FDA Notifcations

Kaletra revisions to packaging approved

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

Specifically, sildenafil — 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 lopinavir/ritonavir. 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. Kaletra is a product of Abbott Laboratories.

Labeling changed on Prezista

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

The updated labeling will be posted soon at Drugs@FDA. Darunavir (Prezista) is a protease inhibitor made by Tibotec, Inc.

Updated Atripla label approved

On Jan. 7, 2010, the FDA approved an updated efavirenz/emtricitabine/tenofovir (Atripla®) label.

It includes new efficacy, safety and resistance data in treatment experienced patients from a trial (Study 073) in which HIV-1 infected adults on a stable antiretroviral regimen were either switched to Atripla or remained on their background regimen to compare the effectiveness (efficacy, safety, and tolerability) of Atripla to that of subjects continuing unmodified HAART as measured by the proportion of subjects who maintain HIV-1 RNA <200 copies/mL on their original assigned regimen at Week 48 based on the time-to-loss of virologic response (TLOVR) analysis.