Approved Drug Label (PDF)
5
Warnings and Precautions
5.11 Hyperprolactinemia
Additions
and/or revisions underlined:
…
In
a short-term placebo-controlled trial (4-weeks) in patients with
schizophrenia, 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 placebo-controlled
trials in patients with schizophrenia, elevated plasma prolactin levels (greater
than or equal to 1.15xULN) 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.
In a short-term, placebo-controlled trial
(4-weeks) in patients with bipolar mania, the mean change from baseline to
endpoint in plasma prolactin levels for the FANAPT group was an increase of
15.66 ng/mL compared to a decrease of 0.58 ng/mL for the placebo group. In this
trial, elevated plasma prolactin levels (greater than or equal to 1.15xULN)
were observed in 35% of adults treated with FANAPT compared to 1% of the
placebo group.
5.14 Priapism
Additions and/or revisions underlined:
Four cases of
priapism were reported in the pre-marketing FANAPT program (3 in the
clinical studies for schizophrenia and 1 in the clinical study for manic and
mixed episodes associated with bipolar I disorder). Drugs with
alpha-adrenergic blocking effects have been reported to induce priapism. FANAPT
shares this pharmacologic activity. Severe priapism may require surgical
intervention.
5.15 Potential for Cognitive and Motor Impairment
Additions and/or revisions underlined:
FANAPT, like other antipsychotics, may cause
somnolence and has the potential to impair judgment, thinking or motor
skills. In short-term, placebo-controlled trials of schizophrenia,
somnolence (including sedation) was reported in 12% (104/874) of adult patients
treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587)
treated with placebo. In a short-term, placebo-controlled trial of bipolar
mania, somnolence (including sedation) was reported in 8% (16/206) of adult
patients treated with FANAPT versus 3% (6/208) treated with placebo.
Patients should be cautioned about operating
hazardous machinery, including motor vehicles, until they are reasonably
certain that therapy with FANAPT does not affect them adversely.
5.16 Intraoperative Floppy Iris Syndrome (IFIS)
Newly added subsection:
IFIS has been observed during cataract surgery in
some patients on or previously treated with alpha-1 adrenergic blockers. This
variant of small pupil syndrome is characterized by the combination of a
flaccid iris that billows in response to intraoperative irrigation currents,
progressive intraoperative miosis despite preoperative dilation with standard
mydriatic drugs, and potential prolapse of the iris toward the
phacoemulsification incisions. The patient’s surgeon should be prepared for
possible modifications to their surgical technique, such as the utilization of
iris hooks, iris dilator rings, or viscoelastic substances. There does not
appear to be a benefit of stopping alpha1 blocker therapy prior to cataract
surgery. The initiation of therapy with FANAPT in patients for whom cataract or
glaucoma surgery is scheduled is not recommended.
5.5 Tardive Dyskinesia
Additions and/or revisions underlined:
…
The risk of developing
tardive dyskinesia and the likelihood that it will become irreversible increase
with the duration of treatment and cumulative dose. The syndrome can develop
after relatively brief treatment periods at low doses. It may also occur after
discontinuation of treatment.
…
5.6 Metabolic Changes
Additions
and/or revisions underlined:
…
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. Assess fasting plasma glucose before or soon after
initiation of antipsychotic medication and monitor periodically during
long-term treatment.
Schizophrenia
In
a 4-week fixed-dose placebo-controlled study of adults with schizophrenia, the
mean change from baseline in serum glucose was 6.6 mg/dL and -0.5 mg/dL for
FANAPT and placebo treated patients, respectively. The proportion of patients
with shifts in fasting glucose from normal (<100 mg/dL) to high (greater
than or equal to 126 mg/dL) were 10.7% and 2.5% for FANAPT and placebo treated
patients, respectively.
In
pooled analyses from clinical studies, for adults with schizophrenia remaining
on treatment with FANAPT 10-16 mg/day glucose increased, on average, from
baseline by 1.8 mg/dL at 3-6 months (N=773) and by 5.4 mg/dL at 6-12 months
(N=723) and at >12 months (N=425) of treatment. In a smaller group of
patients remaining on treatment with FANAPT 20-24 mg/day, glucose decreased by
3.6 mg/dL at 3-6 months (N=34); by 9 mg/dL at 6-12 months (N=31), and by 18
mg/dL at > 12 months (N=20) of treatment.
Bipolar Mania
In
a 4-week fixed dose study of adults with bipolar mania, mean changes from
baseline in serum glucose and the proportion of patients with shifts in fasting
glucose from Normal (<100 mg/dL) to High (greater than or equal to 126
mg/dL) for patients receiving FANAPT were similar to those for patients
receiving placebo.
Dyslipidemia
Undesirable
alterations in lipids have been observed in patients treated with atypical
antipsychotics. Before or soon after initiation of antipsychotic
medications, obtain a fasting lipid profile at baseline and monitor
periodically during treatment.
Schizophrenia
In
a 4-week fixed dose study of adults with schizophrenia, the mean change from
baseline in fasted total cholesterol was 8.2 mg/dL and -2.2 mg/dL for FANAPT
and placebo treated patients, respectively. The effects on LDL were similar to
those on total cholesterol (changes of 9 mg/dL and -1.4 mg/dL for FANAPT and
placebo treated patients, respectively). Mean changes from baseline in fasted
triglycerides were -0.8 mg/dL and 16.5 mg/dL for FANAPT and placebo treated
patients, respectively.
The
proportion of patients with shifts from normal to high fasted total
cholesterol, LDL, and triglycerides were similar for FANAPT and placebo-treated
patients. The proportion of patients with shifts in fasted HDL from normal (greater
than or equal to 40 mg/dL) to low (<40 mg/dL) was greater for placebo
patients (23.8%) compared to patients treated with FANAPT (12.1%).
In
pooled analysis from clinical studies, for adults with schizophrenia remaining
on treatment with FANAPT, on average, both cholesterol and triglycerides
decreased from baseline for adults with schizophrenia remaining on treatment at
3-6 months, 6-12 months, and >12-month time points in both 10-16 mg/day and
20-24 mg/day dose groups.
Bipolar Mania
In
a 4-week fixed dose study of adults with bipolar mania, the mean changes from
baseline for fasted total cholesterol, LDL, HDL, and triglycerides for FANAPT
were similar to those for placebo-treated patients. The proportion of patients
with shifts in fasted total cholesterol from normal (<200 mg/dL) to high (greater
than or equal to 240 mg/dL) was greater for FANAPT treated patients (10.7%)
than placebo-treated patients (7.2%). Shifts from normal to high LDL and
triglycerides and from normal to low HDL occurred at rates for FANAPT similar
to those for placebo treated patients.
Weight
Gain
Weight
gain has been observed with atypical antipsychotic use. Monitor weight at
baseline and frequently thereafter.
Schizophrenia
Across
all short- and long-term studies of adults with schizophrenia, the
overall mean change from baseline at endpoint was 2.1 kg.
In
4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adults
with schizophrenia the mean change in weight (kg) was -0.1, 2, and 2.7 for placebo,
FANAPT 10-16 mg/day, and FANAPT 20-24 mg/day groups, respectively. The
proportion of patients with weight gain >7% increase from baseline
was 4%, 12%, and 18% for placebo, FANAPT 10-16 mg/day, and FANAPT 20-24
mg/day groups, respectively.
Bipolar Mania
In
a 4-week fixed dose study of adults with bipolar mania the mean change in
weight (kg) was 1.6 and 4.6 kg for placebo and FANAPT 24 mg/day groups,
respectively. The proportion of patients with weight gain greater than or equal to 7% increase from
baseline was 14% and 35%, for placebo and FANAPT 24 mg/day groups, respectively.
5.7 Orthostatic Hypotension and Syncope
Additions
and/or revisions underlined:
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 in patients with
schizophrenia, where the dose was increased slowly, as recommended above,
syncope was reported in 0.4% (5/1,344) of patients treated with FANAPT,
compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in
5% of patients given 20 mg to 24 mg/day, 3% of patients given 10 mg to16
mg/day, and 1% of patients given placebo
In a double-blind placebo-controlled short-term
study in patients with bipolar mania, syncope was reported in 0.5% (1/206) of
patients treated with FANAPT, compared with 0% (0/208) on placebo. In this study,
orthostatic hypotension was reported in 4% (9/206) of patients treated with
FANAPT and 2% (5/208) of patients given placebo.
More rapid titration would be expected to increase
the rate of orthostatic hypotension and syncope.
Orthostatic vital signs should be monitored in
patients who are vulnerable to hypotension (e.g., elderly patients, patients
with dehydration, hypovolemia, and concomitant treatment with antihypertensive
medications), patients with known cardiovascular
disease (history of myocardial infarction, ischemic heart disease, heart
failure, or conduction abnormalities), and patients with
cerebrovascular disease
6
Adverse Reactions
Addition of the following
bulleted line listing:
The following adverse reactions are discussed in
more detail in other sections of the labeling:
Increased
Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings
and Precautions (5.1)]
Cerebrovascular Adverse Reactions, Including
Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings
and Precautions (5.2)]
QT Prolongation [see Warnings and Precautions
(5.3)]
Neuroleptic Malignant Syndrome (NMS) [see
Warnings and Precautions (5.4)]
Tardive Dyskinesia [see Warnings and Precautions
(5.5)]
Metabolic Changes [see Warnings and Precautions
(5.6)]
Orthostatic Hypotension and Syncope [see
Warnings and Precautions (5.7)]
Falls [see Warnings and Precautions (5.8)]
Seizures [see Warnings and Precautions (5.9)]
Leukopenia, Neutropenia and Agranulocytosis [see
Warnings and Precautions (5.10)]
Hyperprolactinemia [see Warnings and Precautions
(5.11)]
Body Temperature Regulation [see Warnings and
Precautions (5.12)]
Dysphagia [see Warnings and Precautions (5.13)]
Priapism [see Warnings and Precautions (5.14)]
Potential for Cognitive and Motor Impairment [see
Warnings and Precautions (5.15)]
Intraoperative Floppy Iris Syndrome [see
Warnings and Precautions (5.16)]
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, please refer to label for complete information.
7
Drug Interactions
7.2 Drugs that Prolong the QT Interval
Additions
and/or revisions underlined:
Concomitant
use of drugs that prolong the QT interval may add to the QT effects of FANAPT and
increase the risk of cardiac arrhythmia. Avoid the use of FANAPT in combination
with any other drugs that prolong the QT interval [see Warnings and Precautions (5.3)].
7.3Drugs that Lower Blood Pressure
Newly
added subsection:
Concomitant
use of FANAPT with medications that lower blood pressure could potentially
cause symptomatic hypotension. Avoid coadministration of FANAPT with
alpha-adrenergic blocking agents and adjust medications that affect blood
pressure as needed [see Warnings and
Precautions (5.7)].
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
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 3,210 patients with schizophrenia treated with FANAPT
in clinical trials, 25 (0.5%) were greater than or equal to 65 years old and
there were no patients greater than or equal to 75 years old. Of the 206
patients with bipolar mania treated with FANAPT in a clinical trial, 2 (0.1%)
were 65 years old and there were no patients were >65 years old.
Elderly patients with dementia-related psychosis
treated with FANAPT 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 and Warnings
and Precautions (5.1, 5.2)].
8.6 Hepatic Impairment
Additions and/or revisions underlined:
No dose adjustment to FANAPT is needed in patients
with mild hepatic impairment (Child-Pugh class A). Patients with
moderate hepatic impairment (Child-Pugh class B) may require dose
reduction. FANAPT is not recommended for patients with severe hepatic
impairment (Child-Pugh class C) [see
Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
…
Neuroleptic
Malignant Syndrome (NMS)
Counsel
patients and caregivers about a potentially fatal adverse reaction, NMS,
that has been reported with administration of antipsychotic drugs,
including FANAPT. Advise patients and caregivers to contact the healthcare
provider or to report to the emergency room if they experience signs and
symptoms of NMS [see Warnings and
Precautions (5.4)].
Tardive
Dyskinesia
Counsel
patients on the signs and symptoms of tardive dyskinesia and to contact their
healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].
Metabolic
Changes
Educate
patients
of metabolic changes, how to recognize symptoms of hyperglycemia and
diabetes mellitus, and the need for specific monitoring, including
blood glucose, lipids, and weight. Patients should be counseled that
weight gain has occurred during treatment with FANAPT [see Warnings and Precautions (5.6)].
Orthostatic
Hypotension and Syncope
Educate
patients about
the risk of orthostatic hypotension and syncope, particularly at the
time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)].
Leukopenia/Neutropenia
Advise
patients with a pre-existing low WBC or a history of drug induced
leukopenia/neutropenia that they should have their CBC monitored while taking
FANAPT [see Warnings and Precautions (5.10)].
Heat
Exposure and Dehydration
Educate
patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.12)].
Interference
with Cognitive and Motor Performance
Caution
patients about performing activities requiring mental alertness, such as
operating hazardous machinery or operating a motor vehicle, until they are
reasonably certain that FANAPT therapy does not affect them adversely [see Warnings and Precautions (5.15)].
Intraoperative
Floppy Iris Syndrome
Instruct
patients to tell their ophthalmologist about their use of FANAPT before
cataract surgery or other procedures involving the eyes, even if the patient is
no longer taking FANAPT [see Warnings and
Precautions (5.16)].
…
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