Same Data, Same Day, Different Decision: FDA, EMA On Roche's Protease Inhibitor Invirase

FDA goes for a new warning and a MedGuide; EMA calls for a lower starting dose.

Looking at data from the same Roche-sponsored cardiac safety study of its HIV protease inhibitor Invirase (saquinavir), FDA and EMA took different approaches to managing the risk.

FDA announced Oct. 21 that it has asked Roche to add a cardiac safety warning to the label and to develop a Medication Guide to be given to patients that will include information on the risk of abnormal heart rhythms. The same day, EMA's Committee for Medicinal Products for Human Use (CHMP) recommended that treatment-naive patients take a reduced dose of Invirase during the first week of treatment as a precautionary measure.

"QT and PR interval prolongations have been observed in a healthy volunteer study," the version of the Invirase label FDA approved Oct. 6 says. "Use with caution in patients with preexisting conduction system abnormalities and certain heart diseases."

FDA and EMA have gone in different directions on higher profile drug safety questions recently.

For example, on Jan. 21 Abbott withdrew its anti-obesity drug Meridia (sibutramine) from the European Union markets at the urging of the European Medicines Agency, while in a same-day announcement FDA contented itself with asking the company to strengthen the labeling to contraindicate use of the drug in people with a history of cardiovascular disease, including heart attack, stroke, heart arrhythmias and uncontrolled hypertension (Also see "Weighing Obesity Risk: FDA, EMEA Use Different Scales For Abbott's Meridia" - Pink Sheet, 21 Jan, 2010.). In October, Abbott voluntarily withdrew the drug from the U.S. market as well (Also see "REMS Cannot Save Abbott's Obesity Drug Meridia In Face Of Cardiovascular Issues" - Pink Sheet, 8 Oct, 2010.).

In another high-profile trans-Atlantic regulatory divergence, FDA decided to keep GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone) on the market with a strong Risk Evaluation and Mitigation Strategy that calls for strict distribution restrictions, while CHMP recommended suspension of the drug's marketing authorization after concluding it could not identify additional measures, beyond current labeling restrictions, to reduce the cardiovascular risks that were deemed to outweigh the drug's benefits (Also see "FDA, EMA Decisions On Avandia Reflect The Power Of REMS" - Pink Sheet, 27 Sep, 2010.).

The disparities are not always safety-related; FDA is taking more time than EMA to review the application for AstraZeneca's antithrombotic ticagrelor as it mulls the lower efficacy seen in North American patients (Also see "AstraZeneca's Ticagrelor Gets Positive EU Recommendation, But FDA Could Catch Up Soon" - Pink Sheet, 24 Sep, 2010.).

It seems that Invirase presents yet another case of EMA taking stronger regulatory action to tackle a perceived drug risk than FDA chooses to take based on the same data, although here the split is less dramatic.

A Class-wide Study Results Produces Product-specific Labels

FDA asked Roche to conduct the clinical trial, which enrolled 59 healthy adults on whom electrocardiogram measurements were performed on their third day taking the drug, and issued an early communication about it in February, when the agency was still evaluating the results. Changes in portions of the subjects' EKGs called QT and PR intervals can point to risks of dangerous heart arrhythmias.

FDA has asked manufacturers of other HIV protease inhibitors to conduct thorough QT studies if they have not already done so. The agency explained in an email that "QT studies are now routinely done as part of drug development, so more recently approved PIs have QT studies." FDA's draft guidance on thorough QT studies appeared in 2004, and the final version in October 2005. However, FDA declined to say which manufacturers it had specifically asked to do the studies.

Invirase was the first HIV protease inhibitor FDA approved; it was approved in December 1995. Norvir followed in March 1996. The most recent version of the latter drug's label, approved April 27, states, "PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval."

FDA has not requested any additional update for the Norvir label as a result of its action on Invirase, Abbott said. The company manufactures another HIV protease inhibitor, Kaletra (lopinavir), which was originally approved in September 2000. Kaltera's label has also been updated with cardiac safety information, the company says.

Other protease inhibitors include Merck's Crixivan (indinavir) (approved in March 1996); Agouron Pharmaceuticals' Viracept (nelfinavir) (March 1997); Viiv Healthcare's Agenerase (amprenavir) (April 1999) and Lexiva (fosamprenavir) (October 2003); Bristol-Myers Squibb's Reyataz (atazanavir) (June 2003); Boehringer-Ingelheim's Aptivus (tipranavir) (June 2005) and Tibotec's Prezista (darunavir) (June 2006).

BMS has conducted a thorough QT study for Reyataz, and the latest label for the drug, approved April 26, states that "PR interval prolongation may occur in some patients. Use with caution in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval." Boehringer Ingelheim also conducted a thorough QT study and has updated Aptivus' label accordingly, the company said.

Merck's Crixivan, on the other hand, avoids the QT study altogether. "We have reviewed data from Crixivan clinical trials and post-marketing experience with the FDA," the company said. "A compelling signal for an effect or an association with Torsades de Pointes was not observed during clinical development, or since approval, and the FDA agreed that conducting a thorough QT study was not warranted at the time. We continue to monitor all reports of post-marketing adverse events."

Invirase Label Notes Complete Heart Block

Invirase's U.S. labeling notes that "complete heart block has been reported in patients taking Invirase with Norvir. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems."

In the QT study, "the maximum mean time-matched (95% upper confidence bound) differences in QTcS interval from placebo after baseline-correction were 18.9 (22.0) and 30.2 (33.4) msec for the approved dose of 1000/100 mg twice daily and a supratherapeutic dose of 1500/100 mg twice daily of Invirase/Norvir, respectively," labeling states.

"Although based on multiple cross-study comparisons, the Day 3 mean Cmax of Invirase/Norvir 1000/100 mg twice daily in this healthy volunteer study was estimated to be about threefold higher than the mean steady state Cmax observed with Invirase/Norvir 1000/100 mg twice daily in HIV-1 infected patients," labeling states. "In the same study, PR interval prolongation of >200 msec was also observed in 40% and 47% of subjects receiving Invirase/Norvir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3."

- Martin Berman-Gorvine ([email protected])