Schering-Plough's clinical data for desloratadine supports a one-to-two hour onset of action claim for the antihistamine, the European Public Assessment Report states.

"The onset of action for desloratadine has been demonstrated to occur from one to two hours after administration," the review document states. The EPAR cites "three onset of action studies utilizing controlled-exposure chambers," which "showed that the subjects first became aware of significant improvement in their [seasonal allergic rhinitis] symptoms as early as one hour 15 minutes and up to two hours following desloratadine 5 mg."

Desloratadine was approved in Europe Sept. 21 under the trade names Neoclarityn and Aerius (¹ Also see "Schering To Market Loratadine Metabolite As Aerius In Europe" - Pink Sheet, 16 October, 2000.). The Claritin (loratadine) follow-on agent is pending at FDA under the trade name Clarinex.

Schering's initial regulatory filing included data from four onset of action studies (three in controlled-exposure chambers and one in an outdoor setting) for review. A total of 783 patients were evaluated and 508 received desloratadine.

Two of the three controlled-exposure studies evaluated onset of action of 5 mg or 7.5 mg desloratadine compared to placebo. "Both studies that evaluated desloratadine 7.5 mg determined the onset of action as three hours 30 minutes," the EPAR states. "The reason why the 7.5 mg dose had an apparently longer onset of action than the 5.0 mg dose is not clear."

In response to questions from the EU regulators, Schering submitted results of an open-label, non-comparative study assessing the onset of action of 5 mg desloratadine administered to 28 subjects during exposure to grass pollen.

The median time to onset in the open-label study was 48.5 minutes. "The results obtained are consistent with the 75-minute onset time obtained" in the earlier study, the EPAR states.

A rapid onset of action is one of the features Schering hopes to use to move the market from Claritin to the successor product.

Another of Schering's promotional points for the launch of Neoclarityn in the U.K. -that the product has a nasal decongestant effect - is not supported by the EPAR.

The review document notes that Schering studied cough as a separate symptom relief endpoint in three of its four pivotal studies. "In none of these studies did the change between mean baseline and mean post treatment values attain statistical significance compared to placebo," the EPAR states. "This is also the case for the symptom nasal congestion."

Schering's launch materials for Neoclarityn in the U.K. include a claim that the product is "effective at relieving nasal congestion," citing a 25% improvement in nasal symptom scores.

The EPAR also does not include any statements about cytokine inhibition by desloratadine. The company's U.K. launch materials cite data showing an effect on several cytokines that may have a role in asthma (² Also see "Schering Desloratadine Launch Ads In U.K. Include Decongestant Claim" - Pink Sheet, 12 February, 2001.).

The EU reviewers also concluded that "the clinical efficacy of 5 mg desloratadine is probably not superior to 10 mg loratadine" based on the differences in mean reduction in symptom scores between desloratadine and placebo with other antihistamines.

"Moreover, pharmacokinetic data show that desloratadine exposure is essentially similar after 5 mg desloratadine and 10 mg loratadine," the EPAR states.

Schering's efficacy trials "showed desloratadine 5 mg and 7.5 mg to be superior to placebo and the effect of the two desloratadine doses not to be significantly different," the EPAR states.

"During the first two weeks of treatment, pooled data showed a mean symptom reduction with desloratadine 5 mg of 27.7% versus a placebo reduction of 19.4%," the EPAR states. The mean symptom reduction for 7.5 mg desloratadine was 27.4%.

"The mean change following desloratadine 5 and 7.5 mg might be statistically significantly higher than following placebo," the EPAR observes, "but the numerical difference is small."

The average improvement in symptom scores ranged from 4.2 to 5.1 points in desloratadine groups, while the average improvement in the placebo group ranged from 2.5 to 3.9 points.

However, the EPAR notes, "the reduction of symptom scores was between 25% and 30% from baseline, which seems to be in concordance with the effect seen for other antihistamines" in seasonal allergic rhinitis.

The most common treatment-related adverse event associated with desloratadine was headache, "with 6% in the desloratadine 5 mg group and 4% in the placebo group," the EPAR states. Other "frequently" reported adverse events were dry mouth (3% for desloratadine, 2% for placebo), fatigue (3% vs. 2%) and somnolence (2% in each group).

"The enzyme(s) as well as the tissue site(s) responsible for the metabolism of desloratadine to its primary metabolite 3-OH-desloratadine has not yet been identified," the EPAR notes. "However, it is anticipated that the potential for PK interactions of desloratadine is low, as the metabolism does not appear to be mediated by a known cytochrome P450 enzyme."

However, "the polymorphism seems not to be related to the classical CYP isoenzymes and drug interactions are therefore anticipated to be less than for loratadine," the EPAR notes.

Schering studied effects of desloratadine on QT intervals. No effect was seen, the EPAR states.

One issue that came up during the European review was the length of the clinical trials (2-4 weeks). The EPAR notes that Schering received scientific advice from the Committee for Proprietary Medicinal Products in 1998 to the effect that 4-6 weeks is a typical study duration for antihistamines.

Schering "explained that the available patient population is actually not reliably symptomatic (for the purposes of an efficacy clinical trial) for more than 2-4 weeks." Since trial subjects were required to have moderate to severe symptoms, they were likely enrolled "at the peak of their exposure to the pollen they were sensitized to."

"This peak will not last for four weeks," the EPAR notes. "Therefore, subjects in the placebo groups (as well as those receiving desloratadine) were very likely exposed to a progressively decreasing amount of pollen throughout the study."

All four pivotal trials reviewed in the EU were conducted in the U.S. and presumably formed the basis for the FDA review of desloratadine for the U.S. market.

However, the agency is placing approval of desloratadine on hold until Schering resolves good manufacturing practices deficiencies at certain facilities. Desloratadine was deemed "approvable" Jan. 19 (³ Also see "Schering-Plough Clarinex NDA Approval Awaits Resolution Of GMP Problems" - Pink Sheet, 19 February, 2001.).

Manufacturing issues were raised during the EU review. Schering has "been asked as a follow up measure to re-evaluate and if necessary, tighten the limits for degradation products in the finished product specifications, as soon as the 36 month stability data are available," the EPAR notes.

"The results from three production scale batches initially provided for the U.S. site (which is not proposed for the European market) showed loss of excipients during the granulation process," the EPAR notes.

"Certificates of analysis for three batches from the proposed manufacturing site in Italy were submitted" in response to questions from the EU regulators and "all results are within specifications," the EPAR continues.

The CPMP decided not to request an inspection of the manufacturing sites, the EPAR notes.

Schering's Comazzo, Italy facility will manufacture desloratadine in finished doses for the EU. The plant does not do any manufacturing for the U.S.

FDA inspection documents from a January inspection of the company's Kenilworth, N.J. plant indicates that Schering has manufacturing capacity for the U.S. market in New Jersey and Puerto Rico.

Bulk desloratadine is produced by Schering in Ireland and Singapore for the European market, the EPAR notes.

One of FDA's inspectional observations related to Clarinex questioned whether Schering has sufficient comparability data to demonstrate the equivalence of the two sources of bulk supply (⁴ Also see "Claritin Supply Sufficient For Spring, Schering Says; FDA Lists GMP Problems" - Pink Sheet, 5 March, 2001.).

Schering Desloratadine Onset Of Action Is 1-2 Hours - EU Review Document

More from Archive

More from Pink Sheet