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FANAPT 1 Mg, 2mg, 4mg, 6mg, 8mg Tablets

Submitted by on November 8, 2016 – 3:51 pm | 50 views
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FANAPT 1 Mg, 2mg, 4mg, 6mg, 8mg Tablets

  1. NAME OF THE MEDICINAL PRODUCT

FANAPT 1 mg, 2mg, 4mg, 6mg, 8mg tablets

  1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 mg tablet contains 1 mg iloperidone. Each 2 mg tablet contains 2 mg iloperidone. Each 4 mg tablet contains 4 mg iloperidone. Each 6 mg tablet contains 6 mg iloperidone. Each 8 mg tablet contains 8 mg iloperidone

Excipient with known effect:

Each 1 mg tablet contains 53.8 mg of lactose monohydrate. Each 2 mg tablet contains 85.07 mg of lactose monohydrate. Each 4 mg tablet contains 83.07 mg of lactose monohydrate. Each 6 mg tablet contains 110.10 mg of lactose monohydrate. Each 8 mg tablet contains 166.14 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Immediate release tablet.

White, round, flat, beveled-edge tablets without a score line marked with a logo “

iloperidone ”on one side and tablet strength “1”, “2”, “4”, “6” or “8” on the other side.

  1. CLINICAL PARTICULARS

4.1 Therapeutic indications

FANAPT is indicated for the .

4.2 Posology and method of administration

Posology

Adults

Titration phase

FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg twice daily. Increases to reach the target dose range of 6-12 mg twice daily may be made with daily dosage adjustments to 2 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, 10 mg twice daily, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. Efficacy was demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic medicinal products that do not require similar titration. Prescribers should also be aware that some adverse reactions associated with iloperidone use are dose-related. To minimize initial tolerability issues, patients may want to take the medication with food.

Maintenance treatment

The recommended maintenance dose for FANAPT is 12 mg/day, administered as either 6 mg twice daily or 12 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment.

Maximum dose

The maximum recommended dose is 12 mg twice daily (24 mg/day); FANAPT doses above 24 mg/day have not been systematically evaluated in the clinical trials.

Reinitiation of treatment in patients previously discontinued

Although there are no data to specifically address re-initiation of treatment, it is recommended that the initiation titration schedule be followed whenever patients have had an interval off FANAPT of more than 3 days.

Switching from other antipsychotics

There are no specific data to address how patients with schizophrenia can be switched from other antipsychotics to FANAPT or how FANAPT can be used concomitantly with other antipsychotics. Although immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

Special populations

Paediatric population

Safety and efficacy of FANAPT in patients <18 years of age have not been established. No data are available.

Renal impairment

Because FANAPT is highly metabolized, with less than 1% of the medicinal product excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of FANAPT (see section 5.2).

Hepatic impairment

A study in mild and moderate liver impairment has not been conducted. FANAPT is not recommended for patients with hepatic impairment (see section 5.2).

Elderly

Clinical studies of FANAPT in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3,297 patients treated with FANAPT in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.

FANAPT should not be used in with risk factors for stroke (see section 4.4).

Dosage adjustments due to interactions

The FANAPT dose should be reduced by one-half when administered concomitantly with strong CYP2D6 inhibitors, such as fluoxetine or paroxetine, and/or strong CYP3A4 inhibitors, such as ketoconazole or . When the CYP2D6 and/or CYP3A4 inhibitor(s) is withdrawn from the combination therapy, the FANAPT dose should then be increased to where it was before.

FANAPT should be reduced by one-half for poor metabolizers of CYP2D6.

Method of administration

Iloperidone is for oral use. Iloperidone can be administered without regard to meals.

4.3 Contraindications

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient’s clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

QT interval

Use of FANAPT should be avoided in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines thought to prolong the QT interval including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medicinal products, antipsychotic medicinal products (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medicinal products known to prolong the QTc inteval (e.g., pentamidine, levomethadyl acetate, ).

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with iloperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotics, including iloperidone, should be discontinued.

Tardive dyskinesia

Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterized by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including iloperidone, should be considered. Hyperglycaemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including iloperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemiarelated adverse reactions in patients treated with the atypical antipsychotics included in these studies. Because iloperidone was not marketed at the time these studies were performed, it is not known if iloperidone is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Orthostatic hypotension

Iloperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity. Based on pooled data from four, placebo-controlled, 4- or 6-week, fixed- and flexible-dose trials with iloperidone, orthostatic hypotension was reported in 3% of patients treated with 10-16 mg/day iloperidone, 5% of patients treated with 20-24 mg/day iloperidone, compared with 1% of patients treated with placebo.

Renal impairment

Because iloperidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of iloperidone (see section 5.2).

Hepatic impairment

A study in mild and moderate liver impairment has not been conducted. FANAPT is not recommended for patients with hepatic impairment (see section 5.2).

Elderly patients with dementia

Iloperidone has not been studied in elderly patients with dementia.

Overall mortality

Elderly patients with treated with antipsychotic medical products 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 placebotreated 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.

Cerebrovascular adverse reactions

An approximately 3-fold increase risk of cerebrovascular adverse reactions have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including , aripiprazole and olanzapine. The mechanism for this increased risk is not known. Iloperidone should be used with caution in elderly patients with dementia who have risk factors for stroke.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing FANAPT to patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at an increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including iloperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. Patients should be informed to seek urgent medical care in the case that priapism has not been resolved within 3-4 hours.

Body temperature regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing FANAPT to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.

Hyperprolactinemia

Increases in prolactin levels were observed in some patients with FANAPT. In clinical trials, there were few adverse reactions related to abnormal prolactin levels reported.

Leukopenia, neutropenia and agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic medicinal products. Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue iloperidone at the first sign of a decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue iloperidone and have their WBC followed until recovery.

Seizures

In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated with FANAPT compared to 0.3% (2/587) on placebo. FANAPT should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. FANAPT should be used cautiously in patients at risk for aspiration pneumonia.

Suicide

The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy.

Lactose content

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Caution is advised when prescribing iloperidone with medicines known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhytmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine).

Potential for other medicines to affect iloperidone

Given the primary central nervous system (CNS) effects of iloperidone (see section 4.8), iloperidone should be used with caution in combination with other centrally acting medicines, e.g., anxiolytics, most antipsychotics, hypnotics, , etc. or alcohol.

Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g. ketoconazole) or CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels. When concomitant administration of CYP2D6 or CYP3A4 inhibitors occurs, iloperidone dose should be reduced by half. When these inhibitors are withdrawn from the combination therapy, iloperidone dose could then be increased based on clinical evaluation (see section 4.2).

Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18-45, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.

Fluoxetine: Co-administration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29-44, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, approximately 2-3 fold, and decreased the AUC of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level.

Paroxetine: Co-administration of paroxetine (20 mg/day for 5-8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels.

Paroxetine and ketoconazole: Co-administration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 resulted in a 1.4 fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4 fold decrease in the P95 in the presence of paroxetine. Administering iloperidone with inhibitors of both of its metabolic pathways did not add to the effect of either inhibitor given alone. Iloperidone doses should therefore be reduced by about one-half if administered concomitantly with both a CYP2D6 and a CYP3A4 inhibitor.

Iloperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson’s disease, the lowest effective dose or each treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when iloperidone is administered with other therapeutic agents that have this potential, e.g., other antipsychotics, .

Caution is advised if iloperidone is combined with other medicines known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Potential for Iloperidone to affect other drugs

In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolised by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver microsomes showed that iloperidone does not have enzymeinducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5. In vitro studies have shown that iloperidone is not a P-glycoprotein (P-gp) substrate, and is a weak inhibitor of P-gp.

Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in Cmax of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.

Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data for the use of Fanapt in pregnant women. Iloperidone was not teratogenic in animal studies. Maternal and embryo toxic effects were found in animal studies (see section 5.3). Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder in neonates. Consequently, newborns should be monitored carefully. FANAPT should not be used during pregnancy unless clearly necessary and only if the potential benefit outweighs the potential risk to the foetus.

Breastfeeding

It is unknown whether iloperidone is excreted in human breast milk. Animal studies have shown excretion of iloperidone in breast milk. FANAPT should not be used while breast feeding.

Fertility

There are no data on the effects of iloperidone on human fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

FANAPT can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). In short-term, placebocontrolled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult patients treated with iloperidone at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to iloperidone is known.

4.8

Summary of the safety profile

The most frequent treatment-emergent adverse drug reactions (ADRs) reported in clinical trials were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence (including sedation), tachycardia, and weight gain.

Tabulated summary of adverse reactions

The following are all treatment-emergent ADRs that were reported in iloperidone-treated patients with schizophrenia in clinical trials. The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class Very Common Common Uncommon
Cardiac disorders tachycardia palpitations
Ear and labyrinth

disorders

ear pain
Eye disorders vision blurred dry eye
Gastrointestinal

disorders

 

nausea

dry mouth

 

flatulence

diarrhoea

toothache

abdominal discomfort

gastritis

General disorders

and administration

site conditions

fatigue pain

asthenia

pyrexia

Infections and

infestations

 

nasopharyngitis

upper respiratory tract

infection

tinea pedis

urinary tract infection

bronchitis

rhinitis

Investigations

 

weight gain

heart rate increased

 

creatine phosphokinase

increased

alanine

aminotransferase

increased

Metabolism and

nutrition disorders

Increased appetite

hyperglycaemia

Musculosketal and

connective tissue

disorders

 

back pain

arthralgia

muscle stiffness

myalgia

muscle twitching

muscle rigidity

Nervous system

disorders

 

headache

dizziness

sedation/somnolence

lethargy

 

dyskinesia

dystonia

paraesthesia

dysarthria

extrapyramidal disorder

akathisia

tremor

Psychiatric disorders insomnia

agitation

anxiety

nightmare

mood

anorgasmia
Renal and urinary

disorders

urinary incontinence
Reproductive system

and breast disorders

ejaculation failure erectile dysfunction
Respiratory, thoracic

and mediastinal

disorders

nasal congestion

dyspnoea

epistaxis

sinus congestion
Skin and

subcutaneous

disorders

dry skin
Vascular disorders orthostatic hypotension

Description of selected adverse reactions

Weight gain. Based on the pooled data from the four placebo-controlled, 4- or 6-week, fixedor flexible-dose studies, the proportions of patients having a weight gain of ≥ 7% body weight was 4% for placebo versus 13% for FANAPT combined doses. The mean weight change from baseline to endpoint in the short-term studies was -0.1 kg for placebo versus 2.0 kg for FANAPT-treated patients. Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.

Laboratory Tests. A between-group comparison of the pooled data from the four placebocontrolled, 4- or 6-week studies, revealed no medically important differences betweenFANAPT and placebo in routine haematology, urinalysis, or serum chemistry, including glucose. Similarly, there were no medically important changes in triglyceride and total cholesterol measurements. There were no differences between iloperidone and placebo in the incidence of discontinuation due to changes in haematology, urinalysis, or serum chemistry.

Laboratory Tests: Serum Prolactin. In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in plasma prolactin levels for theFANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with FANAPT compared to 12% in the placebo group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic medicinal products, including risperidone and haloperidol. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with FANAPT, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo-treated patients.

Other special populations

Elderly patients

Clinical Studies of iloperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3297 patients treated with iloperidone in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old. In clinical trials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidents have been reported (see section 4.4).

4.9 Overdose

In pre-marketing trials involving over 3,297 patients, accidental or intentional overdose of FANAPT was documented in eight patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a three-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 four-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed iloperidone 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 iloperidone.

There is no specific antidote for FANAPT. Therefore, appropriate supportive measures should be instituted. In case of acute overdose, the physician should establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. 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 iloperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of iloperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of iloperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: phycholeptics, other antipsychotics, ATC code: N05AX14

Mechanism of action

The mechanism of action of iloperidone, as with other drugs having efficacy in schizophrenia, is unknown. However it is proposed that the efficacy of iloperidone is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonisms.

Pharmacodynamic effects

Iloperidone exhibits high (nM) affinity binding to serotonin 5-HT2A, dopamine D2 and D3 and norepinephrine NEα1 receptors (Ki values of 5.6, 6.3, 7.1, 0.36 nM respectively).

Iloperidone has moderate affinity for dopamine D4, serotonin 5-HT6 and 5-HT7 receptors (Ki values of 25, 43, and 22 respectively), and low affinity for the serotonin 5-HT1A, dopamine D1, and histamine H1 receptors (Ki values of 168, 216 and 473 nM, respectively). Iloperidone has no appreciable affinity (Ki>1000 nM) for cholinergic muscarinic receptors.

Iloperidone functions as an antagonist at the dopamine D2, D3, serotonin 5-HT1A and norepinephrine α1/α2C receptors. 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).

Clinical efficacy and safety

The efficacy of FANAPT in the treatment of schizophrenia was supported by two placeboand active-controlled short-term (4- and 6-week) trials. Both trials enrolled patients who met the DSM-III/IV criteria for schizophrenia.

Two instruments were used for assessing psychiatric signs and symptoms in these studies.

The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia.

A 6-week, placebo-controlled trial (n=706) involved two dose ranges of FANAPT (12-16 mg/day or 20-24 mg/day) compared to placebo and an active control. This study involved titration of FANAPT starting at 1 mg twice daily on day 1 and increasing to 2, 4, 6, 8, 10 and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, as needed. The primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42). Both the 12-16 mg/day and the 20-24 mg/day dose ranges of FANAPT were superior to placebo on the BPRS total score.

A 4-week, placebo-controlled trial (n=604) involved one fixed dose of FANAPT (24 mg/day) compared to placebo and an active control. The titration schedule for this study was similar to that for the 6-week study. This study involved titration of FANAPT starting at 1 mg twice daily on day 1 and increasing to 2, 4, 6, 8, 10 and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7. The primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day FANAPT dose was superior to placebo in the PANSS total score.

Age, gender or race did not have any effect on responsiveness.

In three 52-week trials (n=1281) designed for combined analysis, comparing a dose range of FANAPT (4-16 mg/day given BID, n=981) to haloperidol (5-20 mg/day given BID, n=300), FANAPT was statistically non-inferior to haloperidol in time to relapse. Relapse was defined as: (1) an increase (worsening) of the PANSS total score of at least 25%, including at least a 10-point increase, (2) discontinuation due to lack of efficacy, (3) aggravated psychosis with hospitalisation, or (4) a 2-point increase (worsening) of the CGI-C score after Week 6.

Paediataric population

The European Medicines Agency has wavied the obligation to submit the results of studies with FANAPT in all subsets of the paediatric population in schizophrenia. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

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. Steady-state concentrations are attained within 3-4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

Absorption

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. Iloperidone can be administered without regard to meals.

Distribution

Iloperidone has an apparent clearance (clearance / bioavailability) of 47 to 102 L/h, with an apparent volume of distribution of 1340-2800 L. At therapeutic concentrations, iloperidone and its metabolites are ~95% bound to serum proteins.

Biotransformation and elimination

Iloperidone is metabolized primarily by three biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are two 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 7-10% of Caucasians and 3-8% 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 iloperidone with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3 fold increase in iloperidone plasma exposure, and dosing adjustment is needed.

Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs.

Laboratory tests are available to identify CYP2D6 PMs and dosing adjustments should be considered in this group of patients.

The bulk of the radioactive materials were recovered in the urine (mean 58.2% and 45.1% in EM and PM, respectively), with feces accounting for 19.9% (EM) to 22.1% (PM) of the dosed radioactivity.

In vitro studies have shown that iloperidone is not a P-glycoprotein (P-gp) substrate, and is a weak inhibitor of P-gp. No in vivo data are available and the clinical relevance is unknown.

Pharmacokinetics in special populations

Hepatic impairment

A study in mild and moderate liver impairment has not been conducted. FANAPT is not recommended for patients with hepatic impairment.

Renal impairment

Because iloperidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of iloperidone. Renal impairment (creatinine clearance <30 mL/min) had minimal effect on maximum plasma concentrations (Cmax) of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 any of the three analytes measured. AUC was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.

Elderly patients

Clinical Studies of iloperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3210 patients treated with iloperidone in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.

Race

Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of iloperidone following iloperidone administration.

Gender

There are no differences in the pharmacokinetics of iloperidone between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in patients with schizophrenia.

Smoking status

Based on in vitro studies utilising human liver enzymes, iloperidone is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of iloperidone.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Carcinogenesis

Lifetime carcinogenicity studies were conducted in CD-1 mice and Sprague Dawley rats.

Iloperidone was administered orally at doses of 2.5, 5.0 and 10 mg/kg/day to CD-1 mice and 4, 8 and 16 mg/kg/day to Sprague Dawley rats (0.5, 1.0 and 2.0 times and 1.6, 3.2 and 6.5 times, respectively, the maximum recommended human dose [MRHD] of 24 mg/day on a mg/m2 basis). 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 treatmentrelated increases in neoplasia in rats.

Proliferative and/or neoplastic changes in the mammary gland of rodents have been observed following the chronic administration of antipsychotic drugs and are considered to be prolactin mediated. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with iloperidone.

The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in significant amounts in mice or rats, was given orally to Wistar rats for 26 weeks at doses of 50 or 500 mg/kg/day. Although this study was not adequate for assessment of carcinogenic potential, proliferative responses were seen in several organs: mammary gland hyperplasia in males and females, thyroid follicular hyperplasia in females, ovarian interstitial cell hyperplasia, pituitary cell proliferation in males, and endocrine pancreas proliferation in males and females. The above were seen at both doses except for the ovarian and pancreas effects which were seen at the higher dose only. Plasma levels of P95 (AUC) at the lower dose were 2.5 times those in humans receiving the MRHD of iloperidone, but as indicated above a no-effect dose for the proliferative responses was not determined. It is not known if these proliferative responses will progress to neoplasia with longer term treatment.

Mutagenesis

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

Iloperidone was excreted in milk of rats during lactation.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Hypromellose

Crospovidone

Magnesium stearate

Silica, colloidal anhydrous

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Store in the original package in order to protect from light and moisture and keep the bottle tightly closed.

6.5 Nature and contents of container

HDPE bottle with a child-resistant polypropylene closure containing an aluminum foil heat induction seal, and a silica gel desiccant. The HDPE bottles are placed into paperboard cartons.

6.6 Special precautions for disposal

Any unused product or waste materials should be disposed of in accordance with local requirements.

  1. MANUFACTURER

Vanda Pharmaceuticals Inc.

Rockville, MD 20850, USA

  1. ISRAEL MARKETING AUTHORISATION HOLDER

Megapharm Ltd, POB 519, Hod-HaSharon 45105

  1. MARKETING AUTHORISATION NUMBER

148-32-33482, 148-33-33486, 148-34-33487, 148-35-33488, 148-36-33489

The format of this leaflet was determined by the ministry of health and its content was checked and approved in July 2012

FANASPC 062012 P.1

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