Increased vomiting associated with one-day Zithromax will be a focal point of GlaxoSmithKline's promotional response to the improved dosing for Pfizer's acute otitis media product.

Sales reps for GSK's Augmentin ES-600 will tell doctors that the increased vomiting for one-day Zithromax (azithromycin for oral suspension) dosing creates prescribing uncertainty. A number of the scripts will need to be replaced, necessitating additional communication with the doctor.

The physician will have to make an educated guess about how to replace the script because the amount of drug actually absorbed is unknown, reps will argue.

GSK reps will describe a vomiting rate of more than 10% in patients receiving the single Zithromax dose. However, labeling states that the Zithromax single dose had a 4.9% vomiting rate; the three-day dose had 2.3%. Previously approved five-day dosing had a rate of 1.1%.

Augmentin ES-600 (amoxicillin/clavulanate potassium powder for oral suspension) labeling notes a vomiting rate of 2.2% for its 10-day, twice-daily regimen.

GSK reps will maintain that the new Zithromax dosing could represent a trade-off between convenience and effectiveness and will argue that the most effective dosing is the one that works the first time.

The reps will provide information in response to doctors' questions on Zithromax, but will not actively counter-detail the product.

The Zithromax trial design will also be criticized by GSK reps. The majority of enrollees in the pivotal trials were children over two who often demonstrate higher rates of spontaneous recovery due to more mature immune systems, reps will note.

Another Zithromax study design issue that GSK will focus on is the use of a primary clinical endpoint of test of cure at 28 days. GSK sales reps will point out that within that time period, acute otitis often resolves without treatment.

Zithromax labeling however, does contain clinical efficacy data taken from subjects at the end of treatment (day 12 for three-day dose and day 12 to 16 for the single-dose protocol).

GSK will also point to the exclusion of children treated with antibiotics within 30 days, which reduces the potential for non-responders due to infection with a resistant bacterial strain.

GSK maintains that although Zithromax trials met FDA's minimal acute otitis media study requirements, Pfizer only performed a single tympanocentisis at baseline, whereas Augmentin ES-600 trials used a double-tap methodology. By eliminating the second tympanocentisis, eradication was never fully accessed for one- and three-day Zithromax.

GSK's promotional response will note the lack of pharmacokinetic data for children less than three years of age and the lack of PK data for single-dose Zithromax. Pfizer obtained PK data on 34 children ages 3 to 16 for the three-day regimen, but did not conduct a PK evaluation of pediatric patients on the single dose.

The lack of PK data on the single dose regimen and the issue of re-dosing and actual drug exposure for children who vomit the single Zithromax dose were concerns expressed by Anti-Infective Drugs Advisory Committee members during a Nov. 7 meeting (¹ Also see "Pfizer Zithromax Otitis Media Single-Dose Needs PK Studies, Cmte. Says" - Pink Sheet, 12 November, 2001., p. 27).

Zithromax trials for the improved dosing compared the product to Augmentin but not Augmentin ES-600. FDA cleared the one- and three-day dosing for Zithromax Dec. 17 (see ² Also see "Pfizer Zithromax Short Regimen Promotions Will Include Patient Brochure" - Pink Sheet, 24 December, 2001. ). Augmentin ES was approved on June 22 and launched in October (³ Also see "Augmentin ES-600 Label Places Limit On Use For Penicillin-Resistant Strains" - Pink Sheet, 2 July, 2001., p. 17).

GSK's promotions for Augmentin ES-600 also include a direct-to-consumer mailing for parents containing information on "tough ear infections" and an offering for a free ear infection information kit.

"It's the only antibiotic specifically formulated for tough ear infections, especially those that keep coming back," the brochure states.

In addition to competitive pressure from the new Zithromax dosing regimens, Augmentin ES-600 might also face challenges from Bristol-Myers Squibb's antibiotic Tequin (gatifloxacin).

Results from a Phase II trial program examining Tequin's efficacy for recurrent or difficult-to-treat acute otitis media were presented at the Interscience Conference On Antimicrobial Agents and Chemotherapy in Chicago, Ill. Dec. 18.

In an ongoing, open-label Phase II study, 254 children (ages six months to seven years) were given a once-daily 10 mg/kg dose of Tequin (oral suspension) for 10 days. Preliminary results from 58 patients demonstrate that in those with identified pathogens from the initial tympanocentisis, Tequin eliminated more than 90% of all pathogens from the middle ear fluid within three to five days.

In data available on 233 patients, vomiting occurred in 15% of patients and diarrhea in 5%. Bristol is considering designing a new formulation for the antibiotic to decrease the number of adverse events.

Bristol might also be looking at a Tequin five-day dosing regimen for acute sinusitis in adults. Data from a 445-patient trial presented at the Dec. 18 ICAAC meeting showed the five-day regimen had a 75% clinical cure rate as compared to 80% for the 10-day Tequin regimen and 72% for 10-day Augmentin.

GSK is facing a patent challenge on Augmentin from Teva, Geneva and Ranbaxy. Teva has recently filed to consolidate its suit with Geneva, although no ruling has been made on the motion. If a judgement is not made on the eight Augmentin patents challenged by Geneva, a hearing will be conducted in May 2002.

GSK announced Dec. 17 that a federal judge had ruled in its favor on a patent expiring in December 2002 but ruled in Teva's favor on a GSK patent related to beta-lactamase that is expiring in 2018. GSK plans to appeal as soon as a decision is made in the eastern district of Virginia federal court on the litigation with Geneva.

The extended release tablet Augmentin XR received a "not-approvable" letter from FDA Dec. 14.GSK filed the Augmentin XR application in December 2000 for the treatment of respiratory tract infections including sinusitis in adults.

FDA has asked GSK to submit additional bacteriologic efficacy data for Augmentin XR in the treatment of patients with respiratory tract infections due to penicillin-resistant S. pneumoniae. The company plans to re-submit the GSK application in the next few months.

The resubmission will not require additional trials to be conducted, but rather a submission of data that has already been collected from an ongoing Augmentin XR trial program, GSK said.

GSK Augmentin Response To Zithromax: One-Day Dosing Offset By Vomiting

More from Archive

More from Pink Sheet