WARNER-LAMBERT CEREBYX (FOSPHENYTOIN) WILL BE AVAILABLE IN SEPTEMBER; I.V. DILANTIN TO BE DISCONTINUED AT YEAR-END: CEREBYX PRICED AT PREMIUM TO DILANTIN

Warner-Lambert will launch Cerebyx (fosphenytoin injection) in September following FDA's Aug. 5 approval of the Dilantin prodrug.

Cerebyx is approved for "the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery" and for short-term substitution for oral phenytoin (Dilantin). FDA classified Cerebyx "1S," a new molecular entity receiving standard review. The drug became "approvable" at the agency in February; Warner-Lambert submitted the NDA in February 1995.

Warner-Lambert will discontinue marketing of I.V. Dilantin on Jan. 1, 1997 in favor of the follow-on compound. Oral Dilantin still will be available. The company stressed that Cerebyx offers "improved infusion site tolerance, more rapid rate of I.V. administration than Dilantin, and a well-tolerated intramuscular injection option."

Warner-Lambert will notify I.V. Dilantin prescribers of the discontinuation through direct mail, advertising and sales reps, the company indicated. The hospital sales force has been increased for the launches of the anti-arrythmic Procanbid in April and the upcoming Cerebyx launch ("The Pink Sheet" April 15, p. 13).

Representatives of Warner-Lambert's pharmaceuticals business Parke-Davis will conduct in-service education on the switch from I.V. Dilantin to Cerebyx at 500 hospitals treating large numbers of seizure patients, the company said. Other hospitals will receive company information on the differences between the two anticonvulsants, and Warner-Lambert has established a toll-free telephone line for questions. Advertising will be handled by Cline, Davis & Mann.

The average wholesale price of Cerebyx will be $45 per 10 mL vial, Warner- Lambert said. Cerebyx 10 mL is equivalent, per milligram, to 5 mL of I.V. Dilantin, which costs $3.50. Warner-Lambert will provide hospitals with formulary kits, including pharmacoeconomic data, supporting inclusion of Cerebyx on formularies.

I.V. phenytoin is available generically; ANDAs are held by Solopak, Smith & Nephew, Lyphomed, Marsam, Barre, Sanofi Winthrop, Elkins-Sinn and Abbott. Warner-Lambert posted first quarter sales of the Dilantin line of $80 mil. ("The Pink Sheet" April 22, T&G-5).

Local intolerance to infusion was reported by 9% of I.V. Cerebyx users (n=90), compared to 90% of I.V. Dilantin patients (n=22), according to labeling. Disrupted infusion occurred with 21% of Cerebyx patients v. 67% of I.V. Dilantin patients.

"Infusion disruptions in Cerebyx-treated patients were primarily due to systemic burning, pruritis, and/or paresthesia," labeling states, "while those in phenytoin-treated patients were primarily due to pain and burning at the infusion site." Paresthesia and pruritus associated with Cerebyx "were dose and rate related," the company said. Paresthesia occurred in 4.4% of Cerebyx patients and no Dilantin patients. Pruritis occurred in 48.9% of Cerebyx users and 4.5% of Dilantin patients, according to labeling.

Bold lettering in the Cerebyx label emphasizes dosing rates. "The typical Cerebyx infusion administered to a 50 kg patient would take between 5 and 7 minutes," labeling states. "The delivery of an identical molar dose of phenytoin using parenteral Dilantin...cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min."

Due to the potential for "severe cardiovascular reactions" to phenytoin, "careful cardiac monitoring is needed when administering I.V. loading doses of Cerebyx," labeling warns. Hypotension occurred in 7.7% of Cerebyx and 9.1% of Dilantin I.V. patients. Vasodilation occurred at rates of 5.6% and 4.5%, respectively, labeling states.

The label stresses that Cerebyx should not be administered at rates greater than the equivalent of 150 mg phenytoin/min. Cerebyx 75 mg/mL is "equivalent to 50 mg/mL phenytoin sodium after injection," labeling notes. Unlike phenytoin, Cerebyx is water-soluble, Warner-Lambert said. "It can be mixed with common I.V. fluids." The company also noted that "Cerebyx does not contain I.V. phenytoin's ethanol and propylene glycol vehicles, and has a more physiological pH of 8.6 to 9.0 compared to a pH of 12.0 with I.V. phenytoin."

Like phenytoin, Cerebyx is not indicated for treatment of absence seizures or for "seizures due to hypoglycemic or other metabolic causes," labeling notes. IM Cerebyx should not be used for treatment of status epilepticus.

"IM administration of Cerebyx generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use," labeling says. "Cerebyx IM will provide greater flexibility in administering therapy in a number of short-term, non-emergency clinical situations," Warner-Lambert declared.

The company pointed to situations where oral therapy is difficult as potential opportunities for IM Cerebyx, including "unconsciousness, extreme nausea [and] need for rapid loading." Rapid loading often is necessary for noncompliant patients when "it is important to get therapeutic plasma levels back to normal quickly to prevent further seizures. Because it typically takes at least three to four days to achieve appropriate levels with oral therapy," patients receive loading doses IM or I.V., the company explained. If the situation is not urgent, "the IM route is often preferred because it reduces the cost and time associated with I.V. setup and administration."

Warner-Lambert will conduct post-marketing studies to optimize the clinical utility of Cerebyx, the company said. Studies will be conducted with pediatric patients, in home health care and long-term care settings and for use in emergency medical services.

Labeling notes that "the safety of Cerebyx in pediatric patients has not been established." An article by J.M. Pellock, Medical College of Virginia (Richmond), in Neurology (June 1996) suggests that Cerebyx' potential for IM use would be welcomed for pediatric patients as "problems with venous accessibility and maintenance may complicate I.V. administration of phenytoin in newborns and very sick infants." Dilantin is not indicated for IM use.

Labeling recommends loading doses of Cerebyx of 10-20 mg phenytoin equivalent/kg I.V. or IM and daily maintenance doses of 4-6 mg PE/kg/day. The product will be available in 10 mL or 2 mL vials, equivalent to 500 mg and 100 mg phenytoin, respectively. Warner-Lambert will manufacture Cerebyx in Rochester, Mich., where I.V. Dilantin is produced. The plant has had some recalls of I.V. Dilantin, most recently in October and August 1995 for discoloration due to an incorrect stopper. The manufacturing process for Cerebyx involves several additional steps, Warner-Lambert said.

Warner-Lambert also is studying fosphenytoin as a neuroprotective agent in stroke; the compound is undergoing Phase III trials for that indication. Data are expected for analysis in the second half of 1997. Warner-Lambert licensed fosphenytoin from DuPont.