Nuplazid

Pimavanserin is used to treat hallucinations and delusions in people with psychosis from Parkinson's disease (PD; a disorder of the nervous system that causes difficulties with movement, muscle control, and balance). Pimavanserin is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

Unless your doctor tells you otherwise, continue your normal diet.

Pimavanserin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• swelling of hands, ankles, or feet

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• hallucinations (seeing things or hearing voices that do not exist)
• confusion
• difficulty walking normally

Pimavanserin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

1-10%

Nausea (7%)

Peripheral edema (7%)

Confusional state (6%)

Hallucinations (5%)

Constipation (4%)

Gait disturbance (2%)

Pregnancy

There are no data for 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

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Tell your doctor if you are pregnant or plan to become pregnant.

There are no data on Nuplazid use in pregnant women. That said, the risk for major congenital malformations or miscarriage can not be assessed. In animal studies, no problems in regards to the baby's development were seen.
 

Take Nuplazid exactly as prescribed.

Nuplazid comes in tablet form and is taken by mouth, once a day, with or without food.

Pimavanserin is an antipsychotic medicine that works by changing the actions of chemicals in the brain.

Pimavanserin is used to treat hallucinations and delusions caused by psychosis that is related to Parkinson's disease.

Pimavanserin may also be used for purposes not listed in this medication guide.

Pimavanserin is not approved for use in psychotic conditions related to dementia. Pimavanserin may increase the risk of death in older adults with dementia-related conditions.

Pimavanserin is not approved for use in psychotic conditions related to dementia and not to Parkinson's disease. Pimavanserin may increase the risk of death in older adults with dementia-related conditions.

You should not use pimavanserin if you are allergic to it.

Pimavanserin can cause a serious heart problem, especially if you use certain medicines at the same time, including antibiotics, antidepressants, heart rhythm medicine, antipsychotic medicines, and medicines to treat cancer, malaria, HIV or AIDS. Tell your doctor about all the medicines you use.

To make sure pimavanserin is safe for you, tell your doctor if you have:

• a heart rhythm disorder;
• personal or family history of long QT syndrome;
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);
• liver disease; or
• kidney disease.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether pimavanserin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Pimavanserin is usually taken once daily. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take pimavanserin with or without food.

Your pimavanserin dose may need to be adjusted up or down if you use certain other medications, especially an antibiotic or antifungal medicine, heart or blood pressure medicine, seizure medication, or drugs to treat HIV, hepatitis, or tuberculosis. It is very important to tell your doctor if you start or stop using any other medications.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Store at room temperature away from moisture and heat.

Parkinson's Disease Psychosis

Management of hallucinations and delusions associated with Parkinson's disease psychosis.1 2 10

Not approved for treatment of dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson’s disease psychosis.1 (See Boxed Warning.)

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects.

Contact your doctor right away if you feel dizzy or faint, or have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest pain or discomfort
• fainting
• irregular or slow heart rate
• shortness of breath

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• confusion
• nausea
• rapid weight gain
• unusual weight gain or loss

• Change in walking and balance
• clumsiness or unsteadiness
• difficulty having a bowel movement (stool)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine may cause a type of abnormal heartbeat (prolonged QT interval). If this happens, the chance of other unsafe and sometimes deadly abnormal heartbeats may be raised. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Nuplazid while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Nuplazid is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Reactions have included rash, urticaria, tongue swelling, circumoral edema, and throat tightness.

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 tablets are intended for oral administration only. Each round, white to off-white, immediate-release, film-coated tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.

Carcinogenesis, 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 Ames reverse 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 as early as 14 days following oral daily administration of pimavanserin. The most severely affected organs were the lungs and kidneys. The occurrence of phospholipidosis was both dose- and duration-dependent. Diffuse phospholipidosis with focal/multifocal chronic inflammation was observed in the lungs of rats treated for ≥3 months at doses ≥10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC. As a result of chronic inflammation, inflammatory lung fibrosis was observed in rats treated for 3 and 6 months at doses ≥18-times the MRHD of 34 mg/day based on AUC. The findings in the lungs correlated with increased lung weights (up to 3-times those of controls) and respiratory-related clinical signs including rales, labored breathing, and gasping. Phospholipidosis in lungs of rats caused mortality at doses ≥16-times the MRHD of 34 mg/day based on AUC. The estimated No Observed Effect Level (NOEL) for chronic lung inflammation in rats is 5-fold the MRHD of 34 mg/day based on AUC. Phospholipidosis was associated with increased kidney weights and tubular degeneration in rats at doses ≥10-times the MRHD of 34 mg/day based on AUC. The relevance of these findings to human risk is not known.

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 2, and Figure 3, 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.

The effect of Nuplazid on SAPS-PD improved through the six-week trial period, as shown in Figure 2.

Figure 2 SAPS-PD Change from Baseline through 6 Weeks Total Study Treatment

Figure 3 Proportion of Patients with SAPS-PD Score Improvement at the End of Week 6 (N=185)

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 4). 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.

Avoid drinking alcohol. Dangerous side effects could occur.

Applies to pimavanserin: oral tablet

General

The most commonly reported side effects are peripheral edema and confusional state.[Ref]

Psychiatric

Hallucinations (e.g., visual, auditory, tactile, and somatic)[Ref]

Common (1% to 10%): Confusional state, hallucinations[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, constipation[Ref]

Cardiovascular

Common (1% to 10%): Peripheral edema[Ref]

Nervous system

Common (1% to 10%): Gait disturbance[Ref]

Other

Common (1% to 10%): Fatigue[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection[Ref]

Some side effects of Nuplazid may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Safety has not been established. Excreted into human milk: Unknown Excreted into animal milk: Unknown Comments: The effects in the nursing infant are unknown.

There are no data regarding the presence of this drug in human milk or its effect on milk production.