Primavanserin- Antipsychotic drugs
Drug Name:Primavanserin- Antipsychotic drugs
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
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.
Indication:
DRUG INNOVATION - NOVEL DRUG APPROVALS FOR 2016
No Drug Name Active Ingredient Approval Date FDA-Approved use
on Approval date
8. Nuplazid Primavanserin 4/29/2016 To treat hallucinations and
delutions associated with
psychosis experienced by
some people with Parkinsons
disease
Press Release
Drug Trial 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
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (=5% and twice the rate of placebo):
peripheral edema and confusional state.
Contra-Indications:
CONTRAINDICATIONS
None
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.
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.
Dosages/ Overdosage Etc:
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.
DOSAGE FORMS AND STRENGTHS
Tablets: 17 mg.
OVERDOSE-
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.
Patient Information:
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
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
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.
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.
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.
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.
Pregnancy and lactation:
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 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.
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 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.
5.Renal Impairment
No dosage adjustment for NUPLAZID is needed in patients with mild to
moderate (CrCL =30 mL/min,Cockcroft-Gault) renal impairment
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
.
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.
10. 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.
