April 29, 2016
The U.S. Food and Drug Administration approved Nuplazid (pimavanserin) tablets, the first drug approved to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease.
Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson’s disease at some time during the course of their illness. People who experience them see or hear things that are not there (hallucinations) and/or have false beliefs (delusions). The hallucinations and delusions experienced with Parkinson’s disease are serious symptoms, and can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves.
Pimavanserin is formulated as a tartrate salt. The chemical name of pimavanserin is urea, N–[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2- methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-dihydroxybutanedioate (2:1)
Mechanism of action
In in vitro receptor binding and functional assays, pimavanserin preferentially targets 5-HT2A receptors, where it displays high potency as an inverse agonist. The only other receptor targeted by pimavanserin with any notable activity is the 5-HT2C receptor. However, the selectivity of pimavanserin for 5-HT2A receptors is more than 10-fold higher compared to selectivity for 5-HT2C receptors.
Pimavanserin (Nuplazid, ACADIA Pharmaceuticals), has no dopaminergic, histaminergic, adrenergic, or muscarinic activity.
An inverse agonist acts as an “antagonist” and blocks not only ligand-mediated activity through the receptor but also
constitutive activity that occurs regardless of whether the receptor is occupied by an agonist.Importantly, pimavanserin lacks activity at the 5-HT2B receptor that has been associated with gastrointestinal function and myocardial development.
INDICATIONS AND USAGE
NUPLAZID is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
Dosage and Administration
Recommended dose: 34 mg per day, taken orally as two 17 mg tablets once daily, without titration.
Strong CYP3A4 inhibitors (eg, ketoconazole) increase NUPLAZID concentrations. Reduce the NUPLAZID dose by one-half.
Strong CYP3A4 inducers may reduce NUPLAZID exposure, monitor for reduced efficacy. Increase in NUPLAZID dosage may be needed.
Renal Impairment: No dosage adjustment for NUPLAZID is needed in patients with mild to moderate renal impairment. Use of NUPLAZID is not recommended in patients with severe renal impairment.
Hepatic Impairment: Use of NUPLAZID is not recommended in patients with hepatic impairment. NUPLAZID has not been evaluated in this patient population.
Pediatric Use: Safety and efficacy have not been established in pediatric patients.
Safety & Efficacy
The effectiveness of Nuplazid was shown in a six-week clinical trial of 199 participants. Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson’s disease.
As with other atypical antipsychotic drugs, Nuplazid has a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs to treat older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.
Adverse Drug Reactions
The most common side effects reported by participants taking Nuplazid were: swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue (peripheral edema); nausea; and abnormal state of mind (confused state).
Nuplazid was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with Parkinson’s disease. Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The drug was also granted a priority review. The FDA’s priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.
Nuplazid is marketed by Acadia Pharmaceuticals Inc. of San Diego, California.