Milsaperidone

Neonates exposed to antipsychotic drugs, including milsaperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data with milsaperidone use during pregnancy and available data from pharmacovigilance reports with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) use during pregnancy are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder.

When iloperidone) was administered orally to pregnant rats during organogenesis at doses up to 26 times the maximum recommended human dose (MRHD) of 24 mg/day on mg/m² basis it prolonged the duration of pregnancy and parturition, increased still births, early intrauterine deaths, increased incidence of developmental delays, and decreased post-partum pup survival. When iloperidone was administered orally to pregnant rabbits during organogenesis at doses up to 20-times the MRHD on mg/m² basis it increased early intrauterine deaths and decreased fetal viability at term at the highest dose which was also a maternally toxic dose. The safety margins for milsaperidone are expected to be the same as those seen with iloperidone because exposures to iloperidone, milsaperidone, and their major metabolites are similar when either iloperidone tablets or milsaperidone (milsaperidone) tablets are administered in humans.

The background risk of major birth defects and miscarriage in patients with schizophrenia or bipolar disorder is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

There are no data on the presence of milsaperidone or its major metabolite, P95, in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) is present in rat milk following iloperidone administration. When a drug is present in animal milk, it is likely to be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients not to breastfeed during milsaperidone treatment and for 6 days after the last dose in CYP2D6 normal metabolizers and 8 days after the last dose in CYP2D6 poor metabolizers.

Carcinogenesis

Lifetime carcinogenicity studies were conducted with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) in CD-1 mice and Sprague Dawley rats. Iloperidone was administered orally at doses of 2.5, 5, and 10 mg/kg/day to CD-1 mice and 4, 8, and 16 mg/kg/day to Sprague Dawley rats (0.5, 1, and 2 times and 1.6, 3.2, and 6.5 times, respectively, the MRHD of 24 mg/day on a mg/m² basis). The safety margins for milsaperidone are expected to be the same as those seen with iloperidone because exposure to iloperidone, milsaperidone, and their major metabolites are similar when either iloperidone tablets or milsaperidone tablets are administered in humans. There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats.

The carcinogenic potential of the milsaperidone metabolite P95, which is a major circulating metabolite of milsaperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75, and 200 mg/kg/day in males and 50, 150, and 250 (reduced from 400) mg/kg/day in females. Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of milsaperidone.

Mutagenesis

Milsaperidone was not mutagenic in the Bacterial Reverse Mutation (Ames) Test conducted in multiple bacterial strains with and without metabolic activation. Milsaperidone did not induce structural chromosomal damage in an in vitro cytogenetic assay using Chinese Hamster Ovary (CHO) cells with and without metabolic activation.

Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.

The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo mouse bone marrow micronucleus test.

Impairment of Fertility

Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. The no-effect dose was 4 mg/kg, which is 1.6 times the MRHD of 24 mg/day on a mg/m² basis.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of milsaperidone has been established from adequate and well-controlled studies of iloperidone tablets (referred to hereafter as "iloperidone" (iloperidone and milsaperidone rapidly interconvert in vivo)) in adults with schizophrenia or with mixed or manic episodes associated with bipolar I disorder. Below is a display of the adverse reactions of iloperidone in these adequate and well-controlled studies.

The information below is derived from a clinical trial database for iloperidone that consisted of:

• 3,229 adult patients exposed to iloperidone at a dosage of 10 mg/day or greater, for the treatment of schizophrenia which included 874 patients with schizophrenia in Studies 1, 2, and 3 and another schizophrenia study and
• 312 adult patients exposed to iloperidone at a dosages of 24 mg/day, for the acute treatment of manic or mixed episodes associated with bipolar I disorder (Study 4).

Of these, 999 patients received iloperidone for at least 6 months, with 657 patients exposed to iloperidone for at least 12 months for the treatment of schizophrenia; and 69 patients received iloperidone for at least 6 months (with 28 patients received iloperidone for at least 12 months) for the treatment of bipolar mania. The conditions and duration of treatment with iloperidone varied and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and studies with short-term or longer-term exposure.

Common Adverse Reactions in Adult Patients with Schizophrenia

The information presented below was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adult patients with schizophrenia who received iloperidone at daily dosages within a range of 10 to 24 mg (n=874) (Studies 1, 2, and 3, and another study in schizophrenia).

Table 1 displays adverse reactions that occurred in 2% or more of patients treated with iloperidone in any of the dosing groups, and for which the incidence in iloperidone-treated patients in any dosing group was greater than the incidence in placebo-treated patients in these studies.

Adverse reactions that occurred in ≥5% in the iloperidone-treated patients and at least twice that in placebo-treated patients included dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased.

Table 1. Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Schizophrenia Trials in Adult Patients*:

^* Includes adverse reactions that were reported in 2% or more of patients in any of the iloperidone dosing group and at greater incidence than in the placebo group. Figures rounded to the nearest integer.
^a Somnolence includes somnolence and sedation
^b Tachycardia includes tachycardia and heart rate increased

Common Adverse Reactions in Adult Patients with Bipolar Mania

Table 2 displays the adverse reactions that occurred at an incidence of ≥2% in iloperidone-treated patients and greater than in placebo-treated patients in a placebo-controlled, 4-week bipolar mania trial (Study 4).

In Study 4, the following adverse reactions occurred in ≥5% in the iloperidone- treated patients and at least twice placebo-treated patients: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence.

Table 2. Adverse Reactions that Occurred in Adult Patients in a Short-Term, Fixed-Dose, Placebo-Controlled Bipolar Mania Trial (Study 4)*:

^* Adverse reactions occurring at an incidence of ≥2% in iloperidone-treated patients and greater than in placebo-treated patients. Figures rounded to the nearest integer.
^** Patients with poor CYP2D6 metabolizer status received 12 mg/day.
^a Tachycardia includes postural orthostatic tachycardia syndrome and other similar terms
^b Dizziness includes postural dizziness
^c Hepatic enzyme increased includes: predominantly alanine aminotransferase increased, aspartate aminotransferase increased, and transaminase increased
^d Somnolence includes other similar terms
^e Hypotension includes: orthostatic hypotension
^f Weight increased includes other similar terms
^g Headache includes tension headache
^h Nausea includes vomiting
ⁱ Sexual Dysfunction includes: ejaculation failure, erectile dysfunction, retrograde ejaculation, and ejaculation delayed
^j Fatigue includes similar terms
^k Urinary urgency and polyuria includes: hypertonic bladder, micturition urgency, and urinary incontinence

Dose-Related Adverse Reactions in the Schizophrenia Studies

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients with schizophrenia, adverse reactions that occurred with a greater than 2% incidence in iloperidone-treated patients, and for which the incidence in patients treated with iloperidone 20-24 mg/day were twice than the incidence in patients treated with iloperidone 10-16 mg/day were abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased. Dizziness, tachycardia, and increased weight were at least twice as common on in patients treated with 20-24 mg/day as those treated with 10-16 mg/day.

Extrapyramidal Symptoms in the Schizophrenia and Bipolar Mania Studies

Table 3 displays treatment emergent extrapyramidal symptoms (EPS)-related events in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients with schizophrenia.

Table 3. Percentage of Treatment Emergent EPS-Related Events in 4- or 6-week Schizophrenia Trials:

Table 4 shows the percentage of treatment emergent EPS-related events in a 4-week bipolar mania trial.

Table 4. Percentage of Treatment Emergent EPS-Related Events in a 4-week Bipolar Mania Trial:

^* Patients with poor CYP2D6 metabolizer status received 12 mg/day.

Discontinuation of Treatment Due to Adverse Reactions in the Schizophrenia and Bipolar Mania Studies

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients with schizophrenia (Studies 1, 2, 3, and another study), there was no difference in the incidence of discontinuation due to adverse reactions between iloperidone-treated patients (5%) and placebo-treated patients (5%). The types of adverse reactions that led to discontinuation were similar for the iloperidone- and placebo-treated patients.

In a 4-week, placebo-controlled study in patients with bipolar mania (Study 4), the incidence of discontinuation due to adverse reactions was higher in iloperidone-treated patients (8.7%) than placebo-treated patients (5.3%). Adverse reactions that led to discontinuation in more than one iloperidone-treated patient were liver enzyme elevations, nausea and vomiting, dizziness and hypotension.

Adverse Reactions by Demographic Groups in the Schizophrenia Studies

An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies of patients with schizophrenia (Studies 1, 2, 3, and another study) did not reveal any evidence of differences in safety of iloperidone on the basis of age, sex or race.

Laboratory Test Abnormalities in the Schizophrenia and Bipolar Mania Studies

There were no differences between the iloperidone and placebo groups in the incidence of discontinuation due to changes in hematology laboratory tests, or urinalysis.

Elevated Serum Transaminases: In a short-term placebo-controlled trial in patients with bipolar mania (Study 4), asymptomatic alanine aminotransferase (ALT) elevations ≥3x ULN occurred in 9.2% of iloperidone-treated patients compared to 1.5% of placebo-treated patients. AST elevations were less common.

Decreased Hematocrit: In short-term placebo-controlled trials (4- to 6-weeks) in patients with schizophrenia, 1% (13/1,342) of iloperidone-treated patients had a hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) of placebo-treated patients. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial.

In a short-term placebo-controlled trial (4 weeks) in patients with bipolar mania (Study 4), 3.5% (7/200) of iloperidone-treated patients had a hematocrit at least one time below the extended normal range (<0.85xLLN) during post- randomization treatment, compared to 0.5% (1/196) of placebo-treated patients.

Analysis of clinical laboratory data following iloperidone administration suggested that decreases in hematocrit, hemoglobin, white blood cells, total protein, and albumin were due to hemodilution. Decreases in hematocrit and total protein have been observed with other alpha receptor antagonists and are attributed to hemodilution.

Elevated Serum Urate Levels: In a 4-week placebo-controlled trial in patients with schizophrenia (Study 2), treatment with iloperidone 12 mg twice a day resulted in an increase of serum urate levels of approximately 28 μmol/L (0.471 mg/dL) compared to an increase of 4.2 μmol/L (0.07 mg/dL) with treatment with placebo.

In a 4-week placebo-controlled trial in patients with bipolar mania (Study 4), treatment with iloperidone 12 mg twice a day resulted in an increase of serum urate levels of approximately 27.2 μmol/L (0.457 mg/dL) compared to an increase of 0.1 μmol/L (0.002 mg/dL) to treatment with placebo.

Other Reactions During the Pre-marketing Evaluation of Iloperidone in the Schizophrenia Studies

The following is a list additional adverse reactions (not listed above) in patients with schizophrenia treated with iloperidone (n=3,210) at multiple doses ≥4 mg/day.

Reactions are listed in order of decreasing frequency according to the following definitions: frequent adverse events were those that occurred in at least 1/100 patients (only those not listed in Table 1 appear in this listing); infrequent adverse reactions were those that occurred in 1/100 to 1/1,000 patients; and rare events were those that occurred in fewer than 1/1,000 patients.

• Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency anemia; Rare – leukopenia
• Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)
• Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus
• Endocrine Disorders: Infrequent – hypothyroidism
• Eye Disorders: Frequent – conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival)
• Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare – aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis
• General Disorders and Administrative Site Conditions: Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare – hyperthermia
• Hepatobiliary Disorders: Infrequent – cholelithiasis
• Investigations: Frequent: weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased
• Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehydration, hypokalemia, fluid retention
• Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, muscle spasms; Rare – torticollis
• Nervous System Disorders: Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome
• Psychiatric Disorders: Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression
• Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute
• Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis
• Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus).