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SMITHKLINE BEECHAM’s PAXIL ANTIDEPRESSANT TO BE PRICED AT 12.6% DISCOUNT TO LILLY’s PROZAC; "SIGNIFICANTLY LOWER" RELAPSE RATE IN LABELING

Executive Summary

SmithKline Beecham plans to introduce its antidepressant Paxil at a 12.6% discount to Lilly's Prozac (fluoxetine) and a 3.6% discount to Pfizer's Zoloft (sertraline), based on SmithKline Beecham's estimates of the average per day cost to consumers. Paxil (paroxetine) for treatment of depression will become the third serotonin reuptake inhibitor on the market when it is launched in early 1993. The drug (NDA 20-031) was approved by FDA Dec. 29 after a 37-month review. The NDA for paroxetine was submitted on Nov. 21, 1989, and there were 29 subsequent communications submitted by SmithKline to FDA. Final approval came 12 weeks after FDA's Psychopharmacologic Drugs Advisory Committee unanimously agreed that paroxetine is a safe and effective antidepressant ("The Pink Sheet" Oct. 12, p. 11). Paxil was designated a "1S" drug, or a new molecular entity that received a "standard" review at the agency. Specific details of the launch were not disclosed, but SmithKline said it plans to promote the product aggressively with its 2,000-member detail force. The company estimates Paxil's average daily cost to consumers will be $1.60, compared to $1.66 for Zoloft and $1.82 for Lilly's Prozac. Paxil will be available initially in 20 mg and 30 mg tablets although the NDA approval included 10 mg, 40 mg and 50 mg tabs as well. SmithKline Beecham has a reputation as an active discounter in other crowded fields in which it competes; its entrance into the serotonin reuptake inhibitor class may significantly change the nature of pricing in that class. As an example of its aggressive discounting policies, SmithKline Beecham is said to be one of the companies supplying Medco Containment with discounted products for its Prescriber's Choice program. Although clinical data submitted to FDA did not include any head-to-head trials comparing the three drugs, SmithKline Beecham said it has conducted studies comparing Paxil and Prozac, the results of which will be released within the next few months. Paxil is already available in the U.K., where it is sold as Seroxat, as well as in Germany, Sweden and The Netherlands. After less than two years on the market in the U.K., SmithKline says Seroxat has garnered a 20% market share, compared to 26% for Prozac and 5% for Zoloft. SmithKline said it expects to overtake Prozac in the U.K. in 1993. Labeling for Paxil warns against comparing the side-effect profiles of the three SRIs based on currently available data: "The cited frequencies [of adverse reactions] cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators." Adverse reactions were responsible for a 21% dropout rate among 4,126 patients in worldwide Paxil clinical trials, labeling states. Approximately 3.4% of clinical trial patients discontinued therapy because of nausea, followed by somnolence (2.3%) and insomnia (1.9%). The most common adverse reactions, with an incidence of 5% or more and twice that for placebo, were: nausea, asthenia, somnolence, insomnia, sweating, dizziness, tremor, nervousness, decreased appetite, ejaculatory disturbance and other male genital disorders. Over a four-to-six week period, "there was evidence of adaptation to some adverse effects with continued therapy," such as nausea and dizziness, but less with other effects such as dry mouth, somnolence and asthenia, according to labeling. Included in the labeling are results from a fixed-dose study comparing the incidence of adverse reactions for patients taking paroxetine 10, 20, 30 or 40 mg. The study "revealed a clear dose dependency for some of the more common adverse events associated with paroxetine use." The incidence of nausea increased from 14.7% with 10 mg to 26.9% with 20 mg; 34.7% with 30 mg and 36.3% with 40 mg, compared to a 13.7% rate with placebo. Although "significant weight loss may be an undesirable result of treatment with Paxil for some patients," the average weight loss during clinical trials was about one pound, labeling states. The wording is almost identical to that for Zoloft, but differs from Prozac labeling, which notes that approximately 9% of patients treated with Prozac experienced anorexia, while approximately 13% lost more than 5% of their body weight, compared to 4% with placebo and 3% with tricyclics. Labeling includes a section on geriatric dosing. In a study that dosed elderly patients with 20 mg, 30 mg and 40 mg of paroxetine, "Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in non-elderly subjects. Therefore," labeling notes, "the initial dose in the elderly should be reduced." Seventeen percent (approximately 700) participants in the Paxil clinical trials were 65 years of age or older. There were no overall differences in adverse reactions between elderly and younger patients. Paxil's efficacy as a treatment for depression was established in six, six-week, placebo-controlled studies of patients ranging in age from 18 to 73. Paxil was "shown to be significantly more effective than placebo in treating depression" based on evaluations using the Hamilton Depression Rating Scale, the Hamilton depressed mood item and the Clinical Global Impression -- Severity of Illness, labeling states. Paroxetine was also effective in treating symptoms associated with depression such as sleep disturbance and anxiety. Labeling notes that Paxil's antidepressant action "in hospitalized depressed patients has not been adequately studied." A one-year study demonstrating a "significantly lower relapse rate for patients taking Paxil (15%) compared to those on placebo (39%)," is also reflected in labeling. By comparison, Zoloft labeling notes that there are insufficient data regarding benefits of treatment after 16 weeks; Prozac labeling says the effectiveness for more than five to six weeks of treatment has not been evaluated in controlled trials. All three products carry a recommendation that physicians should "periodically re-evaluate the long-term usefulness of the drug for the individual patient." The recommended initial dose of Paxil is 20 mg once a day, preferably in the morning. Patients who do not respond to the 20 mg dose may receive 10 mg/day increases up to 50 mg/day, with dose changes administered at intervals of at least one week. FDA's Dec. 29 approval letter to SmithKline Beecham includes recommendations for five postapproval studies, including a study to determine if paroxetine doses higher than 20 mg are beneficial. The dosing advice contained in the labeling is based on a fixed-dose study (PAR 09) which "unfortunately, because of design flaws...was unable to definitively address the question of whether or not doses higher than 20 mg provide any additional benefit," the letter states. FDA added that "it is our understanding, based on our December 29, 1992 teleconference, that you will design and conduct another study to answer this question." Several members of the advisory committee expressed dissatisfaction with the available dose-ranging data and strongly suggested the need for additional studies. FDA proposed a fixed-dose study in which patients are titrated to higher doses to allow "a better opportunity to discriminate between the different dose groups." An additional randomized concentration controlled trial could "explore for a plasma level/efficacy relationship," the agency suggested. The letter also refers to an agreement by SmithKline to conduct postmarketing studies on the effects of food on paroxetine pharmacokinetics. Additional studies requested by FDA and agreed to by the company include an analysis of the potential interactions of paroxetine with other drugs metabolized by the enzyme cytochrome P[450]IID[6], such as tricyclic antidepressants and drugs that inhibit the enzyme, such as quinidine. "It would also be important to compare the pharmacokinetics of paroxetine in men and women," the letter noted. A final request by FDA is for SmithKline to consider postmarketing studies involving the use of Paxil to treat depressed children and adolescents.
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