RPR ZAGAM ONCE-DAILY EFFICACY IN COMMUNITY-ACQUIRED PNEUMONIA EQUIVALENT TO ERYTHROMYCIN AND CEFACLOR; FLUOROQUINOLONE LAUNCH SET FOR FIRST QUARTER 1997

Zagam labeling contains data comparing the fluoroquinolone to erythromycin and cefaclor in community-acquired pneumonia, showing similar clinical success rates. Rhone-Poulenc Rorer's Zagam (sparfloxacin) gained approval on Dec. 19.

"The patient clinical success and pathogen eradication rates for sparfloxacin were equivalent to those of the comparators," labeling says. Sparfloxacin eradication rates ranged from 83% to 97% depending on the pathogen, while those for erythromycin ranged from 75% for Chlamydia pneumoniae to 90% to 100% for other pathogens. Eradication rates with cefaclor ranged from 76% to 100%.

Zagam labeling also contains a clinical comparison of sparfloxacin and ofloxacin (Ortho-McNeil's Floxin) for treatment of acute bacterial exacerbations for chronic bronchitis. Sparfloxacin pathogen eradication rates ranged from 82% to 100% depending on the organism and ofloxacin ranged from 80% to 97%.

Zagam's dosing could prove more convenient to patients over the comparative therapies. Erythromycin is taken two to four times per day, Cefaclor (Lilly's Ceclor) is taken three times daily and Ceclor CD has a twice-daily dosing schedule. Ortho-McNeil's once-daily Levaquin (levofloxacin) was approved in December for community-acquired pneumonia, chronic bronchitis and additional indications.

"The recommended daily dose of Zagam in patients with normal renal function is two 200-mg tablets taken on the first day as a loading dose," labeling states. "Thereafter, one 200-mg tablet should be taken every 24 hours for a total of 10 days of therapy." The drug is supplied in 200 mg tablets, which come in blister packs of eleven, or bottles containing 50 tablets. RPR plans to launch Zagam in the first quarter of 1997.

Zagam is indicated for community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, or Streptococcus pneumoniae.

Sparfloxacin is also indicated for acute bacterial exacerbations of chronic bronchitis caused by Chlamydia pneumoniae, Enterobacter cloacae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, or Streptococcus pneumoniae.

RPR filed an NDA for Zagam on Dec. 27, 1995 for the two approved indications and an acute maxillary sinusitis indication, for which it did not receive approval ("The Pink Sheet" March 4, In Brief). The company plans to conduct additional studies for the sinusitis indication. RPR has also studied sparfloxacin in skin infections and complicated urinary tract infections.

Zagam labeling bears a bolded warning concerning phototoxicity for patients being treated with the drug. "Moderate to severe phototoxic reactions have occurred in patients exposed to direct or indirect sunlight or to artificial ultraviolet light...during or following treatment," labeling warns.

"These reactions have also occurred in patients exposed to shaded or diffuse light, including exposure through glass or during cloudy weather." Patients are advised to discontinue therapy "at the first signs or symptoms of a phototoxicity reaction."

"Exposure to direct and indirect sunlight (even when using sunscreens or sunblocks) should be avoided while taking sparfloxacin and for five days following therapy," labeling instructs. "These phototoxic reactions have occurred with and without the use of sunscreens or sunblocks and have been associated with a single dose of sparfloxacin." In clinical trials of 1,585 patients, 7.9% experienced drug-related phototoxicity. The events ranged from mild, 4.1%, to moderate, 3.3%, to severe, .6%.

Zagam is contraindicated for patients receiving disopyramide, amiodarone and other QTc-prolonging antiarrhythmic drugs due to reported incidents of torsade de pointes.

Mean increases in the QTc interval were observed in healthy volunteers, labeling states. "After a single loading dose of 400 mg, a mean increase in QTc interval of 11 msec (2.9%) is seen; at steady-state the mean increase is 7 msec (1.9%)," labeling says. "The magnitude of the QTc effect does not increase with repeated administration, and the QTc returns to baseline within 48 hours of the last dose."

Labeling also includes information for patients which warns that "sparfloxacin may cause neurologic adverse effects" such as dizziness and lightheadedness. Patients are warned to observe their reactions to the drug "before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination."

Patients are informed that the drug can be taken "with food or milk or caffeine-containing products." Erythromycin labeling instructs patients to wait an hour before eating after taking the drug. Mineral supplements, vitamins with iron, zinc or calcium, and sucralfate or magnesium- and aluminum-containing antacids "may be taken four hours after sparfloxacin administration.

Labeling notes that "aluminum and magnesium cations in antacids and sucralfate form chelation complexes with sparfloxacin." Additionally, "the oral bioavailability of sparfloxacin is reduced when an aluminum- magnesium suspension is administered between 2 hours before and 2 hours after sparfloxacin administration."

Discontinuation rates due to adverse events in clinical trials of 3,000 patients were 6.6% for sparfloxacin, compared to 5.6% for cefaclor, 14.8% for erythromycin, 8.9% for ciprofloxacin, 7.4% for ofloxacin, and 8.3% for clarithromycin.

The most frequently reported adverse events among patients receiving sparfloxacin in clinical trials were: photosensitivity reaction (7.9%), diarrhea (4.6%), nausea (4.3%), headache (4.2%), dyspepsia (2.3%), dizziness (2%), insomnia (1.9%), abdominal pain (1.8%), pruritus (1.8%) taste perversion (1.4%), QTc interval prolongation (1.3%), vomiting (1.3%), flatulence (1.1%) and vasodilatation (1%).

Safety data from comparative studies show a similar adverse event rate for sparfloxacin and cefaclor and lower than erythromycin. Diarrhea occurred in 3.9% of sparfloxacin patients compared to 15.8% for erythromycin and 4.3% for cefaclor. The incidence of nausea was 2.8% for sparfloxacin, 15.3% for erythromycin and 2.5% with cefaclor. Vomiting occurred in 2.6% of sparfloxacin patients compared to 7.2% for erythromycin and .6% for cefaclor. Abdominal pain rates were sparfloxacin (1.6%), erythromycin (8.6%) and cefaclor (1.2%).

In comparison with ofloxacin, 7.3% of patients taking sparfloxacin experienced photosensitivity reaction compared to 1.5% of patients taking ofloxacin. Nausea events were reported in 4.1% of sparfloxacin patients and 7.2% of ofloxacin patients. Insomnia was experienced by 1% of patients taking sparfloxacin and 11.4% of patients taking ofloxacin.

Warner-Lambert will receive royalties on sales of sparfloxacin in the U.S. under a sub-licensing agreement signed with RPR in April 1994.

Warner-Lambert acquired rights to the antibiotic for the U.S. from Dainippon in 1989, while RPR had a separate licensing agreement with Dainippon for sparfloxacin in the European market. Warner-Lambert had been developing sparfloxacin separately for Mycobacterium avium in AIDS patients, but dropped development of the product to pursue clinical trials of its own quinolone clinafloxacin, which is in Phase III.