• Zyprexa was approved by the U.S. Food and Drug Administration (FDA) for use in combination with lithium or valproate for the treatment of acute manic episodes associated with bipolar I disorder. The Eli Lilly and Co. brand of olanzapine was approved in 2000 as a monotherapy for the short-term treatment of acute mania. The new approval is based on two clinical trials that showed that the second-generation antipsychotic was more effective at reducing symptoms than was either lithium or valproate alone. The FDA is reviewing Zyprexa for the long-term maintenance of response in bipolar disorder treatment.

• Amid increasing applications for generic versions of market-leading medications, the FDA on August 18 implemented its final rule aimed at speeding up the approval process for generic applications. The new rule allows only one 30-month stay on a generic manufacturer’s application while the manufacturer of the brand-name drug defends existing patents and considers patent-infringement litigation. In addition, the final rule clarifies which patents the FDA will recognize and list in its official register, known as the “Orange Book.” Only patents that cover an active ingredient, formulation or composition, or method of use (tablet, injectable, etc.) will be listed.

• Generic olanzapine will initially be marketed by IVAX Corporation, once patent protection expires on Lilly’s Zyprexa. The FDA confirmed that IVAX submitted the first complete abbreviated new drug application (ANDA), and the company is challenging Lilly’s patents on the medication, which expire in April 2011. As Lilly’s best-selling product, Zyprexa generated an estimated $2.6 billion in U.S. sales during 2002. Lilly is vigorously defending its product patents.

IVAX also last month submitted an ANDA for generic escitalopram, securing the spot as the first to challenge the patent protection of Forest Labs’ Lexapro. Forest, which sold more than $215 million of Lexapro in the second quarter of 2003, said it believes its existing patents on escitalopram, which expire in 2011, are “valid and strong.” Forest’s CEO noted in a press release that “the early filing of ANDAs against well-patented products by generic companies has become standard practice, principally to obtain priority generic approval when the controlling patents do expire.”

• Generic paroxetine hydrochloride could hit pharmacy shelves as early as 2005, if Apotex Corp. wins its patent challenge to GlaxoSmithKline’s Paxil. The FDA has given final approval to Apotex’s ANDA to market 10 mg, 20 mg, 30 mg, and 40 mg paroxetine hydrochloride tablets that will be AB rated (bioequivalent) to Paxil.

• Meanwhile, the FDA approved paroxetine mesylate, which will be marketed by Synthon Pharmaceuticals. A brand name had not been finalized at press time. Paroxetine mesylate differs only in the substitution of the mesylate ion for the hydrochloride ion found in GSK’s Paxil. Both ions are cleaved by stomach acids, leaving equivalent amounts of active paroxetine available for absorption. However, the chemical difference is significant enough, according to both patent and drug regulators, to be approved in its own right. The drug has been available for more than two years in several European countries.

Physicians will have to specify “paroxetine mesylate” or the new brand name on prescriptions versus paroxetine hydrochloride as the two medications will not be legally interchangeable.

The company says the product will be priced in the “generic range” and should be on pharmacy shelves in the fourth quarter of 2003.

• Florida has told physicians to clean up their penmanship. A new law, which took effect July 1, makes Florida the second state (in addition to Washington state) to legislate legibility on prescriptions. The law specifies such things as requiring that the month be written out rather than indicated by number. Refills must also be noted in text rather than numbers. In addition, the quantity of the drug must be written in text as well as in numbers. The legislature placed enforcement of the new law with the state medical board, which so far has not delineated specific penalties. Pharmacists and patients are given the responsibility of “turning in” prescribers who do not write legibly.

• Blood levels of clozapine obtained by a fingerstick method are as accurate and should be considered equivalent to traditional venipuncture methods, according to a new study. Researchers tracked clozapine levels in outpatients with schizophrenia who were stabilized on medication. Both methods were used to measure the blood levels of each patient and compared. Although plasma clozapine levels from venipuncture were consistently greater (by about 27 percent) than those noted by fingerstick, the authors conclude that the fingerstick method is an appropriate alternative as long as an adjustment is made relative to the consistent difference in the two readings.

• Olanzapine offers several relative advantages in therapeutic response over first-generation antipsychotics, notably haloperidol. In a study of 263 patients with first-episode psychosis, the two medications were found to have comparable efficacy; however, olanzapine had a better adverse-event profile. In particular, patients taking olanzapine remained on medication longer than those taking haloperidol. Retention in treatment, the authors noted, is a significant advantage in a population, like this one, at a high risk for relapse.

• Similarly, risperidone offers significant advantages over haloperidol as well. In a two-year, randomized, double-blind comparison in 63 patients, risperidone and low-dose haloperidol (between 6 mg and 16 mg/day) produced similar improvements in positive and negative symptoms and similar risk of psychotic exacerbation. However, risperidone-treated patients appeared to feel subjectively better, as indicated by less anxiety, less depression, and fewer extrapyramidal symptoms, compared with haloperidol-treated patients.

• Oral loading of divalproex leads to a more rapid antimanic effect compared with standard titration of divalproex, lithium, or placebo, and it is better tolerated than olanzapine therapy. A pooled analysis of 348 patients from three randomized, double-blind, placebo-controlled trials found that oral loading of divalproex was more efficacious at days 5, 7, and 10. Divalproex was more effective than lithium through day 8 and was comparable to olanzapine at all time points; however, it produced fewer side effects than olanzapine.

• Combining lithium and divalproex for pediatric patients with bipolar disorder may provide significant advantages for patients who do not respond well to either medication alone. In an open-label study of 90 patients, significant improvement was seen with combination therapy over a 20-week period on the Young Mania Rating Scale, Children’s Depression Rating Scale–Revised, and the Children’s Global Assessment Scale. Forty-seven percent of patients taking combination therapy met a priori criteria for remission.

• Selegiline may be an appropriate alternative for children who have ADHD and do not tolerate or respond adequately to standard stimulant therapy. In a double-blind, randomized trial comparing selegiline and methylphenidate in 28 children with ADHD, no significant differences were found in efficacy of the two medications as measured by Parent and Teacher Rating Scale scores. There were more dropouts during the study due to adverse effects in the methylphenidate group. A selective type B monoamine oxidase inhibitor, selegiline is metabolized to amphetamine and methamphetamine.

• Bristol-Myers Squibb Company and Otsuka Pharmaceuticals Ltd. jointly announced that a supplemental new drug application was submitted in late July for approval of Abilify to treat acute mania in patients with bipolar disorder. The filing is based on data from three three-week, placebo-controlled trials and one 12-week, active controlled study in patients with acute mania. The third-generation antipsychotic has a unique partial dopamine agonist mechanism of action, which the companies believe will offer physicians and patients a new treatment alternative.

• Eli Lilly and Co. announced that in the first six months after its market launch, more than 1 million prescriptions had been written for Strattera, representing approximately 700,000 patients. According to data from IMS Health, Strattera ended its first six months on the market with 12.9 percent of prescriptions written for ADHD treatment. Overall, the drug is prescribed most frequently by child and general psychiatrists, accounting for about 43 percent of prescriptions for the nonstimulant medication, followed by pediatricians at 24 percent, and primary care physicians at 17 percent. ▪