GLAXO’s IMITREX FOR MIGRAINE WILL BE AVAILABLE IN MARCH AFTER DEC. 28 APPROVAL; FIRM WILL CONDUCT PHASE IV STUDY IN PREGNANT WOMEN IN LIEU OF REGISTRY
Glaxo plans to have Imitrex (sumatriptan) injection available to consumers "in late March 1993," following FDA approval of the migraine treatment during the agency's end-of-the-year approval rush. Imitrex injection was approved by FDA on Dec. 28 after a 30- month review. Glaxo filed the NDA on July 2, 1990. FDA gave the Imitrex NDA a "1P" rating, which indicates that the new chemical entity received a "priority" review. Imitrex is the first of a new class of drugs that stimulate the 5HT receptor of serotonin. Glaxo hopes to begin shipping product to the trade within 10 to 12 weeks to guarantee that sufficient product is available to meet consumer demand. The delay in the launch of Imitrex is due to two manufacturing obstacles: Imitrex is being manufactured in the U.K.; and Glaxo had to wait until final FDA approval to begin stockpiling for the U.S. launch because product labeling is included on each syringe. The product will be marketed by Glaxo's CNS marketing group, Cerenex Pharmaceuticals, and its 600-person detail force. Cerenex was formed in late 1990 to market new products emerging from Glaxo's serotonin-receptor research; the division currently markets the anti-nausea agent Zofran (ondansetron). The Glaxo Pharmaceuticals (Zantac) sales force also will help with the launch. Imitrex will be supplied in a SELFdose System kit containing two 6 mg unit-of-use syringes and an autoinjector manufactured by Owen-Mumford. The drug can be used at any time during an acute migraine episode but labeling recommends that an injection be administered as soon as symptoms appear. A second injection can be administered "at least one hour" after the initial dose, but no more than two injections are recommended during a 24-hour period, according to labeling. Pricing of Imitrex injection "has not been finalized" and will be announced "at availability," the company said. The company faces an interesting pricing challenge because of the nature of Imitrex injection -- a treatment for acute episodes of a chronic condition. The company is likely to set a price level in the U.S. for sumatriptan that is similar to Europe, where the product sells at roughly $35-$40 per two-syringe kit and Canada, where the kit sells for $34 (Canadian). While the $34-$40 cost for two syringes is high by a per- dose calculation, in the context of annual costs Imitrex compares favorably to other new chronic-use drugs. Noting that the incidence of headaches varies widely among migraine sufferers, the company estimates the annual cost of injectable sumatriptan treatment overseas at roughly $400-$600 at the factory price level. Glaxo has conducted cost-benefit and quality-of-life studies for sumatriptan and began presenting its case for the drug to benefits managers last fall in anticipation of the approval. Glaxo told securities analysts two years ago that the company had conducted "significant" cost-benefit studies. At that time, the company estimated that the minimum cost of lost labor days in the U.S. due to migraines was approximately $5-$7 bil. annually. In addition, Glaxo management reported on a survey of 900 migraine sufferers that found that over half of the respondents had missed at least 2-1/2 days of work over a four-week period due to migraines and 88% said they had worked more than one week while suffering migraine symptoms. Glaxo calculated the lost labor cost of each worker at between $2,800 and $3,000. Glaxo is now estimating the total societal costs of migraines at roughly $17 bil. Given the large and relatively underserved market for the drug, Imitrex may eventually be a candidate for consumer advertising and educational efforts. No consumer advertising is planned at launch. Glaxo has estimated that only about one-third of migraine sufferers seek treatment from a physician. FDA, in a Dec. 29 press release announcing the approval, estimated the total number of migraine sufferers in the U.S. at between 16 mil. and 18 mil. people. Glaxo puts the number more conservatively at about 11 mil. Glaxo's launch will involve educating patients about use of the product. Patients will receive with the drug an enclosed instruction pamphlet on loading and unloading the autoinjector and discarding empty syringes. In addition, FDA-approved labeling includes a patient information leaflet that explains how the autoinjector should be used, what questions should be asked the patient's physician, the side effects to watch for and how to store the medication. The labeling for Imitrex injection states that the drug "is indicated for the acute treatment of migraine attacks with or without aura." However, labeling also notes that the drug is "not for use in the management of hemiplegic or basilar migraine" and that the drug's safety and effectiveness for treating cluster headaches has "not been established." In Phase III clinical trials in over 1,100 patients with moderate and severe migraine pain, 70% of patients experienced headache relief within one hour of a single 6 mg injection, according to the labeling. Within two hours of the injection, 82% of patients experienced relief and 65% were pain free. The labeling adds that "onset of relief was rapid (less than 10 minutes)." The NDA for Imitrex injection was unanimously recommended for approval by FDA's Peripheral & Central Nervous System Drugs Advisory Committee in October 1991 for the treatment of migraine headaches. However, the committee deferred a recommendation on use of subcutaneous sumatriptan for the treatment of cluster headaches until the company had submitted the results of a second study for that use. The initial NDA for Imitrex contained the results of the cluster headache trial published in the Aug. 1, 1990 New England Journal of Medicine. Glaxo said it is "still pursuing" that indication. Glaxo also is seeking approval to market an oral version of sumatriptan; an NDA has been pending at the agency since December 1990. The oral product has not been before an FDA advisory committee. FDA pronounced Imitrex injection "approvable" on Nov. 30 ("The Pink Sheet" Dec. 7, T&G-1). In the approvable letter to Glaxo, the agency indicated that it was concerned with how the drug's potential cardiovascular side effects would be communicated in the labeling and how to resolve remaining questions about the drug's potential teratogenicity. A toxicity study conducted by Glaxo found the drug was teratogenic in rabbits. However, the drug is not teratogenic in rats and available human data indicate that the drug is not a human teratogen, Glaxo noted. The negotiations with Glaxo reflect the agency's caution in releasing a new class of drug to a potentially huge, diverse and underserved patient population despite the size of Glaxo's NDA database, which includes data from over 6,200 patients who received subcutaneous Imitrex during clinical trials. FDA had asked Glaxo in the approvable letter to consider establishing a patient registry to track use of the drug in pregnant women. FDA, however, apparently was persuaded by Glaxo at a Dec. 8 meeting with company representatives that an extensive postmarketing study would accomplish the same purpose. FDA Office of Drug Evaluation I Director Robert Temple, MD, stated in the approval letter that the agency finds the proposed postmarketing study "an acceptable alternative (in principle) to accomplish the aims of the registry proposed in the approvable letter." The difference between Phase IV studies and a registry may be significant to the long-term viability of the product. A patient registry of pregnant women could have opened the company up to extensive liability challenges. Glaxo already has initiated sumatriptan postmarketing studies in the U.K., France and Germany that will accrue a total of approximately 50,000 to 60,000 patients. In addition, the company hopes to enroll another 25,000 patients in a U.S. postmarketing study. The Phase IV studies are designed as "all-comer" studies that will allow the company to collect information on all aspects of the drug's safety profile. Glaxo also has fairly extensive experience with the drug worldwide; sumatriptan is currently available in over 25 countries and the company estimates that "about 3.2 mil." migraine attacks have been treated with the drug to date. The approved labeling does not contraindicate Imitrex in pregnant women. The "Precautions" section of the labeling points out that sumatriptan "has been shown to be embryolethal in rabbits when given in daily doses producing plasma levels three-fold higher than those attained" under the recommended human dose. Labeling adds that "there is no evidence that establishes that sumatriptan is a human teratogen; however, there are no adequate and well-controlled studies in pregnant women. Imitrex injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." The labeling goes on to explain that embryolethal doses in rabbits were administered intravenously and at levels "at or close to those producing maternal toxicity." Oral sumatriptan given to Dutch Stride rabbits during organogenesis produced "an increased incidence of cervicothoracic vascular defects and minor skeletal abnormalities" in fetuses brought to term, the labeling points out. However, doses producing plasma concentrations 50 times those seen at the recommended human dose given to pregnant rats showed no evidence of embryo/fetal lethality or teratogenicity, labeling adds. The patient information leaflet also addresses use of the drug by pregnant women. Under the heading, "The Use of Imitrex Injection During Pregnancy," the leaflet states: "Do not use Imitrex injection if you are pregnant, think you might be pregnant, are trying to become pregnant, or are not using adequate contraception, unless you have discussed this with your doctor." In addition to the Phase IV human studies, Glaxo also has agreed to conduct follow-up studies of the drug administered subcutaneously in both rats and rabbits. The approval letter to Glaxo asks the company to submit final reports on the rat study within six months and on the rabbit study within 10 months. The drug is contraindicated in patients with ischemic heart disease. According to the labeling, eight patients out of over 1,900 patients who participated in controlled clinical trials "sustained clinical events during or shortly after receiving subcutaneous sumatriptan that may have reflected coronary vasospasm," although none of the events was associated with a "serious clinical outcome." Six of the eight had ECG changes consistent with transient ischemia but with no signs or symptoms, and four of the eight had findings suggestive of coronary artery disease prior to treatment, labeling states. The "Contraindications" section of labeling notes that the drug "should not be given intravenously because of its potential to cause coronary vasospasm." The label adds: "For similar reasons, Imitrex injection should not be given subcutaneously to patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients with Prinzmetal's angina. Also, patients with symptoms or signs consistent with ischemic heart disease should not receive Imitrex injection." Because the drug can cause small increases in blood pressure, Imitrex also is contraindicated in patients with uncontrolled hypertension. The "Warnings" section of labeling recommends that "consideration...be given to administering the first dose of Imitrex injection in the physician's office to patients in whom unrecognized coronary disease is comparatively likely." Included in that group are postmenopausal women, males over 40, and patients with coronary artery disease risk factors such as hypertension, high cholesterol, obesity, diabetes, smoking and strong family history of heart disease.
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