FANAPT TABLETS 6 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
ILOPERIDONE
Available from:
MEGAPHARM LTD
ATC code:
N05AX14
Pharmaceutical form:
TABLETS
Composition:
ILOPERIDONE 6 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
PATHEON INC, CANADA
Therapeutic group:
ILOPERIDONE
Therapeutic area:
ILOPERIDONE
Therapeutic indications:
FANAPT is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults.
Authorization number:
148 35 33488 00
Authorization date:
2017-06-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

06-01-2019

Page

1

19

FULL PRESCRIBING INFORMATION

1 NAME OF THE MEDICINAL PRODUCT(S), ACTIVE INGREDIENT(S) AND ROUTE(S) OF

ADMINISTRATION

FANAPT TABLETS 1 MG,

each 1 mg tablet contains 1 mg iloperidone, oral tablets.

FANAPT TABLETS 2 MG,

each 2 mg tablet contains 2 mg iloperidone, oral tablets.

FANAPT TABLETS 4 MG,

each 4 mg tablet contains 4 mg iloperidone, oral tablets.

FANAPT TABLETS 6 MG,

each 6 mg tablet contains 6 mg iloperidone, oral tablets.

FANAPT TABLETS 8 MG,

each 8 mg tablet contains 8 mg iloperidone, oral tablets.

FANAPT TABLETS 10 MG,

each 10 mg tablet contains 10 mg iloperidone, oral tablets

.

FANAPT TABLETS 12 MG,

each 12 mg tablet contains 12 mg iloperidone, oral tablets.

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 [see

Warnings and Precautions (6.1)].

2 THERAPEUTIC INDICATIONS

FANAPT

is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults.

3 DOSAGE AND ADMINISTRATION

3.1 Usual Dose

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. Dose increases to reach the

target range of 6-12 mg twice daily (12_24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice

daily (4 mg/day). 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. 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 drugs that do not require similar titration. Prescribers should also be aware that some adverse effects

associated with FANAPT use are dose related.

Page

2

19

FANAPT can be administered without regard to meals.

3.2 Dosage in Special Populations

Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal impairment status

[see Use in

Specific Populations (9.6, 9.7)]

Dosage adjustment for patients taking FANAPT concomitantly with potential CYP2D6 inhibitors:

FANAPT dose

should be reduced by one-half when administered concomitantly with strong CYP2D6 inhibitors such as fluoxetine or

paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, FANAPT dose should then be

increased to where it was before

[see Drug Interactions (8.1)]

Dosage adjustment for patients taking FANAPT concomitantly with potential CYP3A4 inhibitors:

FANAPT dose

should be reduced by one-half when administered concomitantly with strong CYP3A4 inhibitors such as ketoconazole or

clarithromycin. When the CYP3A4 inhibitor is withdrawn from the combination therapy, FANAPT dose should be

increased to where it was before

[see Drug Interactions (8.1)]

Dosage adjustment for patients taking FANAPT who are poor metabolizers of CYP2D6:

FANAPT dose should be

reduced by one-half for poor metabolizers of CYP2D6 [

see

Clinical Pharmacology, Pharmacokinetics (13.3)]

Hepatic Impairment:

A study in mild and moderate liver impairment has not been conducted. FANAPT is not

recommended for patients with hepatic impairment.

[see Use in Specific Populations (9.7)]

3.3

Maintenance Treatment

Although there is no body of evidence available to answer the question of how long the patient treated with FANAPT

should be maintained, it is generally recommended that responding patients be continued beyond the acute response.

Patients should be periodically reassessed to determine the need for maintenance treatment.

3.4 Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation 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.

3.5 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.

4 DOSAGE FORMS AND STRENGTHS

FANAPT tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. The tablets

are white, round, flat, beveled-edged and identified with a logo “

” debossed on one side and tablet strength “1”, “2”,

“4”, “6”, “8”, “10”, or “12” debossed on the other side.

5 CONTRAINDICATIONS

Hypersensitivity to the active substance, or to any of the excipients listed in section 13. Anaphylaxis, angioedema, and

other hypersensitivity reactions have been reported

[see Adverse Reactions (7.2)].

Page

3

19

6 WARNINGS AND PRECAUTIONS

6.1 Increased Risks in Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk

of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related

psychosis [see Boxed Warning].

Cerebrovascular Adverse Events, Including Stroke

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a

higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including

fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with dementia-

related psychosis

[see Boxed Warning]

6.2 QT Prolongation

In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated

with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval

was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and

ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4,

FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.

No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical

program.

The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc including Class

1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic

medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of

medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should

also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs

that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of

other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute

myocardial infarction; and/or (6) uncompensated heart failure.

Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism

[see Drug Interactions

(8.1)]

, and in patients with reduced activity of CYP2D6

[see Clinical Pharmacology (13.3)]

It is recommended that patients being considered for FANAPT treatment who are at risk for significant electrolyte

disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia

(and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. FANAPT should be avoided in

patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction,

uncompensated heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to have

persistent QTc measurements >500 msec.

If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g.,

dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.

6.3 Neuroleptic Malignant Syndrome (NMS)

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

Page

4

19

(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include

elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to

identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection,

etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in

the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous

system (CNS) pathology.

The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other

drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment

of any concomitant serious medical problems for which specific treatments are available. There is no general agreement

about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy

should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

6.4 Tardive Dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which may

develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest

among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the inception of

antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in

their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the

duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the syndrome can

develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or

completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially

suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that

symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, FANAPT should be prescribed in a manner that is most likely to minimize the occurrence of

tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic

illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially

less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose

and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued

treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be considered.

However, some patients may require treatment with FANAPT despite the presence of the syndrome.

6.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight

gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class

has its own specific risk profile.

Hyperglycemia 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 FANAPT. 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 events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-

Page

5

19

emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these

studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if FANAPT is

associated with this increased risk.

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.

Data from a 4- week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples were

drawn,are presented in Table 1.

Table 1. Change in Fasting Glucose

FANAPT

-

Placebo

24 mg/day

Mean Change from Baseline(mg/dL)

n=114 n=228

Serum Glucose Change from Baseline

-0.5

Proportion of Patients with Shifts

Serum Glucose Normal to High

(<100 mg/dL to ≥126 mg/dL)

2.5 %

(2/80)

10.7 %

(18/169)

Pooled analyses of glucose data from clinical studies including longer term trials are shown in Table 2.

Table 2: Change in Glucose

Mean Change from Baseline (mg/dL)

3-6 months

6-12 months

>12 months

FANAPT 10-16 mg/day

1.8 (N=773)

5.4 (N=723)

5.4 (N=425)

FANAPT 20-24 mg/day

-3.6 (N=34)

-9.0 (N=31)

-18.0 (N=20)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting blood samples were drawn, in adult subjects

with schizophrenia are presented in Table 3.

Table 3. Change in Fasting Lipids

FANAPT

-

Placebo

24 mg/day

Mean Change from Baseline (mg/dL)

Cholesterol

n= 114

n=228

Change from baseline

-2.17

8.18

LDL

n=109

n=217

Change from baseline

-1.41

9.03

Page

6

19

HDL

n= 114

n=228

Change from baseline

-3.35

0.55

Triglycerides

n= 114

n=228

Change from baseline

16.47

-0.83

Proportion of Patients with Shifts

Cholesterol

Normal to High

(<200 mg/dL to ≥240 mg/dL)

1.4 %

(1/72)

3.6%

(5/141)

LDL

Normal to High

(<100 mg/dL to ≥160 mg/dL)

2.4%

(1/42)

1.1%

(1/90)

HDL

Normal to Low

( ≥40 mg/dL to <40 mg/dL)

23.8%

(19/80)

12.1%

(20/166)

Triglycerides

Normal to High

(<150 mg/dL to ≥200 mg/dL)

8.3%

(6/72)

10.1%

(15/148)

Pooled analyses of cholesterol and triglyceride data from clinical studies including longer term trials are shown in Tables

4 and 5.

Table 4: Change in Cholesterol

Mean Change from Baseline (mg/dL)

3-6 months

6-12 months

>12 months

FANAPT 10-16 mg/day

-3.9 (N=783)

-3.9 (N=726)

-7.7 (N=428)

FANAPT 20-24 mg/day

-19.4 (N=34)

-23.2 (N=31)

-19.4 (N=20)

Table 5: Change in Triglycerides

Mean Change from Baseline (mg/dL)

3-6 months

6-12 months

>12 months

FANAPT 10-16 mg/day

-8.9 (N=783)

-8.9 (N=726)

-17.7 (N=428)

FANAPT 20-24 mg/day

-26.6 (N=34)

-35.4 (N=31)

-17.7 (N=20)

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.

Changes in body weight (kg) and the proportion of subjects with ≥7% gain in body weight from 4 placebo-controlled, 4-

or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.

Table 6. Change in Body Weight

Placebo

FANAPT

10-16 mg/day

FANAPT

20-24 mg/day

n=576

n=481

n=391

Weight (kg)

Page

7

19

Change from Baseline

-0.1

Weight Gain

≥7% increase from Baseline

6.6 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. As with other antipsychotics, 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.

6.7 Orthostatic Hypotension and Syncope

FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-

adrenergic antagonist properties. In double-blind placebo-controlled short-term studies, where the dose was increased

slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated with FANAPT, compared with

0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20-24 mg/day, 3% of patients

given 10-16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to increase the rate of

orthostatic hypotension and syncope.

FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of

myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the

patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of

orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

6.8 Leukopenia, Neutropenia and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to

antipsychotic agents. 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 pre-existing 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 FANAPT 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/mm

should discontinue FANAPT and have their WBC followed until recovery.

6.9 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in

turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-

standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and

male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent

in vitro

a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected

breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated

with FANAPT

[see Nonclinical Toxicology (14.1)]

. Neither clinical studies nor epidemiologic studies conducted to date

have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the

available evidence is considered too limited to be conclusive at this time.

Page

8

19

In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in plasma prolactin levels

for the FANAPT 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 agents. In pooled analysis from

clinical studies including longer term trials, in 3210 adults treated with iloperidone, 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.

6.10 Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate

care is advised when prescribing FANAPT for 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.

6.11 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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia

[see Boxed

Warning]

6.12 Suicide

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

accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets consistent with

good patient management in order to reduce the risk of overdose.

6.13 Priapism

Three cases of priapism were reported in the pre-marketing FANAPT program. Drugs with alpha-adrenergic blocking

effects have been reported to induce priapism. FANAPT shares this pharmacologic activity. Severe priapism may require

surgical intervention.

6.14 Potential for Cognitive and Motor Impairment

FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-term, placebo-

controlled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult patients treated with

FANAPT

at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. Patients should be cautioned about

operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does

not affect them adversely.

7 ADVERSE REACTIONS

7.1 Clinical Studies 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 information below is derived from a clinical trial database for FANAPT consisting of 2070

patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received

FANAPT for at least 6 months, with 463 exposed to FANAPT for at least 12 months. All of these patients who received

FANAPT were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT

Page

9

19

varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and

outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure.

Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using their

own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse

reactions, reactions were grouped in standardized categories using MedDRA terminology.

The stated frequencies of adverse reactions represent the proportions of individuals who experienced a treatment-

emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time

or worsened while receiving therapy following baseline evaluation.

The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed-

or flexible-dose studies in patients who received FANAPT at daily doses within a range of 10 to 24 mg (n=874).

Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and More

Frequent than Placebo

Table 7 enumerates the pooled incidences of treatment-emergent adverse reactions that were spontaneously reported in

four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more

of patients treated with FANAPT in any of the dose groups, and for which the incidence in FANAPT-treated patients in

any dose group was greater than the incidence in patients treated with placebo.

Table 7: Percentage of Treatment-Emergent Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients*

-

Body System or Organ Class

Placebo

%

FANAPT 10-16 mg/day

%

FANAPT 20-24 mg/day

%

Dictionary-derived Term

(N=587)

(N=483)

(N=391)

Body as a Whole

Arthralgia

Fatigue

Musculoskeletal Stiffness

Weight Increased

Cardiac Disorders

Tachycardia

Eye Disorders

Vision Blurred

Gastrointestinal Disorders

Nausea

Dry Mouth

Diarrhea

Abdominal Discomfort

Infections

Nasopharyngitis

Upper Respiratory Tract Infection

Nervous System Disorders

Dizziness

Somnolence

Extrapyramidal Disorder

Tremor

Lethargy

Reproductive System

Ejaculation Failure

<1

Respiratory

Nasal Congestion

Dyspnea

<1

Skin

Rash

Page

10

19

Vascular Disorders

Orthostatic Hypotension

Hypotension

<1

<1

* Table includes adverse reactions that were reported in 2% or more of patients in any of the FANAPT dose groups and

which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.

Dose-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions that

occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in patients

treated with FANAPT

20-24 mg/day were twice than the incidence in patients treated with FANAPT 10-16 mg/day were:

abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased.

Common and Drug-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse

reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate for at least 1

dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight

increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20-24 mg/day as on 10-16

mg/day.

Extrapyramidal Symptoms (EPS) in Clinical Trials

Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding

treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-related

adverse events as shown in Table 8.

Table 8: Percentage of EPS Compared to Placebo

Placebo (%)

FANAPT

10-16 mg/day

(%)

FANAPT

20-24 mg/day

(%)

Adverse Event Term

(N=587)

(N=483)

(N=391)

All EPS events

11.6

13.5

15.1

Akathisia

Bradykinesia

Dyskinesia

Dystonia

Parkinsonism

Tremor

Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference

in the incidence of discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%)

patients. The types of adverse events that led to discontinuation were similar for the FANAPT- and placebo-treated

patients.

Demographic Differences in Adverse Reactions in Clinical Trials

An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not

reveal any evidence of differences in safety on the basis of age, gender or race

[see Warnings and Precautions (6.1)]

Laboratory Test Abnormalities in Clinical Trials

There were no differences between FANAPT and placebo in the incidence of discontinuation due to changes in

hematology, urinalysis, or serum chemistry.

In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with

hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3%

(2/585) on placebo. 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.

Page

11

19

Other Reactions During the Pre-marketing Evaluation of FANAPT

The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions in patients treated with

FANAPT at multiple doses ≥ 4 mg/day during any phase of a trial with the database of 3210 FANAPT-treated patients.

All reported reactions are included except those already listed in Table 7, or other parts of the

Adverse Reactions (6)

section, those considered in the

Warnings and Precautions (6)

, those reaction terms which were so general as to be

uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions

that are otherwise common as background reactions, and reactions considered unlikely to be drug related. It is important

to emphasize that, although the reactions reported occurred during treatment with FANAPT, they were not necessarily

caused by it.

Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to

the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in

Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are

those occurring in fewer than 1/1000 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

Page

12

19

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the

Ministry of Health according to the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.gov.il

7.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FANAPT: retrograde ejaculation and

hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the

face, lips, mouth, and tongue; urticaria; rash; and pruritus). Because these reactions were reported voluntarily from a

population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

8 DRUG INTERACTIONS

Given the primary CNS effects of FANAPT, caution should be used when it is taken in combination with other centrally

acting drugs and alcohol. Due to its -

alpha1-adrenergic receptor antagonism, FANAPT has the potential to enhance the

effect of certain antihypertensive agents.

8.1 Potential for Other Drugs to Affect FANAPT

Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1

enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors,

like smoking, is unlikely.

Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or

CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels.

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 years, increased the area under the curve (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

: Coadministration 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

years , who were classified as CYP2D6 extensive

metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 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:

Coadministration 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 years 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.

Page

13

19

Paroxetine and Ketoconazole:

Coadministration 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

years 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. So giving 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 CYP3A4 inhibitor.

8.2 Potential for FANAPT to Affect Other Drugs

In vitro

studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs

metabolized 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 enzyme

inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19,

CYP3A4 and CYP3A5.

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

the maximum plasma concentrations C

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).

Midazolam (a sensitive CYP 3A4 substrate):

A study in patients with schizophrenia showed a less than 50% increase in

midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and

no effect on midazolam C

. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.

8.3 Drugs that Prolong the QT Interval

FANAPT should not be used with any other drugs that prolong the QT interval

[see Warnings and Precautions (6.2)]

9 USE IN SPECIFIC POPULATIONS

9.1 Pregnancy

Pregnancy Category C

FANAPT caused developmental toxicity, but was not teratogenic, in rats and rabbits.

In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1.6, 6.5, and 26 times the

maximum recommended human dose (MRHD) of 24 mg/day on a mg/m

basis) of iloperidone orally during the period of

organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased

fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also

caused decreased maternal food consumption and weight gain.

In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the MRHD

on a mg/m

basis) 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 additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-

conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included 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. No-effect doses ranged from 4 to 12 mg/kg except for the increase in stillbirth rates

which occurred at the lowest dose tested of 4 mg/kg, which is 1.6 times the MRHD on a mg/m

basis. Maternal toxicity

was seen at the higher doses in these studies.

The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in

significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or 200

Page

14

19

mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant maternal

toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans receiving the

MRHD of iloperidone.

There are no adequate and well-controlled studies in pregnant women.

Non-teratogenic Effects

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.

9.2 Labor and Delivery

The effect of FANAPT on labor and delivery in humans is unknown.

9.3 Nursing Mothers

FANAPT was excreted in milk of rats during lactation. It is not known whether FANAPT or its metabolites are excreted

in human milk. It is recommended that women receiving FANAPT should not breast-feed.

9.4 Pediatric Use

Safety and effectiveness in pediatric and adolescent patients have not been established.

9.5 Geriatric Use

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 3210 patients

treated with FANAPT in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.

Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that there may be a

different tolerability profile (i.e., increased risk in mortality and cerebrovascular events including stroke) in this

population compared to younger patients with schizophrenia

[see Boxed Warning and Warnings and Precautions (6.1)]

The safety and efficacy of FANAPT in the treatment of patients with psychosis associated with Alzheimer’s disease has

not been established. If the prescriber elects to treat such patients with FANAPT, vigilance should be exercised.

9.6 Renal Impairment

Because FANAPT 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 FANAPT. Renal impairment (creatinine clearance <30

mL/min) had minimal effect on C

of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in

any of the 3analytes measured. AUC

0–∞

was increased by 24%, decreased by 6%, and increased by 52% for iloperidone,

P88 and P95, respectively, in subjects with renal impairment.

Page

15

19

9.7 Hepatic Impairment

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

hepatic impairment.

9.8 Smoking Status

Based on

in vitro

studies utilizing human liver enzymes, FANAPT is not a substrate for CYP1A2; smoking should

therefore not have an effect on the pharmacokinetics of FANAPT.

10 DRUG ABUSE AND DEPENDENCE

10.1 Controlled Substance

FANAPT is not a controlled substance.

10.2 Abuse

FANAPT has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical

dependence. While the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not

systematic and it is not possible to predict on the basis of this experience the extent to which a CNS active drug,

FANAPT, will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully

for a history of drug abuse, and such patients should be observed closely for signs of FANAPT misuse or abuse (e.g.

development of tolerance, increases in dose, drug-seeking behavior).

11 OVERDOSAGE

11.1 Human Experience

In pre-marketing 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.

11.2 Management of Overdose

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 FANAPT. Similarly, it is reasonable to expect that the alpha-blocking properties of

bretylium might be additive to those of FANAPT, 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 FANAPT-induced

alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close

medical supervision should continue until the patient recovers.

Page

16

19

12 DESCRIPTION

FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical

name is 4’-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3’-methoxyacetophenone. Its molecular formula is

and its molecular weight is 426.48. The structural formula is:

Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1

N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.

FANAPT tablets are intended for oral administration only. Each round, uncoated tablet contains 1 mg, 2 mg, 4 mg, 6 mg,

8 mg, 10 mg, or 12 mg of iloperidone. Inactive ingredients are: lactose monohydrate, microcrystalline cellulose,

hydroxypropylmethylcellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and purified water (removed

during processing). The tablets are white, round, flat, beveled-edged and identified with a logo “

” debossed on one

side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.

13 CLINICAL PHARMACOLOGY

13.1 Mechanism of Action

The mechanism of action of FANAPT, as with other drugs having efficacy in schizophrenia, is unknown. However it is

proposed that the efficacy of FANAPT is mediated through a combination of dopamine type 2 (D

) and serotonin type 2

(5-HT

) antagonisms.

13.2 Pharmacodynamics

FANAPT exhibits high (nM) affinity binding to serotonin 5-HT

dopamine D

and D

receptors, and norepinephrine

NEα1 receptors (K

values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). FANAPT has moderate affinity for dopamine D

and serotonin 5-HT

and 5-HT

receptors (K

values of 25, 43, and 22, nM respectively), and low affinity for the serotonin

5-HT

, dopamine D

, and histamine H

receptors (K

values of 168, 216 and 437 nM, respectively). FANAPT has no

appreciable affinity (K

>1000 nM) for cholinergic muscarinic receptors. FANAPT functions as an antagonist at the

dopamine D

, serotonin 5-HT

and norepinephrine α

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-HT

value of 3.91) and the NE

α1A

, NE

α1B

, NE

α1D

, and NE

α2C

receptors (K

values of 4.7, 2.7, 8.8 and 4.7 nM respectively).

13.3 Pharmacokinetics

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 2 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%.

Page

17

19

Administration of iloperidone with a standard high-fat meal did not significantly affect the C

or AUC of iloperidone,

P88, or P95, but delayed T

by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. FANAPT 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, the unbound fraction of iloperidone in plasma is

~3% and of each metabolite (P88 and P95) it is ~8%.

Metabolism and Elimination:

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% - 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. Coadministration 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. Laboratory tests are available to identify CYP2D6 PMs.

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.

Transporter Interaction

: Iloperidone and P88 are not substrates of P-gp and iloperidone is a weak P-gp inhibitor.

14 NONCLINICAL TOXICOLOGY

14.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 MRHD of 24 mg/day on a mg/m

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 treatment-related increases in neoplasia in rats.

The carcinogenic potential of the iloperidone metabolite P95, which is a major circulating metabolite of iloperidone 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

iloperidone.

An increase in mammary, pituitary and endocrine pancreas neoplasms has been found in rodents after chronic

administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and

hyperprolactinemia. Increases in serum prolactin were seen in mice and rats treated with iloperidone. The relevance of

these tumor findings in rodents in terms of human risk is unknown.

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 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/m

basis.

Page

18

19

15 CLINICAL STUDIES

The efficacy of FANAPT in the treatment of schizophrenia was supported by 2 placebo- and 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 2 flexible dose ranges of FANAPT (12-16 mg/day or 20-24 mg/day)

compared to placebo and an active control (risperidone). For the 12-16 mg/day group, the titration schedule of FANAPT

was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg

twice daily on Day 7. For the 20-24 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Day 1, 2

mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and

10 mg twice daily on Day 7. 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. The active control antipsychotic drug appeared to be superior to FANAPT in this trial within the

first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for that drug. In patients

in this study who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to the

active control.

A 4-week, placebo-controlled trial (n=604) involved one fixed dose of FANAPT (24 mg/day) compared to placebo and an

active control (ziprasidone). 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. FANAPT appeared

to have similar efficacy to the active control drug which also needed a slow titration to the target dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

FANAPT tablets are white, round and identified with a logo “

” debossed on one side and tablet strength “1”, “2”,

“4”, “6”, “8”, “10”, or “12” debossed on the other side. Tablets are supplied in the following strengths and package

configurations:

Package Configuration

Tablet Strength (mg)

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

1 mg

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

2 mg

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

4 mg

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

6 mg

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

8 mg

Bottles of 8 tablets

10 mg

Page

19

19

Bottles of 14 tablets

Bottles of 60 tablets

Bottles of 8 tablets

Bottles of 14 tablets

Bottles of 60 tablets

12 mg

Titration Pack (Blister Aluminum)

2x1 mg, 2x2 mg, 2x4 mg, 2x6 mg

(Total of 8 tablets)

Not all package sizes may be marketed.

Shelf life

The expiry date of the product is indicated on the packaging materials

After opening: 45 days

Storage

Store below 25°C

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

17 MANUFACTURER

Patheon Inc., Mississauga, Canada for Vanda Pharmaceuticals Inc., Washington, D.C. 20037 USA

18 ISRAEL MARKETING AUTHORISATION HOLDER

Megapharm Ltd, POB 519, Hod-HaSharon 45105

19 MARKETING AUTHORIZATION NUMBER

FANAPT TABLETS 1 MG: 148-32-33482

FANAPT TABLETS 2 MG: 148-33-33486

FANAPT TABLETS 4 MG: 148-34-33487

FANAPT TABLETS 6 MG: 148-35-33488

FANAPT TABLETS 8 MG: 148-36-33489

FANAPT TABLETS 10 MG: 152-13-34129

FANAPT TABLETS 12 MG: 152-14-34130

Vanda and Fanapt

are registered trademarks of Vanda Pharmaceuticals Inc. in the United States and other countries.

The content of this leaflet was approved by the Ministry of Health in June 2014 and updated according to the guidelines of

the Ministry of Health in December 2018.

Page

1

11

03.01.2019

אפור

חקור

דבכנ

וננוצרב

ךעידוהל

לע

ןוכדע

ןולעב

אפורל

רישכתה לש ןכרצל ןולעבו םי

FANAPT TABLETS 1 MG,

each 1 mg tablet contains 1 mg iloperidone, oral tablets.

FANAPT TABLETS 2 MG,

each 2 mg tablet contains 2 mg iloperidone, oral tablets.

FANAPT TABLETS 4 MG,

each 4 mg tablet contains 4 mg iloperidone, oral tablets.

FANAPT TABLETS 6 MG,

each 6 mg tablet contains 6 mg iloperidone, oral tablets.

FANAPT TABLETS 8 MG,

each 8 mg tablet contains 8 mg iloperidone, oral tablets.

FANAPT TABLETS 10 MG,

each 10 mg tablet contains 10 mg iloperidone, oral tablets

.

FANAPT TABLETS 12 MG,

each 12 mg tablet contains 12 mg iloperidone, oral tablets.

:תרשואמה היוותהה

FANAPT® is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults.

ןלהל

תורמחה תוירקיעה פורל ןולעב

םימייק ןכ ומכ . םיפסונ םינוכדע

העדוהב םיטרופמ אלש אפורל ןולעב וז

טסקט ב ןמוסמ עקר

ותועמשמ בוהצ הרמחה

קט טס עקרב ןמוסמ קורי

ןוכדע ותועמשמ

םע םודא טסקטו ותועמשמ הצוח וק הקיחמ

4 5 CONTRAINDICATIONS

Hypersensitivity to the active substance, or to any of the excipients listed in section 13. Anaphylaxis, angioedema, and

other hypersensitivity reactions have been reported

[see Adverse Reactions (67.2)].

5 6 WARNINGS AND PRECAUTIONS

56.1 Increased Risks in Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased

risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-

related psychosis [see Boxed Warning].

Cerebrovascular Adverse Events, Including Stroke

Page

2

11

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was

a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks)

including fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with

dementia-related psychosis

[see Boxed Warning]

56.2 QT Prolongation

In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was

associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on

the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once

daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and

3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.

No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical

program.

[…]

Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of

drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant

use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5)

recent acute myocardial infarction; and/or (6) uncompensated heart failure.

Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism

[see Drug Interactions

(78.1)]

, and in patients with reduced activity of CYP2D6

[see Clinical Pharmacology (1213.3)]

It is recommended that patients being considered for FANAPT treatment who are at risk for significant electrolyte

disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia

(and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. FANAPT should be avoided in

patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction,

uncompensated heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to

have persistent QTc measurements >500 msec.

If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g.,

dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.

56.3 Neuroleptic Malignant Syndrome (NMS)

[…]

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to

identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic

infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important

considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and

primary central nervous system (CNS) pathology.

The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other

drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3)

treatment of any concomitant serious medical problems for which specific treatments are available. There is no

general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug

therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have

been reported.

56.4 Tardive Dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which

may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be

Page

3

11

highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the

inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug

products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as

the duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the

syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially

or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or

partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, FANAPT should be prescribed in a manner that is most likely to minimize the occurrence

of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a

chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but

potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the

smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The

need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be

considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.

56.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight

gain

[see Patient Counseling Information (17.3

]

. While all atypical antipsychotic drugs have been shown to produce

some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

[…]

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

[…]

56.7 Orthostatic Hypotension and Syncope

FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its

alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies, where the dose was

increased slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated with FANAPT,

compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20-24 mg/day,

3% of patients given 10-16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to

increase the rate of orthostatic hypotension and syncope.

FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of

myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose

the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring

of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

56.9 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.

Page

4

11

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in

turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both

female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent

in

vitro

, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously

detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and

rats treated with FANAPT

[see Nonclinical Toxicology (1314.1)]

. Neither clinical studies nor epidemiologic studies

conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis

in humans; the available evidence is considered too limited to be conclusive at this time.

[…]

56.12 Suicide

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

accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets consistent

with good patient management in order to reduce the risk of overdose.

[…]

6 7 ADVERSE REACTIONS

67.1 Clinical Studies Experience

[…]

Table 7: Percentage of Treatment-Emergent Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients*

-

Body System or Organ Class

Placebo

%

FANAPT 10-16 mg/day

%

FANAPT 20-24 mg/day

%

Dictionary-derived Term

(N=587)

(N=483)

(N=391)

Body as a Whole

Arthralgia

Fatigue

Musculoskeletal Stiffness

Weight Increased

Cardiac Disorders

Tachycardia

Eye Disorders

Vision Blurred

Gastrointestinal Disorders

Nausea

Dry Mouth

Diarrhea

Abdominal Discomfort

Infections

Nasopharyngitis

Upper Respiratory Tract Infection

Nervous System Disorders

Dizziness

Page

5

11

Somnolence

Extrapyramidal Disorder

Tremor

Lethargy

Reproductive System

Ejaculation Failure

<1

Respiratory

Nasal Congestion

Dyspnea

<1

Skin

Rash

Vascular Disorders

Orthostatic Hypotension

Hypotension

<1

<1

* Table includes adverse reactions that were reported in 2% or more of patients in any of the FANAPT dose groups

and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.

Dose-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions

that occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in

patients treated with FANAPT

20-24 mg/day were twice than the incidence in patients treated with FANAPT 10-16

mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight

increased.

Common and Drug-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following

adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate

for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension,

and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20-24 mg/day

as on 10-16 mg/day.

Extrapyramidal Symptoms (EPS) in Clinical Trials

Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information

regarding treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-

related adverse events as shown in Table 8.

Table 8: Percentage of EPS Compared to Placebo

Placebo (%)

FANAPT

10-16 mg/day

(%)

FANAPT

20-24 mg/day

(%)

Adverse Event Term

(N=587)

(N=483)

(N=391)

All EPS events

11.6

13.5

15.1

Akathisia

Bradykinesia

Dyskinesia

Dystonia

Parkinsonism

Tremor

[…]

Blood and Lymphatic Disorders: Infrequent

– anemia, iron deficiency anemia;

Rare

– leukopenia

Page

6

11

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

67.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FANAPT: retrograde ejaculation

and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling

of the face, lips, mouth, and tongue; urticaria; rash; and pruritus). Because these reactions were reported voluntarily

from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal

relationship to drug exposure.

[…]

Midazolam (a sensitive CYP 3A4 substrate):

A study in patients with schizophrenia showed a less than 50% increase

in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily)

and no effect on midazolam C

. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.

Page

7

11

8 9 USE IN SPECIFIC POPULATIONS

89.1 Pregnancy

Pregnancy Category C

FANAPT caused developmental toxicity, but was not teratogenic, in rats and rabbits.

In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1.6, 6.5, and 26 times the

maximum recommended human dose (MRHD) of 24 mg/day on a mg/m

basis) of iloperidone orally during the

period of organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and

length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and

variations; this dose also caused decreased maternal food consumption and weight gain.

In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the

MRHD on a mg/m

basis) 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 additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-

conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included

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. No-effect doses ranged from 4 to 12 mg/kg

except for the increase in stillbirth rates which occurred at the lowest dose tested of 4 mg/kg, which is 1.6 times the

MRHD on a mg/m

basis. Maternal toxicity was seen at the higher doses in these studies.

The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in

significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or

200 mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant

maternal toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans

receiving the MRHD of iloperidone.

There are no adequate and well-controlled studies in pregnant women.

Non-teratogenic Effects

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.

89.2 Labor and Delivery

The effect of FANAPT on labor and delivery in humans is unknown.

89.3 Nursing Mothers

FANAPT was excreted in milk of rats during lactation. It is not known whether FANAPT or its metabolites are

excreted in human milk. It is recommended that women receiving FANAPT should not breast-feed.

89.4 Pediatric Use

Safety and effectiveness in pediatric and adolescent patients have not been established.

Page

8

11

89.5 Geriatric Use

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 3210 patients

treated with FANAPT in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.

Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that there may be a

different tolerability profile (i.e., increased risk in mortality and cerebrovascular events including stroke) in this

population compared to younger patients with schizophrenia

[see Boxed Warning and Warnings and Precautions

(56.1)]

. The safety and efficacy of FANAPT in the treatment of patients with psychosis associated with Alzheimer’s

disease has not been established. If the prescriber elects to treat such patients with FANAPT, vigilance should be

exercised.

[…]

ןלהל

תורמחה תוירקיעה ל ןולעב ןכרצ םימייק ןכ ומכ . םיפסונ םינוכדע

וז העדוהב םיטרופמ אלש ןכרצל ןולעב

טסקט ב ןמוסמ עקר

ותועמשמ בוהצ הרמחה

טסקט עקרב ןמוסמ קורי

ןוכדע ותועמשמ

הצוח וק םע םודא טסקטו ותועמשמ הקיחמ

[...]

[...]

2

.

ינפל

שומישה

הפורתב

ןיא

ל

שמתשה

רישכתב

םא

:

התא

שיגר

יגרלא

רמוחל

ליעפה

ןודירפוליא

וא

לכל

דחא

םיביכרמהמ

םיפסונה

רשא

הליכמ

הפורתה

אנא

האר

ףיעס

"

עדימ

ףסונ

.("

,יגרלא םלה לש םירקמ לע חווד תת תויוחיפנ

תוירוע

תורחא תויגרלא תובוגתו ףיעס האר אנא)

.("יאוול תועפות"

[...]

.

תועפות

ול יאו

ומכ

לכ

הפורת

שומישה

טפאנפ

לולע

םורגל

תועפותל

יאוול

קלחב

םישמתשמהמ

לא

להבית

ארקמל

תמישר

תועפות

יאוולה

ןכתי

אלו

לובסת

ףאמ

תחא

ןהמ

ןויטישה תלחממ םילבוסה םישישק לצא תוומל רבגומ ןוכיס :הרהזא

םילוח

הזוכיספמ םילבוסה םישישק

הרושקה

(היצנמד) ןויטישה תלחמל

םילפוטמו

תופורתב

יטנא

תויטוכיספ

םיאצמנ

ןוכיסב

רבגומ

תוומל

וז הפורת

הניא

תרשואמ

לופיטל

םילוחב

םע

הזוכיספ

הרושקה

היצנמדל

Page

9

11

שי

תונפל

דימ

אפורל

םא

תועיפומ

תועפות

יאוולה

תואבה

:

הבוגת

תיגרלא

השק

תוחפנתה

לש

הפה

םייתפשה

וא

ןושלה

רצוק

המישנ

דוריג

החירפ

םוח

וא

הדירי

ץחלב

םדה

םירגובמ

םילבוסה

ןויטישמ

םילטונו

תופורת

יטנא

תויטוכיספ

תורחא

ןוגכ

טפאנפ

םילולע

לובסל

תועפותמ

יאוול

תווהמה

ןמיס

ץבשל

ןוגכ

השלוח

תימואתפ

רסוח

השוחת

םינפב

םיידי

וא

םיילגר

רוביד

אל

רורב

וא

היאר

תשטשוטמ

םא

תחא

תועפותמ

יאוו

ולא

תועיפומ

וליפא

ןמזל

רצק

שי

תשגל

אפורל

דימ

תוחיכש יאוול תועפות

– (frequent)

ךותמ דחא שמתשמ תוחפל לצא תועיפומש תועפות

תוחיכש ןניאש יאוול תועפות

(infrequent)

ב תועיפומש תועפות

1-10

ךותמ םישמתשמ

1,000

תורידנ יאוול תועפות

(rare)

עיפומש תועפות ךותמ דחא שמתשממ תוחפ לצא תו

1,000

:הפמילהו םדה תכרעמב תוערפה

תוחיכש יאוול תועפות תת :

,הדימעב םד ץחל תת

םד ץחל

:תוחיכש ןניאש יאוול תועפות .לזרב רסוחמ תעבונה הימנא ,הימנא ,ןיבולגומיהב הדירי

תורידנ יאוול תועפות ] הינפוקיול : םינבל םד יאת רפסמב הדירי

צוקיול םיטי

םדב םיאתה רפסמב היילע ,[ טירקוטמיהב הדירי ,םדב םיליפורטיונה

:בלב תוערפה

תוחיכש יאוול תועפות .בל תוקיפד ,ריהמ בל בצק :

תורידנ יאוול תועפות

בלה בצקב תוערפה

ירודזורפ הכלוה םסח

הגרד ירדח

יא

תקיפס

תיתשדג ללוכ) בל (הפירחו

:םיינזואב תוערפה

אוול תועפות תוחיכש ןניאש י .םיינזואב םיפוצפצ ,(וגיטרו) תיבוביס תרוחרחס :

תוערפה

:תוינירקודנא

תוחיכש ןניאש יאוול תועפות תת :

.סירתה תטולב תוליעפ

:םייניעב תוערפה

תוחיכש יאוול תועפות

תשטשוטמ הייאר

.(תיגרלא ללוכ) ןיעה תימחל תקלד

תוחיכש ןניאש יאוול תועפות ,השבי ןיע : ,םייפעפעב תקצב ,םיסירה ישרושו םייפעפעה לש תקלד

,ןיעב תוחיפנ .(תימחלה ללוכ) תוימומדא ,ןיעה תשדעב תוריכע ,טקרטק

תוערפה

תכרעמב

:לוכיעה

תוחיכש יאוול תועפות יא ,לושלש ,הפב שבוי ,הליחב :

.ןטבב תוחונ

תוחיכש ןניאש יאוול תועפות יא ,תרבגומ קור תשרפה ,הביקב תקלד :

ילש הט

תלטהב

.הפב םיביכ ,האוצ

תורידנ יאוול תועפות ,הפב תותפא : ןוירסירת ביכ עקב ,

,םייתפשב םיביכ ,הביקב רתי תויצמוח ,יתפערס תקלד יתביק רזחהמ האצותכ טשווה

יטשו תקלד ,

תיריר

.(סיטיטמוטס) הפה

Page

10

11

תוערפה

תויללכ

:ןתמה רוזאב תוערפהו

תוחיכש יאוול תועפות

םיקרפ באכ ושישת , .דלשה ירירשב תושקונ ,ת

תוחיכש ןניאש יאוול תועפות תיללכ) תקצב :

בקע ,תיתמוג

תולחמ

ישוק ,(בל

הכילהב

.אמצ

יאוול תועפות

תורידנ .(רתי םוח) הימרתרפיה :

העודי אל תוחיכשב יאוול תועפות תויוחיפנ ;יגרלא םלה תללוכ) תושיגר :

תת

הפב תוחיפנ ;ןורגב תורציה ;תוירוע ;ןורגבו .(דרגו החירפ ;תילאירקיטרוא החירפ ;ןושלבו הפב ,םייתפשב ,םינפב תוחיפנ

:דבכב תוערפה

תוחיכש ןניאש יאוול תועפות ןודמיע :

הרמ

:תויתנוזתו תוילובטמ תוערפה

תוחיכש יאוול תועפות

הדירי

לקשמב

.לקשמב היילע וא

תועפות

יאוול

ןניאש

תוחיכש

ןובאית

,רבגומ תושבייתה

קופיה (םדב ךומנ ןגלשא) הימל

תריצא

.םילזונ

:רוביח תומקרבו דלשה ירירשב תוערפה

תועפות

יאוול

:תוחיכש ,םירירש יבאכ .םירירש תותיווע

תורידנ יאוול תועפות

ראווצ לותיפ

תוערפה

תכרעמב

םיבצעה

תועפות

יאוול

תוחיכש

ץוחה תכרעמב תוערפה ,תוינונשי ,תרוחרחס

הרושק) תילדימריפ

תועונת תוסיוול רקיעב .(הבוגת רסוחו תוליעפ רסוח לש בצמ) תמדר ,דער ,(תויסקלפר רירש

תועפות

יאוול

ןניאש

תוחיכש

וכיספ תויביטקארפיה ,לומינ

יא ,תירוטומ

א) החכש ,טקש ןורכיזה לש יקלח וא אלמ ןדבו ןורכיזב ןסחואמה עדימ ףולשל תלוכיה לש וא

אל תועונת

לש תוריהמ תוינוצר

םייניעה

תורידנ יאוול תועפות תנומסת :

לגרה

.תצפוקה

תוערפה

תוירטאיכיספ

תועפות

יאוול

תוחיכש

רסוח

החונמ

תונפקות

.תוילשא

תועפות

יאוול

ןניאש

תוחיכש

תוניוע

הדירי

תינימה הקושתב

(אווש תובשחמ) היונרפ עיגהל תלוכי רסוח , קופיסל ינימ

בצמ

לבלובמ

הינאמ

וטטק תוגהנתה) הינ

תירוטומ

הניהש

תנייפואמ

הדיריב

תיתועמשמ

תויתבוגתב

(הביבסל

יבצמ

חור

ףקתה

הדרח

הערפה

תיתייפכ

תינדרוט

הימילוב

(הליכאב הערפה) הזוברנ

םוירילד

רתי תייתש תיגולוכיספ ,ףחדב הטילש תוערפה ,

ןואכיד

.ינילק

תוערפה

תוילכב

יכרדבו

ןתשה

וחיכש יאוול תועפות

ת

יא :

הטילש

ןתמב

ןתש

תוחיכש ןניאש יאוול תועפות

באכ

הנתשהב

הנתשהב תופיכת

הבטרה

תצצח

הילכ

תורידנ יאוול תועפות

תריצא

ןתש

יא

תקיפס

תוילכ

הפירח

תכרעמב תוערפה

הייברה

םיידשבו

Page

11

11

תוחיכש יאוול תועפות .הפקזב הערפה ,ערז טולפל תלוכי רסוח :

ש ןניאש יאוול תועפות תוחיכ באכ :

םיכשאב ,תסווה רוזחמ לש הקספה וא רדעיה , םיבאכ

.םיידשב

תורידנ יאוול תועפות יא :

תסווה רוזחמב תורידס

היטסמוקניג תסו רתי ,

(תסווב םירבגומ םימומיד ןיב םומיד ,

,ירוזחמ םומיד

רחאל

.תינומרע תקלד ,תולבה

הזחה תיב רצימבו הזחה תיבב ,המישנה תכרעמב תוערפה

ת

תוחיכש יאוול תועפו .תונוילעה המישנה יכרדב םוהיז ,ןורגהו ףאה לש תקלד ,המישנ רצוק ,ףאב שדוג :

תוחיכש ןניאש יאוול תועפות ףאהמ םומיד :

המתסא

ףאב תלזנ

םיסוניסב שדוג

שבוי

.ףאב

תורידנ יאוול תועפות ןורגב שבוי : ,הנישב המישנ םוד תנומסת , רצוק

המישנ

.ץמאמב

תוערפה

:רועב

תוחיכש יאוול תועפות .החירפ :

אפורל ןולעה

ןכרצל ןולעהו

חלשנ

תואירבה דרשמ רתאבש תופורתה רגאמל

www.health.gov.il

אלעה ךרוצל םת

רתאל

לבקל ןתינו

םתוא

ספדומ םי

ידי לע

םושירה לעבל הינפ

ד.ת ,מ"עב םראפאגמ

ןורשה דוה

45105

,הכרבב

רנגו דיוויד

מ חקור הנומ

Similar products

Search alerts related to this product

View documents history

Share this information