Med Check

All amphetamine and methylphenidate formulations prescribed for ADHD have new standardized labeling language, the result of negotiations between drug manufacturers and the Food and Drug Administration (FDA) this summer. The agency asked manufacturers to update the warnings, precautions, and adverse-events sections of the labels following a pair of unusually contentious and controversial advisory committee hearings in February and March.

The two committees had come to differing conclusions, with the February meeting resulting in a call for new black-box warnings on all drugs used to treat ADHD. The March meeting, however, resulted in a recommendation that the warning section of the stimulant labels—specifically amphetamines and methylphenidate—be updated, but not with new black-box language (Psychiatric News, April 21).

The new language more closely resembles that recommended by the second advisory committee, centering on stronger and more specific risk information.

On amphetamine labels, new language has been added to existing black-box warnings, while on methylphenidate labels the new warnings appear in the“ warnings” section of the label. Included are warnings against prescribing the medications to children with any known or suspected heart disease. In addition, new language addresses possible psychotic behaviors and mania as adverse events. Prescribers are also cautioned to monitor for any treatment-emergent aggression or worsening of pre-existing aggressive behaviors.

Modafinil received a “nonapprovable” letter from the FDA for the treatment of ADHD. Cephalon had hoped to market the drug for ADHD under the name Sparlon. Modafinil is currently marketed as Provigil for treatment of narcolepsy, obstructive sleep apnea/hypopnea, and shift-work sleep disorder. However, proposed dosing for Sparlon was significantly higher than that approved for Provigil.

The FDA decision, the company said in a press statement, was apparently based on a single reported case (out of 950 children involved in clinical trials in patients with ADHD) of a severe, blistering skin rash, which may have been Stevens-Johnson syndrome. The decision reversed an“ approvable” letter issued October 20, 2005. At a March meeting, the agency's Psychopharmacologic Drugs Advisory Committee expressed concern over side effects of the drug when used in children. In response to the FDA's nonapprovable letter, Cephalon announced August 9 that it would not continue its efforts to gain approval of the drug for ADHD.

Patients taking olanzapine began receiving checks from Eli Lilly and Company last month as part of the company's largest ever liability settlement. Lilly has set aside $700 million to fund the long-anticipated product-injury awards, settling claims from more than 8,300 patients who say the drug caused them to develop problems with control of blood glucose metabolism or full-blown diabetes. Payouts range from the settlement's fixed minimum of $5,000 to over $100,000 per patient.

The settlement was the result of an impending class-action lawsuit that was expected to include claims from thousands of patients. Many of those individual claims were consolidated by the federal district court in New York, which oversaw the settlement.

The settlement is thought to cover about 75 percent of the known claims against the company by users of olanzapine. Lilly has set aside an additional $300 million to cover potential liability related to unsettled cases. The first trial of an unsettled claim is expected to be heard next year.

Donepezil, galantamine, and rivastigmine may, at best, temporarily reduce the risk of nursing-home placement in Medicaid beneficiaries with dementia, according to a new analysis. As a result, the cholinesterase inhibitors (CHEIs) may improve quality of life and preserve personal and societal resources.

The analysis followed 1,188 Florida Medicaid patients with dementia during 1998 and 1999. Of those, 378 were diagnosed with Alzheimer's disease, and about 50 percent of the sample received one of the three currently branded CHEIs or the older, generic tacrine. The patients were followed for up to 36 months.

After adjusting for age, sex, race, and co-occurring diagnoses, dementia patients receiving CHEIs were 28 percent less likely to be in a nursing home within 12 months and 21 percent less likely at 18 months, compared with patients not taking CHEIs. By 36 months, no significant difference in nursing-home placement was seen between those taking the drugs and those not.

Funding was provided by the Florida Agency for Health Care Administration. Alzheimer Dis Assoc Disord 2006; 20:147-152

Risperidone, when added to SSRI therapy, appears to enhance substantially response in patients with treatment-resistant depression. A multicenter, three-phase study included 489 patients who completed four to six weeks of open-label treatment with citalopram monotherapy, followed by four to six weeks of citalopram plus risperidone. Then, all patients entered a 24-week, double-blind, placebo-controlled discontinuation phase. The primary endpoint was the time to relapse.

During citalopram monotherapy, 434 patients had less than a 50 percent reduction in score on the 17-item version of the Hamilton Depression Rating Scale (Ham-D-17). of the 386 who entered the risperidone augmentation phase, 243 (63 percent) remitted, and 241 of those entered the double-blind phase. Median time to relapse was significantly longer, at 102 days, with risperidone augmentation compared with 85 days on placebo. Relapse rates were not significantly different, at 53.3 percent and 54.6 percent, respectively.

A post-hoc analysis of those patients “fully nonresponsive to citalopram” (those with less than a 25 percent reduction in Ham-D-17 score after four to six weeks of citalopram monotherapy) showed median time to relapse was significantly longer with risperidone plus citalopram, at 97 days, compared with 56 days for citalopram plus placebo. Relapse rates were also significantly different, at 56.1 percent and 64.1 percent, respectively.

The study was funded by Janssen Pharmaceutica.

Neuropsychopharmacol 2006; AOP:1-9

Use of some SSRIs in elderly patients may lead to potentially life-threatening reductions in serum sodium concentrations. A review of literature published between 1966 and December 2005 looked for any mention of hyponatremia in association with the SSRIs citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

Numerous case reports, observational studies, case-controlled studies, and one prospective clinical trial have reported hyponatremia associated with SSRI use, with incidence varying from 0.5 percent to as high as 32 percent. Risk factors included older age, female gender, concomitant use of diuretics, lower body weight, and lower baseline serum sodium concentrations.

Hyponatremia was most likely to develop in the first few weeks of treatment and resolve within two weeks of ceasing use of the SSRI involved. In reported cases involving re-challenge (either with the same SSRI or a substitute), some patients became hyponatremic once again.

The study was funded through grants from the Veterans Affairs Health System and the Robert Wood Johnson Foundation. Ann Pharmacother 2006; 40(AOP): 1-6

Amphetamine salts, mixed: Adderall (Shire); generics

Amphetamine salts, mixed (extended release): Adderall XR (Shire); generics

Citalopram: Celexa (Forest); generics

Donepezil: Aricept (eisai/Pfizer)

Escitalopram: Lexapro (Forest Laboratories)

Fluoxetine: Prozac/Serafem (Lilly); generics

Fluvoxamine: Luvox (Solvay); generics

Galantamine: Razadyne (Janssen)

Galantamine (extended release): Razadyne ER (Janssen)

Methylphenidate: Ritalin (Novartis); generics

Methylphenidate (extended release): Concerta (McNeil); Metadate CD/ER (Celltech); Ritalin LA (Novartis)

Modafinil: Provigil (Cephalon)

Olanzapine: ZyPREXA (Lilly)

Paroxetine hydrochloride: Paxil (GSK); generics

Risperidone: Risperdal (Janssen)

Rivastigmine: Exelon (Novartis)

Sertraline: Zoloft (Pfizer); generics

Tacrine: Cognex (Pfizer); generics