Pimavanserin

1 INDICATIONS AND USAGE Pimavanserin capsule is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis [see Clinical Studies (14) ]. Pimavanserin capsule is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. (1)

2 DOSAGE AND ADMINISTRATION Recommended dose is 34 mg taken orally once daily, without titration. ( 2.1 ) Can be taken with or without food. ( 2.2 ) Capsules may be swallowed whole or opened and entire contents sprinkled over a tablespoon of certain types of soft food. ( 2.2 ) 2.1 Recommended Dosage The recommended dose of pimavanserin capsule is 34 mg taken orally once daily, without titration. 2.2 Administration Information Pimavanserin capsule can be taken with or without food [see Clinical Pharmacology (12.3)]. Pimavanserin capsules can be taken whole, or opened and the entire contents sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Consume the drug/food mixture immediately without chewing; do not store for future use. 2.3 Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors and Inducers Coadministration with Strong CYP3A4 Inhibitors The recommended dose of pimavanserin capsules when coadministered with strong CYP3A4 inhibitors 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 pimavanserin capsules [see Drug Interactions (7.1) ].

6 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) ] Most common adverse reactions (≥5% and twice the rate of placebo): peripheral edema and confusional state. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 pimavanserin consists of over 1200 subjects and patients exposed to one or more doses of pimavanserin. 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 pimavanserin 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 pimavanserin 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% pimavanserin 34 mg vs. 2% placebo) and confusional state (6% pimavanserin 34 mg vs. 3% placebo). Adverse Reactions Leading to Discontinuation of Treatment A total of 8% (16/202) of pimavanserin 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% pimavanserin vs. <1% placebo), urinary tract infection (1% pimavanserin vs. <1% placebo), and fatigue (1% pimavanserin 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 Pimavanserin 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 pimavanserin 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pimavanserin. 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.

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 T max 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 T max of 6 hours. Effect of Food Ingestion of a high-fat meal had no significant effect on rate (C max ) and extent (AUC) of pimavanserin exposure. C max 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 pimavanserin (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 14 C-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 and 8.7) ] . Figure 1 Effects of Intrinsic Factors on Pimavanserin Pharmacokinetics *Less than 10% of the administered dose of pimavanserin was recovered in the dialysate. Drug Interaction Studies CYP3A4 Inhibitor: ketoconazole, a strong inhibitor of CYP3A4, increased pimavanserin C max by 1.5-fold and AUC by 3-fold. Population PK modeling and simulation show that steady-state exposure (C max,ss and AUC tau ) for 10 mg pimavanserin with ketoconazole is similar to exposure for 34 mg pimavanserin alone [see Dosage and Administration (2.3) 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 C max 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 C max,ss and AUC tau at steady state decreased by approximately 60% and 70%, respectively [see Dosage and Administration (2.3) 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 pimavanserin-figure-1 pimavanserin-figure-2