DRUG INTERACTIONS

 

 • Strong CYP3A4 Inhibitors (e.g., ketoconazole):  Reduce NUPLAZID dose by one-half. 

 

• Strong CYP3A4 Inducers:  Monitor for reduced efficacy.  Increase in NUPLAZID dosage may be needed. 

DRUG INNOVATION - NOVEL DRUG APPROVALS FOR 2016

 

No    Drug Name   Active Ingredient   Approval Date   Approved use

                                                                                           on Approval date

 

8.    Nuplazid         Pimavanserin         4/29/2016          To treat hallucinations and 

                                                                                           delutions associated with

                                                                                           psychosis experienced by                                                                                                some people with Parkinsons                                                                                              disease genoytpes 1 and 4                                                                                                  infections                                                                                                                                                                                                                                                                            Press Release

                                                                                                Drug trials Snapshot

 

Approved by FDA  on 4/29/2016  (Ref- FDA approved List- 2016) 

 

 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

NUPLAZID safely and effectively. See full prescribing information for

NUPLAZID.

 

NUPLAZID (pimavanserin) tablets, for oral use

Initial U.S. Approval: 2016                                                                                                                                                                     

Approved by FDA  on 4/29/2016  (Ref- FDA approved List- 2016)                                                                                                                                                                                                                                                                                                                             HIGHLIGHTS OF PRESCRIBING INFORMATION

 

These highlights do not include all the information needed to use

NUPLAZID safely and effectively. See full prescribing information for NUPLAZID. NUPLAZID® (pimavanserin) tablets, for oral use

 

Initial U.S. Approval: 2016

 

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.

 

 Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. 

 NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.

 

RECENT MAJOR CHANGES

 

­ Contraindications 

 

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 is 34 mg, taken orally as two 17 mg tablets once daily, without titration. 

• Can be taken with or without food.                                               

 

 

 

ADVERSE REACTIONS

 

 Most common adverse reactions (=5% and twice the rate of placebo):  peripheral edema and confusional state. 

 

CONTRAINDICATIONS-

None

 

WARNINGS AND PRECAUTIONS

 

 • QT Interval Prolongation:  Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. 

 

 

 

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 is 34 mg, taken orally as two 17 mg tablets once daily, without titration. 

• Can be taken with or without food.                                               

 

 

 PATIENT COUNSELING INFORMATION

 

Concomitant Medication 

Advise patients to inform their healthcare providers if there are any changes to their current prescription or over-the-counter medications, since there is a potential for drug interactions 

 

 

 

Distributed by:

ACADIA Pharmaceuticals Inc.  San Diego, CA 92130 USA NUPLAZID™ is a trademark of ACADIA Pharmaceuticals Inc.  © 2016 ACADIA Pharmaceuticals Inc.  All rights reserved.  

 

12 CLINICAL PHARMACOLOGY

 

12.1 Mechanism of Action

The mechanism of action of pimavanserin in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis is unknown.  However, the effect of pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors.  12.2 Pharmacodynamics  In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki value 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki value 0.44 nM).  Pimavanserin shows low binding to sigma 1 receptors (Ki value 120 nM) and has no appreciable affinity (Ki value >300 nM), to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.

 

Cardiac Electrophysiology The effect of NUPLAZID on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. 

 

A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. 

 

A pharmacokinetic/ pharmacodynamic analysis with NUPLAZID suggested a concentration-dependent QTc interval prolongation in the therapeutic range. In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of NUPLAZID 34 mg. 

 

These data are consistent with the profile observed in a thorough QT study in healthy subjects.  Sporadic QTcF values =500 msec and change from baseline values =60 msec were observed in subjects treated with NUPLAZID 34 mg; although the incidence was generally similar for NUPLAZID and placebo groups.  There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of NUPLAZID, including those patients with hallucinations and delusions associated with PDP [see Warnings and Precautions (5.2)].

 

12.3 Pharmacokinetics 

Pimavanserin demonstrates dose-proportional pharmacokinetics after single oral doses from 17 to 255 mg (0.5- to 7.5-times the recommended dosage).  The pharmacokinetics of pimavanserin are similar in both the study population and healthy subjects. 

 

The mean plasma half-lives for pimavanserin and the active metabolite (N-desmethylated metabolite) are approximately 57 hours and 200 hours, respectively.

 

Absorption

The median Tmax of pimavanserin was 6 (range 4-24) hours and was generally unaffected by dose.  The bioavailability of pimavanserin oral tablet and pimavanserin solution was essentially identical.  The formation of the major circulating N-desmethylated metabolite AC-279 (active) from pimavanserin occurs with a median Tmax of 6 hours. 

 

Ingestion of a high-fat meal had no significant effect on rate (Cmax) and extent (AUC) of pimavanserin exposure.  Cmax decreased by about 9% while AUC increased by about 8% with a high-fat meal.  

Reference ID: 3924821

 

 

9 

Distribution

Pimavanserin is highly protein bound (~95%) in human plasma.  Protein binding appeared to be doseindependent and did not change significantly over dosing time from Day 1 to Day 14.

 

  Following administration of a single dose of NUPLAZID (34 mg), the mean (SD) apparent volume of distribution was 2173 (307) L.   

 

Elimination Metabolism

Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5 and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes.  CYP3A4 is the major enzyme responsible for the formation of its major active metabolite (AC-279).  Pimavanserin does not cause clinically significant CYP inhibition or induction of CYP3A4. 

Based on in vitro data, pimavanserin is not an irreversible inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4). Based on in vitro studies, transporters play no significant role in the disposition of pimavanserin.  AC-279 is neither a reversible or irreversible (metabolism-dependent) inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).

 

  AC-279 does not cause clinically significant CYP3A induction and is not predicted to cause induction of any other CYP enzymes involved in drug metabolism.

 

Excretion

Approximately 0.55% of the 34 mg oral dose of 14C-pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days.  Less than 1% of the administered dose of pimavanserin and its active metabolite AC-279 were recovered in urine. 

 

Specific Populations

Population PK analysis indicated that exposure of pimavanserin in patients with mild to moderate renal impairment was similar to exposure in patients with normal renal function.

 

  Age, sex, ethnicity, and weight do not have clinically relevant effect on the pharmacokinetics of pimavanserin. Pimavanserin has not been studied in patients with severe renal impairment or mild to severe hepatic impairment [see Use in Specific Populations (8.6, 8.7)]. 

 

 Drug Interaction Studies CYP3A4 Inhibitor:  ketoconazole, a strong inhibitor of CYP3A4, increased pimavanserin Cmax by 1.5-fold and AUC by 3-fold [see Dosage and Administration (2.2) and Drug Interactions (7.1)]. 

Reference ID: 3924821

 

 

10 

The effect of pimavanserin on other drugs is shown in Figure 1. Figure 1 The Effects of Pimavanserin on the Pharmacokinetics of Other Drugs 

 

 

USE IN SPECIFIC POPULATIONS

 

1. Pregnancy Risk Summary

There are no data on NUPLAZID use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage. 

 

In animal reproduction studies, no adverse developmental fects were seen when pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively.

 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 

 

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.  

 

2, Lactation Risk Summary

There is no information regarding the presence of pimavanserin in human milk, the effects on the breastfed infant, or the effects on milk production. 

 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NUPLAZID and any potential adverse effects on the breastfed infant from NUPLAZID or from the underlying maternal condition.

 

3.Pediatric Use

Safety and effectiveness of NUPLAZID have not been established in pediatric patients. 

 

4.Geriatric Use

No dose adjustment is required for elderly patients. Parkinson’s disease is a disorder occurring primarily in individuals over 55 years of age. 

 

The mean age of patients enrolled in the 6-week clinical studies with NUPLAZID [see Adverse Reactions (6.1)] was 71 years, with 49% 65-75 years old and 31% >75 years old. 

 

No clinically meaningful differences in safety or effectiveness were noted between these two groups.   

 

5.Renal Impairment

No dosage adjustment for NUPLAZID is needed in patients with mild to moderate (CrCL =30 mL/min, Cockcroft-Gault) renal impairment [see Clinical Pharmacology (12.3)].

 

Use of NUPLAZID is not recommended in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault).  NUPLAZID has not been evaluated in this patient population.

 

6.Hepatic Impairment

Use of NUPLAZID is not recommended in patients with hepatic impairment.  NUPLAZID has not been evaluated in this patient population. 

 

7.Other Specific Populations

No dosage adjustment is required based on patient’s age, sex, ethnicity, or weight.  These factors do not affect the pharmacokinetics of NUPLAZID [see Clinical Pharmacology (12.3)].

 

8.DRUG ABUSE AND DEPENDENCE

 Controlled Substance NUPLAZID is not a controlled substance.

 

 Abuse

NUPLAZID has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. 

 While short-term, placebo-controlled and long-term, open-label clinical trials did not reveal increases in drugseeking behavior, the limited experience from the clinical trials do not predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

 

9.OVERDOSAGE

 

 Human Experience- The pre-marketing clinical trials involving NUPLAZID in approximately 1200 subjects and patients do not provide information regarding symptoms with overdose.  In healthy subject studies, dose-limiting nausea and vomiting were observed. 

 

 Management of Overdose- There are no known specific antidotes for NUPLAZID.  In managing overdose, cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias 

 

If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of NUPLAZID 

 

Consider the long plasma half-life of pimavanserin (about 57 hours) and the possibility of multiple drug involvement.  Consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.