FDA Approvals: Fanapt and Cycloset

Yael Waknine

May 14, 2009

May 14, 2009 — The US Food and Drug Administration (FDA) has approved iloperidone tablets for the treatment of acute schizophrenia in adults, and bromocriptine mesylate quick-release tablets for the management of type 2 diabetes mellitus.

Iloperidone (Fanapt) Approved to Treat Acute Schizophrenic Episodes in Adults

On May 6, the FDA approved iloperidone tablets (Fanapt; Pantheon, Inc) for the acute treatment of schizophrenia in adults. Schizophrenia is a chronic, severe, and disabling brain disorder.

"Schizophrenia can be a devastating illness requiring lifelong treatment and therapy," said Thomas Laughren, MD, director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. "Medications for schizophrenia can ease many symptoms, allowing people to live more independent lives."

Iloperidone is a mixed dopamine D2/serotonin 5HT2A receptor antagonist and belongs to the class of atypical antipsychotics.

Its approval by FDA was based on results from 2 placebo-controlled phase 3 clinical studies and safety data derived from more than 3000 patients.

The first study was a randomized, double-blind, multicenter, 4-week inpatient trial of 604 patients, demonstrating that a 24-mg daily dose of iloperidone was significantly more effective than placebo for ameliorating schizophrenic symptoms, as evaluated by the Positive and Negative Syndrome Scale (PANSS) score with use of the Mixed Method Repeated Measures methodology (PANSS total, P = .006). Symptom relief was observed across both negative and positive domains (P = .027 and P = .0009, respectively).

PANSS is a multi-item inventory that measures positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

Results also showed that iloperidone efficacy was markedly improved, relative to the overall population, in a subpopulation of patients with a polymorphism in a gene that is present in approximately 70% of patients and hypothesized to be associated with the pathogenesis of schizophrenia (P = .002).

These findings were supported by data from a 6-week placebo-controlled trial (n = 706), which showed that in addition to improving PANSS scores, both iloperidone dose ranges (12 - 16 mg/day and 20 - 24 mg/day) were significantly more effective than placebo for improving ratings on the Brief Psychiatric Rating Scale (BPRS).

The BPRS is an 18-item scale measuring positive symptoms, general psychopathology, and affective symptoms. Some items (eg, mannerisms and posturing) can be rated simply on observation of the patient; other items (eg, anxiety) involve an element of self-reporting by the patient. It is particularly useful in gauging the efficacy of treatment in patients who have moderate to severe psychoses.

The recommended starting dose for iloperidone is 1 mg taken twice daily; titration to the 6- to 12-mg dose range (12 - 24 mg/day) can be achieved by daily increases of 1 mg per dose (2 mg/day). The FDA notes that dosing should be reduced by half when administered concomitantly with strong cytochrome P 450 isoenzyme 2D6 (CYP 2D6) inhibitors (eg, fluoxetine and paroxetine) and strong CYP 3A4 inhibitors (eg, ketoconazole and clarithromycin). Iloperidone is not recommended for patients with hepatic impairment.

Although the optimal duration of therapy remains unknown, it is generally recommended that responding patients continue iloperidone therapy beyond the acute response. Periodic assessments are advised to determine the need for continued treatment.

Adverse events most commonly associated with iloperidone therapy in clinical trials (incidence, ≥ 5%) included dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increase.

Weight gain was mild (overall mean increase, 2.1 kg [4.6 lbs]), and no clinically relevant elevations in glucose, triglycerides, or cholesterol levels were observed; elevations in prolactin levels were modest (24 mg/day, 2.6 ng/mL) vs the large elevations observed with other atypical antipsychotic agents. The incidence of extrapyrimidal symptoms was likewise low (10 - 16 mg/day, 5%; 20 - 24 mg/day, 4% vs placebo, 4%).

As with other atypical antipsychotics, iloperidone may affect heart rhythm parameters; other products should be considered first in patients with certain risk factors such as use of class 1A (eg, quinidine and procainamide) or class III (eg, amiodarone and sotalol) antiarrhythmic medications, antipsychotic medications (eg, chlorpromazine and thiordazine), antibiotics (eg, gatifloxacin and moxifloxacin), or any other class of medications known to prolong the QTc interval (eg, pentamidine, levomethadyl acetate, and methadone).

Because of the increased mortality risk, iloperidone and other atypical antipsychotics should not be used for the off-label treatment of dementia-related psychosis in elderly patients.

Bromocriptine Mesylate (Cycloset) Approved for Type 2 Diabetes

On May 5, the FDA approved bromocriptine mesylate 0.8-mg tablets (Cycloset; VeroScience, LLC [marketed with S2 Therapeutics, Inc]) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The product is a quick-release formulation of bromocriptine, a centrally-acting dopamine D2 receptor agonist. When administered as a single timed morning dose, bromocriptine is thought to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients.

Bromocriptine may be used as monotherapy or as adjunctive therapy to sulfonylurea, metformin/sulfonylurea, and single or dual oral hypoglycemic agent therapies; use with insulin has not been studied.

According to a company news release, bromocriptine is the first diabetes drug to be approved under the FDA's new guidelines requiring clinical trials to demonstrate no increased cardiovascular risk. In a 52-week, double-blind, placebo-controlled safety trial (n = 3000), treatment with bromocriptine did not increase the risk for a composite of myocardial infarction, stroke, hospitalization for unstable angina, congestive heart failure, and revascularization surgery (hazard ratio, 0.58; 95% confidence Interval, 0.35 - 0.96).

"For patients newly diagnosed with type 2 diabetes or those who cannot adequately control their blood sugar with currently available medications, Cycloset provides a completely new approach to treating diabetes," said J. Michael Gaziano, MD, in the news release. "In addition, patients with type 2 diabetes are at high-risk for cardiovascular events, so it's important that Cycloset has been demonstrated not to increase the risk of cardiovascular events such as heart attacks, and may actually have potential to lower this risk."

Dr. Gaziano is a cardiologist and associate professor for the Division of Aging at Brigham and Women's Hospital and served as principal investigator in the Cycloset Safety Trial.

The recommended starting dose of bromocriptine is 0.8 mg daily and is increased in 0.8-mg increments weekly until the target range (1.6 - 4.8 mg) or until maximal tolerance is reached. Doses should be administered once daily within 2 hours of waking in the morning and with food to reduce the risk for gastrointestinal tract adverse effects such as nausea.

Adverse events most commonly reported in clinical trials of bromocriptine included nausea, fatigue, vomiting, headache, and dizziness. These events lasted a median of 14 days and were more likely to occur during initial titration of the drug. None of the reports of nausea or vomiting were described as serious.

The FDA warns that bromocriptine can cause orthostatic hypotension and syncope, particularly on initiation of therapy and dose escalation. Caution is advised when treating patients who are receiving antihypertensive therapy; orthostatic vital signs should be evaluated at baseline and periodically thereafter.

Bromocriptine products were previously approved by the FDA for the treatment of pituitary tumors and Parkinson's disease.

Fanapt Prescribing Information

Cycloset Prescribing Information