Med Check
Regulatory and Legal Briefs
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Varenicline received final approval for marketing from the U.S. Food and Drug Administration (FDA) last month. The new oral tablet is indicated as an aid to smoking cessation and will be marketed by Pfizer under the brand name Chantix. The agency granted the drug application fast-track status because of its potential to be a significant therapeutic advance over existing therapies.
The drug is thought to work by binding to alpha-4, beta-2 nicotinic acetylcholine receptors where it acts as a partial agonist. By partially activating the nicotinic receptor complex, the intensity of a smoker's craving for nicotine and withdrawal symptoms are both significantly reduced. Yet because of the drug's binding, nicotine itself is blocked from binding to the receptor, effectively diminishing a significant portion of the physiologic effect (the reward) of nicotine, should the patient smoke after taking the medication.
Efficacy was demonstrated in randomized, double-blind studies involving more than 2,000 patients. On average, patients had smoked over two packs a day for nearly 25 years. Twelve weeks of daily varenicline therapy increased the odds of a patient's quitting smoking by nearly four times compared with placebo and nearly twice the rate of smoking cessation of a control group treated with oral bupropion.
The most frequent treatment-emergent adverse events during clinical trials with varenicline were nausea, changes in dreaming, constipation, gas, and vomiting.
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Indiplon-immediate release was granted“ approvable” status by the FDA last month, while the extended-release formulation of the drug was deemed by the agency to be“ nonapprovable.” Indiplon, which was developed by Neurocrine Biosciences and will be marketed by Pfizer, is a novel nonbenzodiazepine sedative/hypnotic.
The FDA ruled that the clinical trials data submitted supported the efficacy and safety of the 5 mg and 10 mg immediate-release capsule versions of the drug. However, the approvable action—short of full approval—indicated the agency had at least some concern or question that the company would need to address. Notably, with regard to the nonapprovable action on the extended-release formulation, the agency indicated that it“ did not have an opportunity to review all of the information submitted during the NDA review cycle.” Federal law requires the agency to issue at least a preliminary action within defined time periods on new drug applications. The agency's action indicates reviewers simply ran out of time before the deadline arrived as opposed to rejecting the extended-release formulation due to significant concerns over efficacy or safety.
The immediate-release tablets were shown to be safe and effective in patients with sleep-onset insomnia but did not benefit patients who wake multiple times after falling asleep. The extended-release tablet is intended to both shorten time to sleep onset and increase sleep duration.
Neurocrine Biosciences expressed disappointment over the split ruling but emphasized that the company was “dedicated to working with the agency to expedite response to the action letters.”
Research Briefs
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Sertraline appears to prolong the time to recurrence after an initial major depressive episode in patients with diabetes mellitus. A randomized, double-blind, placebo-controlled trial studied 152 patients with diabetes who recovered from a depressive episode following open-label treatment with sertraline. After recovery, 79 of the patients were randomly and blindly assigned to continue to receive sertraline for 52 weeks or until their depression recurred. The remaining 73 patients were randomly assigned to placebo for the duration of the trial. Patients taking sertraline were half as likely to suffer a recurrence during the 52 weeks compared with those receiving placebo. The average elapsed time to recurrence was 226 days for those on sertraline compared with 57 days for those on placebo. Standard diabetic measures (blood glucose levels; glycosylated hemoglobin) decreased overall during the initial open treatment with sertraline and did not differ between those continuing on sertraline during the double-blind phase of the study compared with those receiving placebo.
Arch Gen Psychiatry 2006; 63:521-529
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Haloperidol may be an effective treatment in relieving migraine-associated pain. A small randomized, double-blind trial involving 40 patients investigated the use of 5 mg haloperidol IV versus a placebo injection of normal saline in patients with acute migraine headache. Significant pain relief was experienced by 80 percent of those who received haloperidol, compared with 15 percent of those receiving the placebo injection, as measured using the Visual Analog Scale. Pain was rated one hour before injection and one and three hours post injection. Seventeen patients who received a placebo injection and had no demonstrable relief by three hours were subsequently given open-label haloperidol IV. Of the 17, 79 percent experienced significant pain relief. Of the 40 patients in the study, 7 percent returned within 24 hours with relapse of migraine pain.
The most common side effects noted by those receiving haloperidol IV were sedation and akathesia. Sixteen percent of patients rated the sedation and/or akathesia as intolerable and declined the possibility of receiving open-label treatment of their migraine pain with haloperidol.
Headache 2006; 46:781-787
Industry Briefs
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Duloxetine is safe and effective in the treat-ment of generalized anxiety disorder (GAD), according to a supplemental new drug application filed with the FDA by Eli Lilly and Co. last month. The drug is already approved for the treatment of major depressive disorder and the management of diabetic peripheral neuropathic pain in adults.
Lilly submitted data from two randomized, double-blind clinical trials of duloxetine in patients with GAD. A nine-week study of just under 500 patients showed significant improvements in core anxiety symptoms such as anxious mood, fears, and tension in 51 percent of patients taking 60 mg of duloxetine a day, compared with 50 percent of patients taking 120 mg duloxetine a day and only 32 percent of patients blindly receiving placebo. Physical symptoms of pain associated with anxiety were also significantly improved in those on duloxetine (an average 41 percent reduction in pain in those taking 60 mg a day and 37 percent reduction in those taking 120 mg a day) compared with placebo (an average 16 percent reduction in pain). Duloxetine was also associated with greater improvement in several quality-of-life measures.
The most common treatment-emergent adverse events associated with those patients receiving duloxetine in the two trials were nausea, dizziness, dry mouth, fatigue, hyperhidrosis, insomnia, constipation, diarrhea, decreased libido, anorexia, somnolence, vomiting, and sedation.
The following medications appear in this edition of Med Check:
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Duloxetine: Cymbalta (Eli Lilly & Co.)
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Haloperidol: Haldol (McNeil); generics
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Indiplon: Brand name pending FDA approval (Pfizer/Neurcrine)
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Sertraline: Zoloft (Pfizer)
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Varenicline: Chantix (Pfizer) ▪▪
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Published online: 2 June 2006
Published in print: June 2, 2006
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