Iloperidone

426.48

426.48

1308068-626-2

VPO7KJ050N

DTXSID6049060

White to off-white finely crystalline powder|Crystals from ethanol

N05AX14|N - Nervous system

29349990

64.8

4.1

white to beige

1.204±0.06 g/cm3(Predicted)

118-120°C

593.7±50.0 °C(Predicted)

9℃

1.57

DMSO: soluble5mg/mL, clear

-20°C Freezer, Under Inert Atmosphere

8.1X10-11 mm Hg at 25 deg C (est)

Henry's Law constant = 3.0X10-15 atm-cu m/mol at 25 °C (est)

pKa1 = 7.91 (est)

Hydroxyl radical reaction rate constant = 1.42X10-10 cu cm/molec-sec at 25 °C (est)

UN2811 - class 6.1 - PG 3 - EHS - Toxic solids, organic, n.o.s., HI: all

1

11-23/24/25-39/23/24/25

16-36/37-45

KM5777850

F,T

Stable if stored as directed; avoid strong oxidizing agents.

P264, P270, P301+P310, P321, P330, P405, P501

H300

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including iloperidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H300 (90.48%): Fatal if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|Aggregated GHS information provided by 42 companies from 4 notifications to the ECHA C&L Inventory.

Personal protective equipment as follows: Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles.

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, fededral, state and local regulations/.

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.|Information for safe handling: avoid inhalation and contact with skin, eyes and clothing ... .

Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased.|IDENTIFICATION AND USE: Ilperidone is a white to off-white finely crystalline powder formulated into oral tablets. Iloperidone is considered an atypical or second-generation antipsychotic agent. It is used for the treatment of adults with schizophrenia. HUMAN EXPOSURE AND TOXICITY: In premarketing trials involving over 3210 patients, accidental or intentional overdose of iloperidone was documented in 8 patients with no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension). Elderly patients with dementia-related psychosis treated with iloperidone are at an increased risk of death and therefore iloperidone is not approved for use in that population. Iloperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including iloperidone. Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has also been reported in patients receiving atypical antipsychotic agents, including iloperidone. Iloperidone has two predominate metabolites, P88 and P95. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug. ANIMAL STUDIES: Lifetime carcinogenicity studies were conducted in mice and rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to mice and up to 16 mg/kg/day to rats. 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 iloperidone metabolite P95 was studied in rats at oral doses up to 200 mg/kg/day in males and up to 250 mg/kg/day in females. Drug-related neoplastic changes occurred in the pituitary gland (pars distalis adenoma) and in the pancreas (islet cell adenoma). Iloperidone also caused developmental toxicity, but was not teratogenic in rats and rabbits. Pregnant rats were given up to 64 mg/kg/day of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. In a similar study, pregnant rabbits were given up to 25 mg/kg of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. Additional studies in rats given iloperidone either pre-conception or from day 17 of gestation and continuing through weaning caused adverse reproductive effects including prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. 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.

Liver test abnormalities occur in 1% to 3% of patients on long term therapy with iloperidone, but similar rates are reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to iloperidone therapy.

Because disruption of body temperature regulation is possible, iloperidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.|Because of additive effects on QT-interval prolongation, concomitant use of iloperidone with other drugs known to prolong the corrected QT (QTc) interval, including class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., levomethadyl acetate (no longer commercially available in the US), methadone, pentamidine, tetrabenazine), should be avoided.|Concomitant use of iloperidone with other CNS agents or alcohol may produce additive CNS effects. Caution is advised when iloperidone and other CNS agents are used concomitantly; use of alcohol during iloperidone therapy should be avoided.|Because of its alpha1-adrenergic blocking activity and potential to cause orthostatic hypotension and syncope, the manufacturer recommends that iloperidone be used with caution in patients receiving antihypertensive agents and other drugs that can cause hypotension; monitoring of orthostatic vital signs should be considered in such patients.|For more Interactions (Complete) data for Iloperidone (13 total), please visit the HSDB record page.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), 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 the risk of death 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 the placebo group. 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Fanapt is not approved for the treatment of patients with dementia-related psychosis.|Iloperidone is not recommended in patients with any degree of hepatic impairment.|Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Fanapt should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole.

Treatment of acute schizophrenia.|FDA Label|Treatment of schizophrenia

Iloperidone is a second generation (atypical) antipsychotic agent that is used for treatment of schizophrenia. Iloperidone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.

Antipsychotic Agents

An atypical, negative symptom antipsychotic agent.|Fanapt tablets are indicated for the treatment of adults with schizophrenia. /Included in US product label/

/BOXED WARNING/ 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. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), 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 the risk of death 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 the placebo group. 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Fanapt is not approved for the treatment of patients with dementia-related psychosis.|Geriatric patients with dementia-related psychosis treated with iloperidone are at an increased risk of death compared with those receiving placebo. In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that the safety and efficacy of iloperidone in the treatment of psychosis associated with Alzheimer's disease have not been established and that the drug is not approved for the treatment of patients with dementia-related psychosis. If a clinician decides to treat such patients with iloperidone, the manufacturer recommends that vigilance be exercised.|An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that iloperidone is not approved for the treatment of patients with dementia-related psychosis.|A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Fanapt. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.|For more Drug Warnings (Complete) data for Iloperidone (28 total), please visit the HSDB record page.

Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors.

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)

Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion.|Renal (in which <1% of iloperidone is excreted unchanged).|Apparent Vd = 1340-2800 L|Apparent clearance (clearance/bioavilability) = 47-102 L/h.|Iloperidone has an apparent clearance (clearance/bioavailability) of 47 to 102 L/hr, with an apparent volume of distribution of 1340 to 2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is approximately 3% and of each metabolite (P88 and P95) it is approximately 8%.|The majority of radiolabeled iloperidone was recovered in the urine (mean 58.2% and 45.1% in extensive and poor metabolizers of CYP2D6, respectively), with feces accounting for 19.9% (extensive metabolizers) and 22.1% (poor metabolizers) of the radiolabeled dose.|Iloperidone is well absorbed after administration of the tablet with peak plasma concentrations occurring within 2 to 4 hours; while the relative bioavailability of the tablet formulation compared to oral solution is 96%. Administration of iloperidone with a standard high-fat meal did not significantly affect the Cmax or AUC of iloperidone, P88, or P95, but delayed Tmax by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. Fanapt can be administered without regard to meals.|... The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS ... .

Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively).|Iloperidone is primarily metabolized by carbonyl reduction, cytochrome P-450 (CYP) isoenzyme 2D6-mediated hydroxylation, and CYP3A4-mediated O-demethylation; the drug's two principal metabolites, P88 and P95, undergo further oxidation and/or conjugation with glucuronic acid. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug.|Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively. Approximately 7% to 10% of Caucasians and 3% to 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of Fanapt with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone plasma exposure, and therefore one-half of the Fanapt dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half.|Iloperidone has known human metabolites that include 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, and 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-a-methylbenzene methanol.

The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively.|The mean elimination half-lives of iloperidone, P88, and P95 are 18, 26, and 23 hours, respectively, in extensive metabolizers of CYP2D6 and 33, 37, and 31 hours, respectively, in poor metabolizers of CYP2D6.

Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent.|Iloperidone is a piperidinyl-benzisoxazole derivative structurally related to risperidone; the drug has been referred to as an atypical or second-generation antipsychotic agent. Although the exact mechanism of action of iloperidone and other antipsychotic agents in schizophrenia is unknown, it has been suggested that the efficacy of iloperidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine (5-HT2)) receptors.|Fanapt exhibits high (nM) affinity binding to serotonin 5-HT2A dopamine D2 and D3 receptors, and norepinephrine NEalpha1 receptors (Ki values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). FANAPT has moderate affinity for dopamine D4, and serotonin 5-HT6 and 5-HT7 receptors (Ki values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT1A, dopamine D1, and histamine H1 receptors (Ki values of 168, 216 and 437 nM, respectively). Fanapt has no appreciable affinity (Ki >1000 nM) for cholinergic muscarinic receptors. Fanapt functions as an antagonist at the dopamine D2, D3, serotonin 5-HT1A and norepinephrine alpha1/alpha2C receptors. The affinity of the FANAPT metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEalpha1A, NEalpha1B, NEalpha1D, and NEalpha2C receptors (Ki values of 4.7, 2.7, 8.8, and 4.7 nM respectively).|Iloperidone has demonstrated an interesting monoamine receptor profile in radioligand binding studies, with nanomolar affinity for certain noradrenaline, dopamine, and serotonin receptors. In this study, the agonist/antagonist activity of iloperidone was determined in cell lines expressing recombinant human D(2A), D(3), alpha(2C), 5-HT(1A), or 5-HT(6) receptors. With the exception of 5-HT(6) receptors, these receptors are negatively coupled to cyclase. Thus, after stimulation with forskolin, the agonists dopamine (at D(2A) and D(3)), noradrenaline (at alpha(2C)), or 8-OH-DPAT (at 5-HT(1A)) induced a reduction in cAMP accumulation. Conversely, activation of the 5-HT(6) receptor by 5-HT led to an increase in cAMP accumulation. Iloperidone alone was devoid of significant agonist activity but inhibited the agonist response in all 5 cell lines in a surmountable and concentration-dependent fashion. Iloperidone was most potent at D(3) receptors (pK(B) 8.59 + or - 0.20; n = 6), followed by alpha(2C) (pK(B) 7.83 + or - 0.06; n = 15), 5-HT(1A) (pK(B) 7.69 + or - 0.18; n = 10), D(2A) (pK(B) 7.53 + or - 0.04; n = 11) and 5-HT(6) (pK(B) 7.11 + or - 0.08; n = 11) receptors.|Iloperidone ... demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 uM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 uM) and alpha-1 receptors (IC50 = 0.00037 uM). ...

Emergency and supportive measures: 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. 2. Treat coma, seizures, hypotension, and hyperthermia if they occur. 3. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. /Antipsychotic drugs/|Specific drugs and antidotes. There is no specific antidote.1. Dystonic reactions. Give diphenhydramine ... or benztropine ... . 2. QRS interval prolongation: treat quinidine-like cardiotoxic effects with bicarbonate ... . 3. Hypotension from these drugs probably involves vasodilation caused by alpha-1 receptor blockade. Treat with iv fluids and, if needed a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta-2 activity (eg, epinephrine, isoproterenol) may worsen hypotension. 4. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing. /Antipsychotic drugs/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antipsychotic drugs/|Enhanced elimination. Owing to extensive tissue distribution, these drugs are not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated. /Antipsychotic drugs/|For more Antidote and Emergency Treatment (Complete) data for Iloperidone (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Fanapt should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.|/SIGNS AND SYMPTOMS/ Geriatric patients with dementia-related psychosis treated with iloperidone are at an increased risk of death compared with those receiving placebo. In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that the safety and efficacy of iloperidone in the treatment of psychosis associated with Alzheimer's disease have not been established and that the drug is not approved for the treatment of patients with dementia-related psychosis. If a clinician decides to treat such patients with iloperidone, the manufacturer recommends that vigilance be exercised.|/SIGNS AND SYMPTOMS/ In premarketing trials involving over 3210 patients, accidental or intentional overdose of Fanapt was documented in 8 patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a 3-day period. No fatalities were reported from these cases. The largest confirmed single ingestion of Fanapt was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of Fanapt was 438 mg over a 4-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed Fanapt treatment for an additional 11 months. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension) of Fanapt.|/SIGNS AND SYMPTOMS/ A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Fanapt. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

Fanapt

Table: Iloperidone Preparations [Table#8205]

HPLC determination in plasma.|A sensitive and rapid isotope dilution LC-MS/MS method has been developed for the simultaneous determination of iloperidone and its two major metabolites in human plasma. The analytes and their deuterated analogs as internal standards were quantitatively extracted from 100-uL human plasma by SPE. The method was validated over the concentration range of 0.01-6 ng/ml for all the analytes. Baseline separation of analytes was possible within 3 min on ACE 5 C8 column. The accuracy and precision (%CV) of the method varied from 96.2 to 105%, and 1.17 to 4.75%, respectively. The extraction recovery was >84%, while the internal standard-normalized matrix factors ranged from 0.97-1.03 for all three analytes. ...

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