Trials Experience: Treatment-Naive Adults, under Less Common Adverse Reactions: drug hypersensitivity, angioedema and urticaria were added. In Section 6.2 Clinical Trials Experience: Treatment-Experienced Adults, under Less Common Adverse Reactions: urticaria was added. A new section was added to identify osteonecrosis as an Adverse Drug Reaction (ADR). Section 6.4 Additional ADRs to Prezista/ritonavir identified in adult subjects in other clinical trials. The additional ADR of interest identified from other clinical trials was osteonecrosis. The Postmarketing Experience Section (Section 6.7) was updated to include: redistribution of body fat and toxic epidermal necrolysis. Drug Interactions (Section 7), Table 7 was updated with the maraviroc drug interaction data. In summary maraviroc concentrations are increased when co-administered with Prezista/ritonavir. When used in combination with Prezista/ritonavir, the dose of maraviroc should be 150 mg twice daily. The Microbiology section (Section 12.4) is updated with additional resistance data and baseline genotype and phenotype virologic analyses and cross-resistance data.

Full product information is available online at www.prezista.com.

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 Videx or Videx EC (didanosine). 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.

Data Summary

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 (e.g., 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.
	Full product information is available online: (Videx) and (Videx EC).

On January 29, 2009, FDA approved revisions to the Kaletra (lopinavir/ritonavir) package insert to include drug-drug interaction information for concurrent Kaletra administration with inhaled medicines such as salmeterol or salmeterol in combination with fluticasone propionate (Serevent, Advair) and sildenafil (Revatio).

Specifically, sildenafil (Revatio) when used for the treatment of pulmonary arterial hypertension is listed under Contraindications (Section 4, Table 3) because a safe and effective dose has not been established when used with Kaletra. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erections and syncope. Additionally, in Section 7 Drug Interactions, Table 9 was revised to include this information and differentiate use of PDE5 inhibitors for pulmonary arterial hypertension and for erectile dysfunction.

Section 7 Drug Interactions Table 9 was revised to include the following information on salmeterol.

Concurrent administration of salmeterol and Kaletra is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Section 17 Patient Counseling Information was revised to state:

	If they are receiving sildenafil, tadalafil, or vardenafil they may be at increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor
	If they are taking or before they begin using Serevent (salmeterol) and Kaletra, they should talk with their doctor about problems these two medicines may cause when taken together. The doctor may choose not to keep someone on Serevent (salmeterol)
	If they are taking or before they begin using Advair (salmeterol in combination with fluticasone propionate) and Kaletra, they should talk to their doctor about problems these two medicines may cause when taken together. The doctor may choose not to keep someone on Advair (salmeterol in combination with fluticasone propionate).
	Similar changes were made to the Medication Guide.
	Full product information is available online at www.kaletra.com.