Monday, October 15, 2007

Abilify. FDA Approved

Abilify DrugAbilify was approved by the FDA for the treatment of schizophrenia in November 2002. On March 1, 2005, it was approved as a maintenance therapy for Bipolar disorder.

The Food and Drug Administration (FDA) issued a public health advisory on April 11, 2005, to warn that the drugs known as the atypical antipsychotics are associated with an increased risk of death when used to treat dementia in elderly patients.

The atypical antipsychotics affected by the FDA advisory are Aripiprazole (ABILIFY), olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL), clozapine (CLOZARIL) and ziprasidone (GEODON). None of these drugs, however, are approved for the treatment of behavioral disorders in patients with dementia.

Abilify is a member of a relatively new family of drugs known as atypical antipsychotics. These drugs are also being referred to as second-generation antipsychotics. All antipsychotic drugs usually improve symptoms such as agitation, delusions, hallucinations, and suspiciousness. Atypical antipsychotics additionally tend, more than the older antipsychotics, to improve negative symptoms such as apathy, disorientation, emotional withdrawal, and lack of pleasure. However, there is no clear evidence that atypical antipsychotics are more effective or are better tolerated than the older conventional antipsychotics such as haloperidol (HALDOL).

Three of the five short-term trials submitted to the FDA for Abilify’s approval showed the efficacy of the drug in doses ranging from 10 milligrams to 30 milligrams per day. There appeared to be no therapeutic advantage of the 30 milligram dose over the lower doses. The FDA-approved dose for the drug ranges from 10 milligrams to 15 milligrams per day. Of the two remaining studies, Abilify could not be differentiated from placebo in one, and the other trial failed.One of our reviewers suggests starting with the new 5 milligram dose to minimize the risk of adverse effects.

These trials were not conducted in a way to make direct comparisons between Abilify and haloperidol or risperidone, which were used as comparator drugs. And nothing in these five trials can lead one to believe that Abilify is a meaningful advancement in the treatment of schizophrenia.

The editors of the highly respected Medical Letter on Drugs and Therapeutics concluded in their evaluation of Abilify that “published comparisons with other atypical antipsychotics are needed to determine its relative efficacy and safety.”

We are concerned about the possibility of eye toxicity with the use of Abilify. The studies done in rats before the drug was approved clearly showed degeneration of the retina in animals receiving Abilify. The studies done in mice and monkeys found no retinal degeneration, but they were invalid studies. The company committed to doing additional postmarketing research on retinal degeneration in animals as a condition for the approval of Abilify. These are studies that clearly should have been completed before the drug was approved.

There are additional findings from the FDA’s safety review of Abilify that are important. An alteration in the electrical conduction of the heart known as QT prolongation is an important safety issue with both old and new antipsychotic drugs. QT prolongation can lead to life-threatening heart rhythm disturbance.

There was no evidence of QT prolongation with Abilify at doses up to 30 milligrams per day. However, in a special study that explored doses of the drug up to 90 milligrams per day, there was substantial prolongation of the QT interval at doses of 75 milligrams and 90 milligrams per day.

In February 2005, the French regulatory agency warned of a risk of stroke associated with the use of Abilify. In three 10-week placebo controlled trials of Abilify, strokes and transient ischemic attacks (small strokes caused by a temporary blockage of blood flow to part of the brain) were twice as frequent among patients taking arpiprazole. Two of the patients who had strokes died.

In March 2005, the FDA revised the product package label of apiprazole regarding an increased incidence of cerebrovascular adverse events (stroke and transient ischemic attacks), including fatalities in Abilify-treated patients. Abilify is not approved for the treatment of patients with dementia related psychosis.

Weight gain has also been a problem with the antipsychotic drugs, particularly with the atypical antipsychotics. In the short-term trials, there was a small difference in average weight gain between Abilify and placebo patients. The patients given Abilify gained on average 1.5 pounds, while the placebo patients lost 0.1 pounds on average. The number of patients gaining more than 7% of their body weight who were taking Abilify was equal to 8%, compared to 3% of the placebo patients.

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