Nuplazid
Generic Name: pimavanserin
tartrate
Dosage Form: tablet, coated
Medically reviewed by
Drugs.com. Last updated on May 1, 2019.
WARNING: INCREASED MORTALITY IN ELDERLY
PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
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 [see Warnings and Precautions (5.1)].
Indications
and Usage for Nuplazid
Nuplazid® is indicated for the
treatment of hallucinations and delusions associated with Parkinson's disease
psychosis [see Clinical Studies (14)].
Nuplazid
Dosage and AdministrationGeneral Dosing Information
The recommended dose of Nuplazid is 34
mg taken orally once daily, without titration.
Nuplazid can be taken with
or without food.
Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors
and Inducers
Coadministration with Strong CYP3A4
Inhibitors
The recommended
dose of Nuplazid when coadministered with strong CYP3A4 inhibitors (e.g.,
ketoconazole) is 10 mg, taken orally as one tablet once daily [see Drug Interactions (7.1)].Coadministration with Strong or
Moderate CYP3A4 Inducers
Avoid
concomitant use of strong or moderate CYP3A4 inducers with Nuplazid [see Drug Interactions (7.1)].Dosage
Forms and Strengths
Nuplazid (pimavanserin) is
available as:
34 mg strength capsules. The
capsules are opaque white and light green with "PIMA" and
"34" printed in black.10 mg strength tablets. The
orange, round, coated tablets are debossed on one side with a
"P" and "10" on the reverse side.Contraindications
Nuplazid is contraindicated
in patients with a history of a hypersensitivity reaction to pimavanserin or
any of its components. Rash, urticaria, and reactions consistent with
angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and
dyspnea) have been reported [see Adverse Reactions (6.2)].
Warnings
and PrecautionsIncreased Mortality in Elderly Patients with Dementia-Related
Psychosis
Antipsychotic drugs increase
the all-cause risk of death in elderly patients with dementia-related
psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials
(modal duration of 10 weeks and largely in patients taking atypical
antipsychotic drugs) revealed a risk of death in the drug-treated patients of
between 1.6- to 1.7-times that in placebo-treated patients. Over the course of
a typical 10-week controlled trial, the rate of death in drug-treated patients
was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.
Although the causes of death
were varied, most of the deaths appeared to be either cardiovascular (e.g.,
heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
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 [see Boxed Warning].
QT Interval Prolongation
Nuplazid prolongs the QT
interval. The use of Nuplazid should be avoided in patients with known QT
prolongation or in combination with other drugs known to prolong QT interval
including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3
antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications
(e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics
(e.g., gatifloxacin, moxifloxacin) [see Drug Interactions (7.1)]. Nuplazid
should also be avoided in patients with a history of cardiac arrhythmias, as
well as other circumstances that may increase the risk of the occurrence of
torsade de pointes and/or sudden death, including symptomatic bradycardia,
hypokalemia or hypomagnesemia, and the presence of congenital prolongation of
the QT interval [see Clinical Pharmacology (12.2)].
Adverse
Reactions
The following serious
adverse reactions are discussed elsewhere in the labeling:
Increased Mortality in Elderly
Patients with Dementia-Related Psychosis
[see Boxed Warning and Warnings and Precautions (5.1)]QT Interval Prolongation
[see Warnings and Precautions (5.2)]Clinical Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
The clinical trial database
for Nuplazid consists of over 1200 subjects and patients exposed to one or more
doses of Nuplazid. Of these, 616 were patients with hallucinations and
delusions associated with Parkinson's disease psychosis (PDP). In the
placebo-controlled setting, the majority of experience in patients comes from
studies evaluating once-daily Nuplazid doses of 34 mg (N=202) compared to
placebo (N=231) for up to 6 weeks. In the controlled trial setting, the study
population was approximately 64% male and 91% Caucasian, and the mean age was
about 71 years at study entry. Additional clinical trial experience in patients
with hallucinations and delusions associated with PDP comes from two
open-label, safety extension studies (total N=497). The majority of patients
receiving long-term treatment received 34 mg once-daily (N=459). Over 300
patients have been treated for more than 6 months; over 270 have been treated
for at least 12 months; and over 150 have been treated for at least 24 months.
The following adverse
reactions are based on the 6-week, placebo-controlled studies in which Nuplazid
was administered once daily to patients with hallucinations and delusions
associated with PDP.
Common Adverse Reactions
(incidence ≥5% and at least twice the rate of placebo): peripheral edema (7%
Nuplazid 34 mg vs. 2% placebo) and confusional state (6% Nuplazid 34 mg vs. 3%
placebo).
Adverse
Reactions Leading to Discontinuation of Treatment
A total of 8% (16/202) of
Nuplazid 34 mg-treated patients and 4% (10/231) of placebo-treated patients
discontinued because of adverse reactions. The adverse reactions that occurred
in more than one patient and with an incidence at least twice that of placebo
were hallucination (2% Nuplazid vs. <1% placebo), urinary tract infection
(1% Nuplazid vs. <1% placebo), and fatigue (1% Nuplazid vs. 0% placebo).
Adverse reactions that
occurred in 6-week, placebo-controlled studies and that were reported at an
incidence of ≥2% and >placebo are presented in Table
1.
Table 1 Adverse Reactions in
Placebo-Controlled Studies of 6-Week Treatment Duration and Reported in ≥2%
and >Placebo
|
|
Percentage of Patients Reporting Adverse
Reaction
|
|
|
Nuplazid 34 mg
|
Placebo
|
|
N=202
|
N=231
|
|
Gastrointestinal disorders
|
|
Nausea
|
7%
|
4%
|
|
Constipation
|
4%
|
3%
|
|
General disorders
|
|
Peripheral
edema
|
7%
|
2%
|
|
Gait
disturbance
|
2%
|
<1%
|
|
Psychiatric disorders
|
|
Hallucination
|
5%
|
3%
|
|
Confusional
state
|
6%
|
3%
|
Adverse
Reactions in Demographic Subgroups
Examination of population
subgroups in the 6-week, placebo-controlled studies did not reveal any
differences in safety on the basis of age (≤75 vs. >75 years) or sex.
Because the study population was predominantly Caucasian (91%; consistent with
reported demographics for PD/PDP), racial or ethnic differences in the safety
profile of Nuplazid could not be assessed. In addition, in the 6-week,
placebo-controlled studies, no clinically relevant differences in the incidence
of adverse reactions were observed among those with a Mini-Mental State
Examination (MMSE) score at entry of <25 versus those with scores ≥25.
Postmarketing Experience
The following adverse
reactions have been identified during postapproval use of Nuplazid. Because
these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. These reactions include rash, urticaria,
reactions consistent with angioedema (e.g., tongue swelling, circumoral edema,
throat tightness, and dyspnea), somnolence, falls, agitation, and aggression.
Drug
InteractionsDrugs Having Clinically Important Interactions with Nuplazid
Table 2 Clinically Important Drug
Interactions with Nuplazid
|
|
QT Interval Prolongation
|
|
Clinical
Impact:
|
Concomitant use
of drugs that prolong the QT interval may add to the QT effects of Nuplazid
and increase the risk of cardiac arrhythmia.
|
|
Intervention:
|
Avoid the use of
Nuplazid in combination with other drugs known to prolong QT interval [see Warnings and Precautions (5.2)].
|
|
Examples:
|
Class 1A
antiarrhythmics: quinidine, procainamide, disopyramide;
Class 3 antiarrhythmics: amiodarone, sotalol;
Antipsychotics: ziprasidone, chlorpromazine, thioridazine;
Antibiotics: gatifloxacin, moxifloxacin
|
|
Strong CYP3A4 Inhibitors
|
|
Clinical
Impact:
|
Concomitant use
of Nuplazid with a strong CYP3A4 inhibitor increases pimavanserin
exposure [see Clinical Pharmacology (12.3)].
|
|
Intervention:
|
If Nuplazid is
used with a strong CYP3A4 inhibitor, reduce the dosage of Nuplazid [see Dosage and Administration (2.2)].
|
|
Examples:
|
itraconazole,
ketoconazole, clarithromycin, indinavir
|
|
Strong or Moderate CYP3A4 Inducers
|
|
Clinical
Impact:
|
Concomitant use
of Nuplazid with strong or moderate CYP3A4 inducers reduces pimavanserin
exposure [see Clinical Pharmacology (12.3)].
|
|
Intervention:
|
Avoid
concomitant use of strong or moderate CYP3A4 inducers with Nuplazid [see Dosage and Administration (2.2)].
|
|
Examples:
|
Strong inducers:
carbamazepine,St. John'swort, phenytoin, rifampin
Moderate inducers: modafinil, thioridazine, efavirenz, nafcillin
|
Drugs Having No Clinically Important Interactions with Nuplazid
Based on pharmacokinetic
studies, no dosage adjustment of carbidopa/levodopa is required when
administered concomitantly with Nuplazid [see Clinical Pharmacology (12.3)].
USE IN
SPECIFIC POPULATIONSPregnancy
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 effects 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. Administration of pimavanserin to pregnant
rats during pregnancy and lactation resulted in maternal toxicity and lower pup
survival and body weight at doses which are 2-times the MRHD of 34 mg/day [see Data].
The estimated background
risk of major birth defects and miscarriage for the indicated population is
unknown. In theU.S.general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal
Data
Pimavanserin was not
teratogenic in pregnant rats when administered during the period of
organogenesis at oral doses of 0.9, 8.5, and 51 mg/kg/day, which are 0.2- and
10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC at
mid and high doses, respectively. Maternal toxicity included reduction in body
weight and food consumption at the highest dose.
Administration of
pimavanserin to pregnant rats during pregnancy and lactation at oral doses of
8.5, 26, and 51 mg/kg/day, which are 0.14- to 14-times the MRHD of 34 mg/day
based on AUC, caused maternal toxicity, including mortality, clinical signs
including dehydration, hunched posture, and rales, and decreases in body
weight, and/or food consumption at doses ≥26 mg/kg/day (2-times the MRHD based
on AUC). At these maternally toxic doses there was a decrease in pup survival,
reduced litter size, and reduced pup weights, and food consumption.
Pimavanserin had no effect on sexual maturation, neurobehavioral function
including learning and memory, or reproductive function in the first generation
pups up to 14-times the MRHD of 34 mg/day based on AUC.
Pimavanserin was not
teratogenic in pregnant rabbits during the period of organogenesis at oral
doses of 4.3, 43, and 85 mg/kg/day, which are 0.2- to 12-times the MRHD of 34
mg/day based on AUC. Maternal toxicity, including mortality, clinical signs of
dyspnea and rales, decreases in body weight and/or food consumption, and
abortions occurred at doses 12-times the MRHD of 34 mg/day based on AUC.
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.
Pediatric Use
Safety and effectiveness of
Nuplazid have not been established in pediatric patients.
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. In the pooled
population of patients enrolled in 6-week, placebo-controlled studies (N=614),
27% had MMSE scores from 21 to 24 compared to 73% with scores ≥25. No
clinically meaningful differences in safety or effectiveness were noted between
these two groups.
Patients with Renal Impairment
No dosage adjustment for
Nuplazid is needed in patients with mild to severe renal impairment or end
stage renal disease (ESRD); however, increased exposure (Cmax and AUC) to Nuplazid
occurred in patients with severe renal impairment (CrCL <30 mL/min,
Cockcroft-Gault) in a renal impairment study [see Clinical Pharmacology (12.3)].
Nuplazid should be used with
caution in patients with severe renal impairment and end stage renal disease.
In a renal impairment study,
dialysis did not appear to significantly affect the concentrations of
Nuplazid [see Clinical Pharmacology (12.3)].
Patients with Hepatic Impairment
No dosage adjustment for
Nuplazid is recommended in patients with hepatic impairment based on the
exposure differences observed in patients with and without hepatic impairment
in a hepatic impairment study [see Clinical Pharmacology (12.3)].
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)].
Drug Abuse
and DependenceControlled 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 drug-seeking 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.
OverdosageHuman 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 [see Warnings and Precautions (5.2)]. 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 [see Drug Interactions (7.1)]. Consider
the long plasma half-life of pimavanserin (about 57 hours) and the possibility
of multiple drug involvement. Consult aCertifiedPoisonControlCenter(1-800-222-1222) for up-to-date guidance and advice.
Nuplazid
Description
Nuplazid contains
pimavanserin, an atypical antipsychotic, which is present as pimavanserin
tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-dihydroxybutanedioate
(2:1). Pimavanserin tartrate is freely soluble in water. Its molecular formula
is (C25H34FN3O2)2∙C4H6O6 and its molecular
weight is 1005.20 (tartrate salt). The chemical structure is:
The molecular formula of
pimavanserin free base is C25H34FN3O2 and its molecular weight is 427.55.
Nuplazid capsules are intended
for oral administration only. Each capsule contains 40 mg of pimavanserin
tartrate, which is equivalent to 34 mg of pimavanserin free base. Inactive
ingredients include magnesium stearate and microcrystalline cellulose.
Additionally, the following inactive ingredients are present as components of
the capsule shell: black iron oxide, FD&C blue #1, hypromellose, titanium
dioxide, and yellow iron oxide.
Nuplazid tablets are
intended for oral administration only. Each round, orange, immediate-release,
film coated tablet contains 11.8 mg of pimavanserin tartrate, which is
equivalent to 10 mg pimavanserin free base. Inactive ingredients include
magnesium stearate, pregelatinized starch, and silicified microcrystalline
cellulose. Additionally, the following inactive ingredients are present as
components of the film coat: polyethylene glycol, polyvinyl alcohol, red iron
oxide, talc, titanium dioxide, and yellow iron oxide.
Nuplazid -
Clinical PharmacologyMechanism of Action
The mechanism of action of
pimavanserin in the treatment of hallucinations and delusions associated with
Parkinson's disease psychosis is unclear. 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.
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)].
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.
Administration of one 34 mg
capsule once daily results in plasma pimavanserin concentrations that are
similar to exposure with two 17 mg tablets once daily.
Distribution
Pimavanserin is highly
protein bound (~95%) in human plasma. Protein binding appeared to be
dose-independent 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 age, sex, ethnicity, and weight do not have clinically relevant
effect on the pharmacokinetics of pimavanserin. In addition, the analysis
indicated that exposure of pimavanserin in patients with mild to moderate renal
impairment was similar to exposure in patients with normal renal function.
The effects of other
intrinsic factors on pimavanserin pharmacokinetics is shown in Figure 1 [see Use in Specific Populations (8.6, 8.7)].
Figure
1 Effects of Intrinsic Factors on Pimavanserin Pharmacokinetics
*Less than 10% of the
administered dose of Nuplazid was recovered in the dialysate.
Drug
Interaction Studies
CYP3A4 Inhibitor:
ketoconazole, a strong inhibitor of CYP3A4, increased pimavanserin Cmax by 1.5-fold and AUC by
3-fold. Population PK modeling and simulation show that steady-state exposure
(Cmax,ss and
AUCtau)
for 10 mg pimavanserin with ketoconazole is similar to exposure for 34 mg
pimavanserin alone [see Dosage and Administration (2.2) and Drug Interactions (7.1)].
CYP3A4 Inducer: In a
clinical study where single doses of 34 mg pimavanserin were administered on
Days 1 and 22, and 600 mg rifampin, a strong inducer of CYP3A4, was given daily
on Days 15 through 21, pimavanserin Cmax and AUC decreased by 71% and 91%, respectively, compared
to pre-rifampin plasma concentrations. In a simulation with a moderate CYP3A4
inducer (efavirenz), physiologically based pharmacokinetic (PBPK) models
predicted pimavanserin Cmax,ss and AUCtau at steady state decreased by approximately 60% and 70%,
respectively [see Dosage and Administration (2.2) and Drug Interactions (7.1)].
There is no effect of pimavanserin
on the pharmacokinetics of midazolam, a CYP3A4 substrate, or carbidopa/levodopa
as shown in Figure 2.
Figure
2 Effects of Pimavanserin on the Pharmacokinetics of Other Drugs
*AUC and Cmax depict levodopa
levels.
Nonclinical
ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There was no increase in the
incidence of tumors following daily oral administration of pimavanserin to mice
or rats for 2 years. Mice were administered pimavanserin at oral doses of 2.6,
6, and 13 (males)/8.5, 21, and 43 mg/kg/day (females) which are 0.01- to 1-
(males)/0.5- to 7- (females) times the MRHD of 34 mg/day based on AUC. Rats
were administered pimavanserin at oral doses of 2.6, 8.5, and 26 (males)/4.3,
13, and 43 mg/kg/day (females) which are 0.01- to 4- (males)/0.04- to 16-
(females) times the MRHD of 34 mg/day based on AUC.
Mutagenesis
Pimavanserin was not
mutagenic in the in vitro Amesreverse mutation test, or in the in vitro mouse lymphoma assay, and was not
clastogenic in the in vivo mouse bone
marrow micronucleus assay.
Impairment
of Fertility
Pimavanserin was
administered orally to male and female rats before mating, through mating, and
up to Day 7 of gestation at doses of 8.5, 51, and 77 mg/kg/day, which are
approximately 2-, 15-, and 22-times the maximum recommended human dose (MRHD)
of 34 mg/day based on mg/m2, respectively. Pimavanserin had no effect on fertility or
reproductive performance in male and female rats at doses up to 22-times the
MRHD of 34 mg based on mg/m2. Changes in uterine parameters (decreases in the number of
corpora lutea, number of implants, viable implants, and increases in
pre-implantation loss, early resorptions and post-implantation loss) occurred
at the highest dose which was also a maternally toxic dose. Changes in sperm
parameters (decreased density and motility) and microscopic findings of
cytoplasmic vacuolation in the epididymis occurred at doses approximately
15-times the MRHD of 34 mg/day based on mg/m2.
Animal Toxicology and/or Pharmacology
Phospholipidosis (foamy
macrophages and/or cytoplasmic vacuolation) was observed in multiple tissues
and organs of mice, rats, and monkeys following oral daily administration of
pimavanserin. The occurrence of phospholipidosis was both dose- and
duration-dependent. The most severely affected organs were the lungs and
kidneys. In rats, diffuse phospholipidosis was associated with increased lung
and kidney weights, respiratory-related clinical signs including rales, labored
breathing, and gasping, renal tubular degeneration, and, in some animals,
focal/multifocal chronic inflammation in the lungs at exposures ≥10-times those
at the maximum recommended human dose (MRHD) of 34 mg/day based on AUC.
Phospholipidosis caused mortality in rats at exposures ≥16-times the MRHD of 34
mg/day based on AUC. The chronic inflammation in the rat lung was characterized
by minimal to mild focal collagen positive fibroplasia as shown by specialized
staining. Chronic inflammation of the lungs was not seen in monkeys treated for
12 months (exposures 9-times the MRHD). Based on the exposures at the estimated
No Observed Effect Level (NOEL) for chronic lung inflammation in rats, there is
a 5- to 9-times safety margin after 6-months of treatment and a 2- to 4-times
safety margin after 24-months (lifetime) treatment compared to exposure at the
MRHD. The relevance of these findings to human risk is not clear.
Clinical
Studies
The efficacy of Nuplazid 34
mg as a treatment of hallucinations and delusions associated with Parkinson's
disease psychosis was demonstrated in a 6-week, randomized, placebo-controlled,
parallel-group study. In this outpatient study, 199 patients were randomized in
a 1:1 ratio to Nuplazid 34 mg or placebo once daily. Study patients (male or
female and aged 40 years or older) had a diagnosis of Parkinson's disease (PD)
established at least 1 year prior to study entry and had psychotic symptoms
(hallucinations and/or delusions) that started after the PD diagnosis and that
were severe and frequent enough to warrant treatment with an antipsychotic. At
entry, patients were required to have a Mini-Mental State Examination (MMSE)
score ≥21 and to be able to self-report symptoms. The majority of patients were
on PD medications at entry; these medications were required to be stable for at
least 30 days prior to study start and throughout the study period.
The PD-adapted Scale for the
Assessment of Positive Symptoms (SAPS-PD) was used to evaluate the efficacy of
Nuplazid 34 mg. SAPS-PD is a 9-item scale adapted for PD from the Hallucinations
and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with
0 being none and 5 representing severe and frequent symptoms. Therefore, the
SAPS-PD total score can range from 0 to 45 with higher scores reflecting
greater severity of illness. A negative change in score indicates improvement.
Primary efficacy was evaluated based on change from baseline to Week 6 in
SAPS-PD total score.
As shown in Table 3, Figure 3,
and Figure 4, Nuplazid 34 mg (n=95) was
statistically significantly superior to placebo (n=90) in decreasing the
frequency and/or severity of hallucinations and delusions in patients with PDP
as measured by central, independent, and blinded raters using the SAPS-PD
scale. An effect was seen on both the hallucinations and delusions components
of the SAPS-PD.
Table 3 Primary Efficacy Analysis Result
Based on SAPS-PD (N=185)
|
|
Endpoint
|
Treatment
Group
|
Mean Baseline Score (SD)
|
LS Mean Change from Baseline (SE)
|
Placebo-subtracted Difference* (95% CI)
|
|
SD: standard
deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence
interval.
|
|
*
Difference (drug minus placebo) in least-squares
mean change from baseline.
†
Statistically significantly superior to placebo.
‡
Supportive analysis.
|
|
SAPS-PD
|
Nuplazid
|
15.9 (6.12)
|
-5.79 (0.66)
|
-3.06† (-4.91, -1.20)
|
|
Placebo
|
14.7 (5.55)
|
-2.73 (0.67)
|
--
|
|
SAPS-PD
Hallucinations‡
|
Nuplazid
|
11.1 (4.58)
|
-3.81 (0.46)
|
-2.01 (-3.29, -0.72)
|
|
Placebo
|
10.0 (3.80)
|
-1.80 (0.46)
|
--
|
|
SAPS-PD
Delusions‡
|
Nuplazid
|
4.8 (3.59)
|
-1.95 (0.32)
|
-0.94 (-1.83, -0.04)
|
|
Placebo
|
4.8 (3.82)
|
-1.01 (0.32)
|
--
|
The effect of Nuplazid on
SAPS-PD improved through the six-week trial period, as shown in Figure 3.
Figure
3 SAPS-PD Change from Baseline through 6 Weeks Total Study Treatment
Figure
4 Proportion of Patients with SAPS-PD Score Improvement at the End of Week 6
(N=185)
|
Complete
response = SAPS-PD score reduced to zero from baseline value.
|
|
Patients with
missing values were counted as non-responders.
|
|
|
Motor
Function in Patients with Hallucinations and Delusions Associated with
Parkinson's Disease Psychosis
Nuplazid 34 mg did not show
an effect compared to placebo on motor function, as measured using the Unified
Parkinson's Disease Rating Scale Parts II and III (UPDRS Parts II+III) (Figure 5). A negative change in score indicates
improvement. The UPDRS Parts II+III was used to assess the patient's
Parkinson's disease state during the 6-week double-blind treatment period. The
UPDRS score was calculated as the sum of the 40 items from activities of daily
living and motor examination, with a range of 0 to 160.
|
LSM:
least-squares mean; SE: standard error. The error bars extend one SE below
the LSM.
|
|
Figure 5 Motor Function Change from Baseline to Week 6 in UPDRS Parts
II+III (LSM - SE)
|
|
|
How
Supplied/Storage and Handling
Nuplazid (pimavanserin) is
available as:
34
mg Capsule:
Opaque white and light green
capsule with "PIMA" and "34" printed in black.
Bottle of
30: NDC 63090-340-30
10
mg Tablet:
Orange,
round, coated tablet debossed with "P" on one side and "10"
on the reverse.
Bottle of
30: NDC 63090-100-30
Storage
34
mg Capsule:
Store at 20°C to 25°C (68°F
to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP
Controlled Room Temperature]. To prevent potential capsule color fading,
protect from light.
10
mg Tablet:
Store at 20°C to 25°C (68°F
to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP
Controlled Room Temperature].
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 [see Warnings and Precautions (5.2), Drug Interactions (7)].
Distributed by:
ACADIA Pharmaceuticals Inc.
San Diego,CA92130USA
Nuplazid® is a trademark of
ACADIA Pharmaceuticals Inc.
© 2019 ACADIA Pharmaceuticals Inc. All rights reserved.
PRINCIPAL
DISPLAY PANEL - 34 mg Capsule Bottle Label
NDC 63090-340-30
34
mg
Nuplazid®
(pimavanserin) capsules
34 mg per capsule
Rx
only
30 Capsules
PRINCIPAL
DISPLAY PANEL - 60 Tablets Bottle Label
60
tablets
NDC 63090-170-60
Nuplazid™
(pimavanserin) tablets
17
mg
Rx
Only
PRINCIPAL
DISPLAY PANEL - 10 mg Tablet Bottle Label
NDC 63090-100-30
10
mg
Nuplazid®
(pimavanserin) tablets
10 mg per tablet
Rx
only
30 Tablets
|
Nuplazid
pimavanserin tartrate capsule
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:63090-340
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
pimavanserin
tartrate (pimavanserin)
|
pimavanserin
|
34 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
magnesium
stearate
|
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
HYPROMELLOSE
2910 (15 MPA.S)
|
|
|
titanium
dioxide
|
|
|
FERRIC
OXIDE YELLOW
|
|
|
FD&C
BLUE NO. 1
|
|
|
FERROSOFERRIC
OXIDE
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE, GREEN
|
Score
|
score with
uneven pieces
|
|
Shape
|
CAPSULE
|
Size
|
4mm
|
|
Flavor
|
|
Imprint
Code
|
PIMA;34
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:63090-340-30
|
30 CAPSULE in
1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA210793
|
06/28/2018
|
|
|
|
Nuplazid
pimavanserin tartrate tablet, coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:63090-170
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
pimavanserin
tartrate (pimavanserin)
|
pimavanserin
|
17 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
starch,
corn
|
|
|
magnesium
stearate
|
|
|
microcrystalline
cellulose
|
|
|
hypromellose
2910 (15 MPA.S)
|
|
|
talc
|
|
|
titanium
dioxide
|
|
|
polyethylene
glycol 3350
|
|
|
saccharin
sodium anhydrous
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
7mm
|
|
Flavor
|
|
Imprint
Code
|
P;17
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:63090-170-60
|
60 TABLET,
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207318
|
04/29/2016
|
04/30/2022
|
|
|
Nuplazid
pimavanserin tartrate tablet, coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:63090-100
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
pimavanserin
tartrate (pimavanserin)
|
pimavanserin
|
10 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
starch,
corn
|
|
|
magnesium
stearate
|
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
POLYETHYLENE
GLYCOL 1000
|
|
|
talc
|
|
|
titanium
dioxide
|
|
|
FERRIC
OXIDE YELLOW
|
|
|
FERRIC
OXIDE RED
|
|
|
|
Product
Characteristics
|
|
Color
|
ORANGE
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
7mm
|
|
Flavor
|
|
Imprint
Code
|
P;10
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:63090-100-30
|
30 TABLET,
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207318
|
06/28/2018
|
|
|
|
Labeler - ACADIA Pharmaceuticals Inc (963571302)
|
ACADIA
Pharmaceuticals Inc
