HIGHLIGHTS
OF
PRESCRIBING INFORMATION
These highlights
do
not include all the information needed to use
FINTEPLA safely and effectively. See full prescribing information for FINTEPLA.
FINTEPLA® (fenfluramine) oral solution, CIV Initial U.S. Approval: 1973
WARNING: VALVULAR HEART DISEASE and
PULMONARY
ARTERIAL HYPERTENSION
See
full prescribing information
for complete boxed warning.
• There is an association between serotonergic drugs with
5-HT2B receptor agonist activity, including fenfluramine (the
active ingredient in
FINTEPLA), and valvular heart
disease
and
pulmonary arterial hypertension. (5.1, 5.2)
• Echocardiogram assessments
are
required before, during, and after treatment
with
FINTEPLA. (2.1, 2.4, 5.1, 5.2)
• FINTEPLA is available only through a restricted program called the FINTEPLA REMS. (5.3)
----------------------------INDICATIONS AND
USAGE--------------------------
FINTEPLA is indicated for the treatment of
seizures
associated with Dravet syndrome in patients 2 years
of age and older. (1)
------------------------DOSAGE AND
ADMINISTRATION---------------------
• FINTEPLA is
to be administered orally and may be taken with or without food. (2.2)
• The
initial starting and maintenance dosage is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy
and tolerability. (2.2)
• Patients not on concomitant stiripentol: The maximum daily
maintenance dosage of
FINTEPLA is 0.35 mg/kg twice daily
(maximum daily dosage of 26 mg). (2.2)
• Patients taking concomitant stiripentol plus clobazam: The maximum daily maintenance dosage of
FINTEPLA for
patients
taking these medications is 0.2 mg/kg twice daily (maximum daily dosage of 17
mg). (2.2)
----------------------DOSAGE FORMS
AND
STRENGTHS--------------------
Oral
solution: 2.2 mg/mL fenfluramine (3)
--------------------------------CONTRAINDICATIONS----------------------------
• Hypersensitivity to fenfluramine or
any
of the excipients in FINTEPLA (4)
•
Within 14 days of
the
administration of monoamine oxidase inhibitors
due
to an increased risk of
serotonin syndrome (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
• 
Decreased Appetite and Decreased Weight: Advise patients
that FINTEPLA can cause decreased appetite and decreased weight. (5.4)
• Somnolence, Sedation, and Lethargy: Monitor
for
somnolence and sedation. Advise patients not to drive or operate machinery until they
have gained sufficient experience on FINTEPLA. (5.5)
• Suicidal Behavior and Ideation: Monitor patients
for
suicidal behavior and thoughts. (5.6)
• Withdrawal of Antiepileptic Drugs: FINTEPLA should be gradually
withdrawn to minimize the risk of increased seizure frequency and
status epilepticus. (5.7)
• Serotonin Syndrome: Advise patients that serotonin syndrome is
a potentially life-threatening condition and may occur
with
FINTEPLA, particularly with concomitant administration of FINTEPLA with other serotonergic drugs. (5.8)
•
Increase in Blood Pressure: Monitor blood pressure during treatment. (5.9)
•
Glaucoma: Discontinue therapy in patients with acute decrease in visual acuity or
ocular pain. (5.10)
-------------------------------ADVERSE REACTIONS-----------------------------
The
most common adverse reactions (incidence at least 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea;
constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia,
balance disorder, gait disturbance; blood pressure increased; drooling, salivary
hypersecretion; pyrexia; upper
respiratory tract infection; vomiting; decreased weight; fall; status epilepticus. (6.1)
To
report SUSPECTED ADVERSE REACTIONS, contact Zogenix Inc. at
1-866-964-3649 (1-866-Zogenix)
or
FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------------
• Dose
adjustment is
required for patients
taking stiripentol plus
clobazam. (2.2, 2.3, 7.1)
• Strong CYP1A2 and CYP2B6 Inducers: Coadministration with rifampin or
a strong CYP1A2 and CYP2B6 inducer
will decrease fenfluramine
plasma concentrations. Consider
an
increase in FINTEPLA dosage when
coadministered with rifampin or
a strong CYP1A2 and CYP2B6 inducer. (7.1)
------------------------USE IN SPECIFIC POPULATIONS---------------------
• Administration to patients with moderate or severe renal impairment is not recommended. (8.6)
• Administration to patients with hepatic impairment is not recommended. (8.7)
See 17 for PATIENT COUNSELING
INFORMATION and
Medication
Guide.
Revised: 6/2020
FULL PRESCRIBING INFORMATION
WARNING: VALVULAR HEART
DISEASE and PULMONARY ARTERIAL HYPERTENSION
There
is an association between serotonergic
drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA),
and
valvular heart disease and
pulmonary arterial hypertension[see Warnings and Precautions
(5.1,5.2)].
Echocardiogram assessments
are required before, during,
and
after treatment with
FINTEPLA. The
benefits versus the risks of initiating or continuing FINTEPLA must be considered, based on echocardiogram findings[see Dosage and
Administration (2.1,2.4) and Warnings and Precautions (5.1,5.2)].
Because of the risks of valvular heart disease
and
pulmonary arterial hypertension,
FINTEPLA is available
only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS) called the FINTEPLA REMS[see
Warnings and Precautions
(5.3)].
1
INDICATION
S AND USAGE
FINTEPLA is
indicated for the treatment of
seizures associated with Dravet syndrome in patients
2 years
of age and older.
2
DOSAG
E AND ADMINISTRATION
2.1
A
ssessments Prior to Initiating FINTEPLA
Prior to starting treatment
with FINTEPLA, obtain an echocardiogram assessment to evaluate for
valvular heart disease and pulmonary arterial
hypertension[see Dosage and Administration (2.4) and Warnings
and Precautions (5.1,5.2)].
2.2
D
osing Information
• FINTEPLA is to be
administered orally and may be taken with
or without food.
• The initial
starting and maintenance dosage is 0.1 mg/kg twice daily,
which can be increased
weekly based
on efficacy and tolerability. Table 1 provides the recommended
titration schedule, if needed.
• Patients not on concomitant stiripentol who
are
tolerating FINTEPLA at 0.1
mg/kg twice daily and require further reduction
of seizures may benefit
from a dosage increase up to a maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26
mg).
• Patients taking concomitant
stiripentol and clobazam
who are tolerating FINTEPLA at
0.1 mg/kg twice daily and require further reduction of seizures may benefit
from a dosage increase up to a
maximum recommended
maintenance dosage of 0.2
mg/kg twice daily (maximum
daily dosage of 17
mg) [see Drug Interactions (7.1)].
Table
1: FINTEPLA Recommended
Titration Schedule*
|
|
Without concomitant stiripentol*
|
With concomitant stiripentol and clobazam
|
|
Weight-based Dosage
|
Maximum Total Daily Dosage
|
Weight-based Dosage
|
Maximum Total Daily Dosage
|
|
Initial Dosage
|
0.1 mg/kg twice daily
|
26 mg
|
0.1 mg/kg twice daily
|
17 mg
|
|
Day 7
|
0.2 mg/kg twice daily
|
26 mg
|
0.15 mg/kg twice daily
|
17 mg
|
|
Day 14
|
0.35 mg/kg twice daily
|
26 mg
|
0.2 mg/kg twice daily
|
17 mg
|
*
For patients not on concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days
2.3
A
ssessments
During
and After Administration of FINTEPLA
To evaluate for valvular heart
disease and
pulmonary arterial hypertension,
obtain an echocardiogram assessment every 6 months during treatment with
FINTEPLA, and 3 to 6 months after the final dose of FINTEPLA [see Warnings
and Precautions (5.1,5.2)].
2.4
A
dministration
Instructions
A calibrated
measuring device (either a 3
mL
or 6 mL oral
syringe) will
be provided by the pharmacy and
is recommended to measure and administer the prescribed
dose
accurately
[see How Supplied/Storage and Handling
(16.1)]. A household
teaspoon or tablespoon is not an
adequate measuring device and
should not be used.
Discard any unused
FINTEPLA oral solution remaining after 3 months of first opening the bottle
or the “Discard After” date on
the bottle, whichever is sooner.
FINTEPLA is
compatible
with commercially available gastric and nasogastric feeding tubes.
2.5
D
iscontinuation
of
FINTEPLA
When discontinuing FINTEPLA, the
dose should be decreased gradually. As
with all antiepileptic drugs,
abrupt discontinuation should be avoided when
possible to minimize the risk of
increased seizure frequency and
status epilepticus [see Warnings
and Precautions (5.7)].
3
DOSAG
E FORMS AND STRENGTHS
Oral solution: 2.2 mg/mL fenfluramine as a clear, colorless,
cherry flavored liquid.
4
CONTRAINDICATIONS
FINTEPLA is
contraindicated
in patients with:
• Hypersensitivity to
fenfluramine
or any of the excipients in FINTEPLA[see Description
(11)]
• Concomitant use
of, or within 14 days of the administration of
monoamine oxidase inhibitors because of an increased
risk of serotonin syndrome[see Warnings and Precautions
(5.8)]
5
WARNINGS AND
PRECAUTIONS
5.1
V
alvular Heart Disease
Because of the association between serotonergic drugs
with 5-HT2B receptor agonist activity,
including fenfluramine (the
active ingredient in
FINTEPLA),
and valvular heart
disease, cardiac monitoring is
required prior to
starting treatment, during treatment,
and
after treatment with
FINTEPLA concludes.Cardiac monitoring via echocardiogram
can identify evidence of valvular
heart disease prior to a patient becoming symptomatic, aiding in early detection
of this condition. In clinical trials of
up to 3 years
in duration, no patient receiving FINTEPLA developed valvular
heart disease [see Boxed Warning
and Adverse Reactions
(6.1)].
Monitoring
Prior to starting treatment,
patients must undergo an echocardiogram
to evaluate for valvular
heart disease.
Echocardiograms
should be repeated every 6
months, and once 3-6
months post-treatment with
FINTEPLA.
If valvular heart
disease is
observed on an echocardiogram, the
prescriber must consider the
benefits
versus the risks of initiating or continuing treatment with
FINTEPLA.
FINTEPLA is
available only through
a restricted program
under a REMS[see Warnings and Precautions (5.3)].
5.2
P
ulmonary Arterial Hypertension
Because of the association
between
serotonergic drugs with
5-HT2B
receptor agonist activity,
including fenfluramine (the
active ingredient in FINTEPLA),
and pulmonary arterial hypertension,
cardiac monitoring is
required prior to
starting treatment, during treatment, and
after treatment
with FINTEPLA concludes.
Cardiac monitoring via echocardiogram can
identify evidence of pulmonary arterial
hypertension prior to a patient
becoming symptomatic,
aiding in early detection of
this condition. In clinical trials of up to 3
years in duration,
no patient receiving FINTEPLA developed
pulmonary arterial hypertension [see Boxed Warning
and Adverse Reactions (6.1)].
Monitoring
Prior to
starting treatment,
patients must undergo an echocardiogram
to evaluate for pulmonary arterial
hypertension.
Echocardiograms
should be repeated every 6
months, and once 3-6
months post-treatment with
FINTEPLA.
If pulmonary arterial
hypertension is observed on an
echocardiogram, the
prescriber must
consider the benefits
versus
the risks of initiating or continuing treatment
with
FINTEPLA.
FINTEPLA is
available only through
a restricted program
under a REMS[see Warnings and Precautions (5.3)].
5.3
F
INTEPLA REMS Program
FINTEPLA is available only through a restricted distribution program
called the
FINTEPLA
REMS program because of the risk of
valvular heart disease and
pulmonary arterial
hypertension [see Warnings and Precautions (5.1,5.2)].
Notable requirements
of the FINTEPLA REMS Program include:
• Prescribers must be certified
by
enrolling in the FINTEPLA REMS
program.
• Prescribers
must counsel patients
receiving FINTEPLA about the risk of valvular heart
disease and pulmonary arterial
hypertension, how to recognize signs and
symptoms
of valvular heart disease and pulmonary arterial
hypertension, the need for baseline
(pretreatment) and periodic cardiac monitoring via echocardiogram
during FINTEPLA treatment, and
cardiac monitoring after FINTEPLA treatment.
• Patients must enroll in the REMS program and
comply with ongoing monitoring
requirements[see Warnings and Precautions
(5.1,5.2)].
• The pharmacy must be
certified by enrolling in the
REMS program
and must only dispense to
patients who are authorized
to receive FINTEPLA.
•
Wholesalers
and distributers must only distribute
to certified
pharmacies.
Further information
is available at www.FinteplaREMS.com or by telephone at
1-877-964-3649.
5.4
Decre
ased Appetite and Decreased Weight
FINTEPLA can cause decreases in appetite
and weight. In Study 1 and
Study
2 combined, approximately 37% of patients treated with
FINTEPLA reported, as an
adverse reaction,
decreased appetite and approximately 9% reported decreased weight, as
compared to 8% and 1%, respectively,
of
patients on placebo [see Adverse Reactions (6.1)].By the end of
the controlled
studies, 19% of patients treated with FINTEPLA had a measured
decrease in weight
of 7% or greater from
their baseline
weight, compared
to 2% of patients on placebo. This
measured decrease in
weight
appeared to be dose-related,
with 26% of patients on FINTEPLA
0.7 mg/kg/day,
19% of patients
on FINTEPLA 0.4 mg/kg/day in
combination with stiripentol, and
13% of patients taking FINTEPLA 0.2
mg/kg/day experiencing at least a 7% decrease in weight from baseline. Most
patients resumed the expected
measured increases
in weight by the
end of the open-label extension
study.
Given
the frequency of these adverse reactions,
the growth
of pediatric patients treated
with FINTEPLA should
be carefully monitored.
Weight should be monitored regularly during treatment
with FINTEPLA and dose modifications
should be considered if
a decrease in weight is observed.
5.5
Somnolence, Sedation, and Lethargy
FINTEPLA can cause somnolence,
sedation,
and lethargy. In
Study
1 and Study 2 combined, the incidence of somnolence, sedation, and
lethargy was
25% in patients treated with
FINTEPLA, compared with
11% of patients on placebo. In general,
these effects
may
diminish with continued treatment [see Adverse Reactions (6.1)].
Other central
nervous system
(CNS) depressants,
including alcohol,
could potentiate these effects
of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and
should advise patients not to drive or operate machinery until they have gained
sufficient experience on FINTEPLA to
gauge whether it
adversely affects their ability
to drive or operate
machinery.
5.6
Suicidal Behavior
and Ideation
Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts
or behavior in patients taking
these drugs
for
any indication.
Patients treated with
an AED for any indication should be monitored for the emergence or worsening of depression,
suicidal thoughts or behavior, or any
unusual changes in mood or behavior.
Pooled analyses
of 199 placebo-controlled
clinical trials
(mono- and adjunctive therapy) of
11 different AEDs that did not include FINTEPLA showed
that patients randomized
to one of the AEDs had approximately twice the risk
(adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of
suicidal thinking or behavior compared to patients
randomized to placebo. In these trials, which
had a median treatment
duration
of 12 weeks, the
estimated incidence rate of suicidal behavior or ideation
among 27,863 AED-treated patients was 0.43%,
compared to 0.24% among
16,029 placebo-treated
patients, representing an
increase of approximately one case of suicidal
thinking or behavior for every 530
patients treated.
There were four suicides in drug-treated patients in the trials and
none in placebo-treated patients,
but the number is too small to allow any conclusion
about drug effect on suicide.
The increased risk
of suicidal thoughts
or behavior with
AEDs was observed
as early as 1 week after starting drug treatment
with AEDs and persisted for the duration
of treatment
assessed. Because most
trials
included in the analysis
did not extend beyond
24 weeks, the
risk of suicidal
thoughts or behavior beyond 24 weeks
could not be assessed.
The risk of
suicidal thoughts or
behavior was generally consistent
among
drugs
in the data analyzed.
The finding of increased risk
with AEDs of varying mechanisms of
action and across
a range of indications
suggests that the risk applies
to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the
clinical trials
analyzed. Table
2 shows
absolute and relative risk by indication
for all evaluated
AEDs.
Table 2: Risk
of Suicidal Thoughts or Behaviors by Indication
for
Antiepileptic Drugs
in the Pooled Analysis
|
Indication
|
Placebo Patients with Events per 1000 Patients
|
Drug Patients with Events per 1000 Patients
|
Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients
|
Risk Difference: Additional Drug Patients with Events per 1000 Patients
|
|
Epilepsy
|
1.0
|
3.4
|
3.5
|
2.4
|
|
Psychiatric
|
5.7
|
8.5
|
1.5
|
2.9
|
|
Other
|
1.0
|
1.8
|
1.9
|
0.9
|
|
Total
|
2.4
|
4.3
|
1.8
|
1.9
|
The relative risk
for
suicidal thoughts or
behavior was
higher in
clinical trials in patients with
epilepsy than
in clinical trials in patients with
psychiatric or other conditions,
but the absolute risk differences
were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing
FINTEPLA or any other AED must balance the risk
of suicidal thoughts or
behaviors with
the risk of untreated
illness. Epilepsy and many other illnesses
for which AEDs are prescribed are themselves associated
with morbidity and mortality and
an increased risk
of suicidal thoughts
and behavior.
Should suicidal thoughts and behavior
emerge during treatment,
consider whether the emergence of these symptoms in any given
patient may
be related to the illness
being treated.
5.7
Withdrawal of Antiepileptic Drugs
As with most AEDs, FINTEPLA should generally be withdrawn gradually because of the risk
of increased seizure frequency and status
epilepticus. If withdrawal
is needed because
of a serious
adverse reaction,
rapid discontinuation can
be considered.
5.8
Serotonin Syndrome
Serotonin syndrome, a potentially life-threatening
condition, may occur with
FINTEPLA, particularly with concomitant administration of
FINTEPLA with
other serotonergic drugs,
including, but not limited
to, selective serotonin-norepinephrine reuptake inhibitors
(SNRIs), selective
serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants
(TCAs),
bupropion, triptans, dietary supplements (e.g.,
St. John’s Wort, tryptophan), drugs that impair metabolism of serotonin (including
monoamine oxidase inhibitors
[MAOIs], which are contraindicated
with FINTEPLA [see Contraindications (4)],dextromethorphan,
lithium, tramadol, and antipsychotics with
serotonergic agonist
activity. Patients should be monitored for the emergence of signs and
symptoms
of
serotonin syndrome, which
include mental status
changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g.,
tachycardia,
labile blood pressure, hyperthermia), neuromuscular signs
(e.g., hyperreflexia, incoordination), and/or gastrointestinal
symptoms
(e.g., nausea, vomiting,
diarrhea). If serotonin syndrome is suspected,
treatment
with FINTEPLA should be stopped immediately and symptomatic treatment
should be started.
5.9
Increase in Blood Pressure
FINTEPLA can cause an increase in blood pressure [see Adverse Reactions
(6.1)].Significant
elevation in blood pressure, including hypertensive crisis,
has been reported
rarely in adult patients treated with
fenfluramine, including patients
without a history of hypertension.
Monitor blood pressure in
patients treated
with FINTEPLA. In clinical trials of
up to 3 years
in duration, no patient
receiving FINTEPLA developed a hypertensive
crisis.
5.10
G
laucoma
Fenfluramine can
cause mydriasis and can
precipitate angle closure glaucoma. Consider
discontinuing treatment with FINTEPLA in
patients with acute decreases in visual acuity or ocular pain.
6
ADVERS
E REACTIONS
The following clinically significant adverse reactions
are
described elsewhere in labeling:
• Valvular Heart
Disease[see Warnings and Precautions (5.1)]
• Pulmonary Arterial Hypertension[see Warnings
and Precautions
(5.2)]
• Decreased Appetite
and Decreased
Weight[see Warnings
and Precautions (5.4)]
• Somnolence, Sedation,
and
Lethargy[see Warnings and Precautions
(5.5)]
• Suicidal Behavior and Ideation[see Warnings
and Precautions
(5.6)]
• Withdrawal of Antiepileptic Drugs[see Warnings
and Precautions (5.7)]
• Serotonin
Syndrome[see Warnings
and Precautions (5.8)]
• Increase
in Blood Pressure[see Warnings and Precautions (5.9)]
• Glaucoma[see Warnings and Precautions
(5.10)]
6.1 Clinical
Trials Experience
Because clinical
trials
are conducted under widely varying conditions,
adverse reaction
rates observed in the
clinical trials of
a drug cannot be
directly compared to rates in
the clinical trials of
another drug and
may
not reflect the
rates observed in practice.
In controlled
and uncontrolled
trials
in patients with Dravet
syndrome, 341 patients
were treated
with FINTEPLA,
including 312 patients
treated for more than 6 months, 284 patients treated
for
more than 1 year, and
138 patients treated for more than 2 years.
In placebo-controlled
trials
of patients with Dravet syndrome, 122 patients
were treated with
FINTEPLA [see Clinical Studies
(14)]. The duration
of treatment in these trials was
16 weeks (Study 1) or 17 weeks (Study 2). In
Study
1 and Study 2, the
mean age was 9 years
(range 2 to 19
years) and
approximately 46% of patients were female and
74%
were White.
All patients were receiving at
least one other AED.
In Study 1
and Study 2, the rates
of discontinuation as
a result of any adverse reaction were 13%, 0%,
and 7% for patients treated with FINTEPLA 0.7 mg/kg/day,
0.2 mg/kg/day, and
0.4 mg/kg/day in
combination with stiripentol, respectively,
compared to 6% for patients
on
placebo. The most
frequent adverse reaction
leading to discontinuation in the patients treated with any dose of FINTEPLA was
somnolence (n=3,
3%).
The most common
adverse reactions
that occurred in
patients treated with
FINTEPLA (incidence at
least 10% and greater than placebo) were decreased
appetite; somnolence,
sedation,
lethargy;
diarrhea; constipation;
abnormal echocardiogram; fatigue, malaise,
asthenia;
ataxia,
balance disorder, gait
disturbance; blood pressure increased; drooling, salivary hypersecretion;
pyrexia;
upper respiratory tract
infection; vomiting; decreased
weight; fall;
status epilepticus.
Table 3 lists the adverse reactions
that were reported in 5%
or more of patients
treated with FINTEPLA and
at a rate greater than those
on placebo during the titration and
maintenance phases of Study 1 and
Study
2.
Table 3: Adverse Reactions in 5% or More of Patients Treated
with
FINTEPLA and Greater Than Placebo in
Placebo-Controlled
Trials
|
|
FINTEPLA Dose Group
|
Combined Placebo Group(2)
|
|
Study 1
|
Study 2
|
|
0.2 mg/kg/day
|
0.7 mg/kg/day
|
0.4 mg/kg/day(1)
|
|
N=39
%
|
N=40
%
|
N=43
%
|
N=84
%
|
|
Decreased appetite
|
23
|
38
|
49
|
8
|
|
Somnolence, sedation, lethargy
|
26
|
25
|
23
|
11
|
|
Abnormal echocardiogram(3)
|
18
|
23
|
9
|
6
|
|
Diarrhea
|
31
|
15
|
23
|
6
|
|
Constipation
|
3
|
10
|
7
|
0
|
|
Fatigue, malaise, asthenia
|
15
|
10
|
30
|
5
|
|
Ataxia, balance disorder, gait disturbance
|
10
|
10
|
7
|
1
|
|
Abnormal behavior
|
0
|
8
|
9
|
0
|
|
Blood pressure increased
|
13
|
8
|
0
|
5
|
|
Drooling, salivary hypersecretion
|
13
|
8
|
2
|
0
|
|
Hypotonia
|
0
|
8
|
0
|
0
|
|
Rash
|
8
|
8
|
5
|
4
|
|
Blood prolactin increased
|
0
|
5
|
0
|
0
|
|
Chills
|
0
|
5
|
2
|
0
|
|
Decreased activity
|
0
|
5
|
0
|
1
|
|
Dehydration
|
0
|
5
|
0
|
0
|
|
Insomnia
|
0
|
5
|
5
|
2
|
|
Pyrexia
|
15
|
5
|
21
|
14
|
|
Stereotypy
|
0
|
5
|
0
|
0
|
|
Upper respiratory tract infection
|
21
|
5
|
7
|
10
|
|
Vomiting
|
10
|
5
|
5
|
8
|
|
Weight decreased
|
13
|
5
|
7
|
1
|
|
Croup
|
5
|
3
|
0
|
1
|
|
Ear infection
|
8
|
3
|
9
|
5
|
|
Gastroenteritis
|
8
|
3
|
2
|
0
|
|
Increased heart rate
|
5
|
3
|
0
|
2
|
|
Irritability
|
0
|
3
|
9
|
2
|
|
Rhinitis
|
8
|
3
|
7
|
2
|
|
Tremor
|
3
|
3
|
9
|
0
|
|
Urinary incontinence
|
5
|
3
|
0
|
0
|
|
Decreased blood glucose
|
0
|
0
|
9
|
1
|
|
Bronchitis
|
3
|
0
|
9
|
1
|
|
Contusion
|
5
|
0
|
0
|
0
|
|
Eczema
|
0
|
0
|
5
|
0
|
|
Enuresis
|
5
|
0
|
0
|
0
|
|
Fall
|
10
|
0
|
0
|
4
|
|
Headache
|
8
|
0
|
0
|
2
|
|
Laryngitis
|
0
|
0
|
5
|
0
|
|
Negativism
|
5
|
0
|
0
|
0
|
|
Status epilepticus
|
3
|
0
|
12
|
2
|
|
|
FINTEPLA Dose Group
|
Combined Placebo Group(2)
|
|
Study 1
|
Study 2
|
|
0.2 mg/kg/day
|
0.7 mg/kg/day
|
0.4 mg/kg/day(1)
|
|
N=39
%
|
N=40
%
|
N=43
%
|
N=84
%
|
|
Urinary tract infection
|
5
|
0
|
5
|
0
|
|
Viral infection
|
0
|
0
|
5
|
1
|
(1) 0.4
mg/kg/day was
not an intermediate dose. Patients on the 0.4 mg/kg/day dose were also taking concomitant stiripentol
plus
clobazam, which increases exposure of FINTEPLA.
(2) Patients in placebo groups
from Studies 1 and 2 were pooled.
(3)
Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic.
Echocardiographic Safety Assessments
of Valvular Heart Disease and Pulmonary Arterial Hypertension
Valvular heart
disease and pulmonary arterial
hypertension were evaluated in the placebo- controlled
and open-label extension studies via echocardiography for up to 3
years in duration [see Warnings and Precautions (5.1,5.2)].
No patient
developed echocardiographic
findings consistent with
either valvular heart
disease or pulmonary arterial
hypertension
in the placebo-controlled
studies or during the open-label extension study of up to 3 years
in duration. In Study 1
and Study 2, 16% of patients
taking FINTEPLA compared to 6%
of patients taking placebo were reported to have trace mitral regurgitation, and
3% of patients taking
FINTEPLA and no patients taking placebo
were found
to have trace aortic regurgitation.
During the open-label
extension study, trace mitral
regurgitation
and trace aortic regurgitation were reported in 14%
and 0.4%, respectively,
of patients taking FINTEPLA. Trace and
mild mitral regurgitation,
and trace aortic regurgitation
are
considered physiologic in the absence of structural valve abnormalities.
7
DRU
G INTERACTIONS
7.1
Effect of Other Drugs
on FINTEPLA
Stiripentol
Plus Clobazam
Coadministration of
FINTEPLA with stiripentol plus clobazam,
with or without valproate, increases
fenfluramine plasma concentrations and decreases its metabolite, norfenfluramine,
because of the inhibition
of the metabolism of fenfluramine [see Clinical Pharmacology (12.3)].If FINTEPLA is
coadministered
with stiripentol plus clobazam,
the maximum daily dosage of
FINTEPLA is 0.2 mg/kg
twice daily ( maximum daily dosage of 17
mg)[see Dosage
and Administration (2.3)].
Strong CYP1A2
and CYP2B6 Inducers
Coadministration
with rifampin or strong CYP1A2 and CYP2B6 inducers
will decrease fenfluramine
plasma concentrations, which may lower the efficacy of FINTEPLA [see Clinical
Pharmacology (12.3)].
Consider an increase in FINTEPLA dosage when coadministered
with rifampin or a strong CYP1A2 and
CYP2B6 inducer; however, do not exceed
the maximum daily dosage [see Dosage and Administration (2.2)].
7.2
Effects of
Serotonin Receptor Antagonists
Cyproheptadine and potent
5-HT1A, 5-HT1D, 5-HT2A, and
5-HT2C serotonin receptor
antagonists may decrease the efficacy of FINTEPLA. If cyproheptadine or potent
5-HT1A, 5-HT1D, 5-HT2A,
or 5-HT2C serotonin receptor antagonists
are
coadministered with FINTEPLA,
patients should be monitored appropriately.
7.3
Serotonergic Drugs
Concomitant administration
of FINTEPLA and
drugs
(e.g.,
SSRIs,
SNRIs, TCAs,
MAO inhibitors, trazodone,
etc.), over-the-counter medications (eg,
dextromethorphan), or herbal supplements (e.g.,
St. John’s Wort) that increase serotonin may increase the risk of
serotonin syndrome [see Warnings and
Precautions (5.8)].Concomitant use
of FINTEPLA with
MAOIs is
contraindicated. Use FINTEPLA with
caution
in patients taking other medications that increase serotonin.
8
US
E IN SPECIFIC POPULATIONS
8.1
Pre
gnancy
Pregnancy Exposure Registry
There is
a pregnancy exposure registry that
monitors pregnancy outcomes in
women
exposed to antiepileptic drugs
(AEDs), such
as FINTEPLA, during pregnancy.
Encourage women
who
are taking FINTEPLA during pregnancy to enroll
in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling
the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org.
Risk Summary
There are no adequate human
or animal data on the developmental risks
associated with
the use of FINTEPLA in pregnant women.
In the U.S.
general
population, the estimated background risk of
major birth defects and
miscarriage in clinically recognized pregnancies
is 2 to 4% and 15 to 20%, respectively.
The
background
risks of major birth defects
and miscarriage for the indicated
populations
are unknown.
8.2
Lactation
Risk Summary
There are no
data on the
presence of fenfluramine or its metabolites
in human milk, the effects
on the breastfed infant,
or
the effects on milk production.
The developmental and health benefits
of breastfeeding should
be considered along with the mother’s clinical need for FINTEPLA and
any potential
adverse effects
on the breastfed
infant from FINTEPLA or from
the underlying maternal
condition.
8.4
Pe
diatric Use
The safety and effectiveness of
FINTEPLA for the treatment
of seizures associated
with Dravet syndrome have been
established in patients 2 years
of age and
older.
Safety and effectiveness in
patients less than 2 years of
age have not been established. Juvenile Animal Data
Oral administration
of fenfluramine
(0, 3.5, 9, or 20 mg/kg/day) to young rats
for
10 weeks starting
on postnatal day 7 resulted in reduced
body
weight and
neurobehavioral changes
(decreased locomotor
activity and
learning and
memory deficits) at all
doses tested. Neurobehavioral
effects
persisted after dosing
was
discontinued. Bone size was
decreased at
the mid and high doses;
brain
size
was decreased at the
highest dose. Partial or complete recovery was
seen for these endpoints. A
no-effect dose for postnatal developmental toxicity was not identified. The lowest
dose
tested (3.5 mg/kg/day) was
associated with
plasma fenfluramine
exposures (AUC) less
than that in humans at the maximum
recommended human dose
(MRHD of 30 mg/day) and
norfenfluramine
(metabolite) exposures
(AUC) approximately 3
times that in humans at the
MRHD.
8.5
Ger
iatric Use
Clinical
studies of FINTEPLA for the treatment of
Dravet syndrome did
not include patients
65 years of
age and over to
determine whether they respond
differently from younger patients. In general,
dose
selection for an
elderly patient
should be cautious, usually starting at the
low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and
of concomitant disease or other drug therapy.
8.6
Re
nal Impairment
Administration of FINTEPLA to
patients with moderate or severe renal impairment
is not recommended[see Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Administration of FINTEPLA to
patients with hepatic impairment is not recommended[see Clinical Pharmacology (12.3)].
9
DRU
G ABUSE AND DEPENDENCE
9.1
C
ontrolled Substance
FINTEPLA contains
fenfluramine, a Schedule IV controlled
substance.
10
OVERDOSAG
E
Overdose
has not been observed in the
FINTEPLA clinical trial program.
However,
overdose of fenfluramine,
the
active ingredient
in FINTEPLA, has been
reported at
higher doses than those included in the clinical
trial
program. Some of the cases
were fatal. Events reported after
overdose include mydriasis,
tachycardia, flushing, tremors/twitching/muscle spasms,
agitation/restlessness/anxiety,
increased muscle tone/rigor/opisthotonos, respiratory distress or failure, and
seizure.
Seizure, coma, and cardiorespiratory arrest
were reported
in most of the fatal
overdoses.
There is no available specific antidote
to the overdose reactions of
FINTEPLA. In
the event of overdose, standard
medical practice for the management
of drug overdosage should be used. An
adequate airway, oxygenation,
and ventilation should be ensured;
monitoring of cardiac rhythm
and vital sign measurement
is recommended. A certified
poison control center should be contacted for updated
information on the management
of overdose with FINTEPLA.
11
DESCRIPTIO
N
FINTEPLA oral
solution contains 2.2 mg/mL fenfluramine, equivalent
to 2.5 mg/mL of the hydrochloride salt.
The active
ingredient,
fenfluramine hydrochloride,
is designated
chemically as N-ethyl-α methyl-3-(trifluoromethyl)phenethylamine hydrochloride.
The structural formula is:
Fenfluramine hydrochloride is a
white to off-white crystalline solid. The pKa of fenfluramine
is 10.2.
FINTEPLA is
a clear, colorless solution, pH 5.
FINTEPLA contains
the following inactive
ingredients: cherry flavor,
citric acid,
ethylparaben hydroxyethylcellulose,
methylparaben, potassium citrate,
sucralose,
and
water.
FINTEPLA contains
no ingredient made from gluten-containing
grain (wheat,
barley, or rye).
12
CLINICA
L PHARMACOLOGY
12.1
Mec
hanism of Action
The mechanisms by which fenfluramine exerts
its therapeutic effects in the treatment of
seizures associated with
Dravet
syndrome are unknown. Fenfluramine and
the metabolite, norfenfluramine,
increase extracellular levels
of serotonin through interaction with
serotonin transporter proteins,
and
exhibit agonist activity at serotonin 5HT-2 receptors.
12.2
P
harmacodynamics
Cardiac Electrophysiology
At a dose 4
times the maximum
recommended dose,
FINTEPLA did
not prolong the QT interval
when
tested in an adult population.
12.3
P
harmacokinetics
The pharmacokinetics
of fenfluramine and
norfenfluramine
were studied in healthy subjects and
in pediatric patients with
Dravet syndrome.
The
steady-state systemic exposure (Cmax and AUC) of fenfluramine
was slightly greater than dose proportional
over the dose
range of 13
to
51.8 mg twice-daily fenfluramine
(i.e., 1 to 4 times the maximum
recommended dose). In
pediatric patients
who received FINTEPLA 0.7 mg/kg/day, up to a total daily dose of 26 mg
fenfluramine, the geometric mean
steady-state fenfluramine (coefficient
of variation)
Cmax was 68.0 (41%) ng/mL and
AUC0-24h was
1390 (44%) ng*h/mL.
Absorption
Fenfluramine has a time to
maximum
plasma concentration (Tmax) of 4
to 5 hours at steady state. The absolute
bioavailability of fenfluramine is
approximately 68-74%. There was no effect of
food on the pharmacokinetics
of fenfluramine or norfenfluramine.
Distribution
The geometric mean (CV%) apparent volume of distribution
(Vz/F) of fenfluramine is 11.9 (16.5%) L/kg following
oral administration of FINTEPLA in healthy subjects. Fenfluramine is 50%
bound to human plasma proteins
in vitro and binding is independent of drug concentrations.
Elimination
The elimination
half-life of fenfluramine was 20 hours and
the geometric mean
(CV%) clearance (CL/F) was 24.8
(29%) L/h,
following oral administration
of FINTEPLA in
healthy subjects.
Metabolism
Over 75% of fenfluramine is
metabolized
to norfenfluramine
prior to elimination, primarily by
CYP1A2, CYP2B6, and
CYP2D6. Other CYP enzymes
involved to a minor extent
are
CYP2C9, CYP2C19, and
CYP3A4/5. Norfenfluramine is
then deaminated and oxidized to form inactive
metabolites.
Excretion
Most of an orally administered dose
of fenfluramine (greater than 90%) is excreted in the
urine as fenfluramine,
norfenfluramine, or other metabolites with
fenfluramine
and norfenfluramine
accounting for less
than 25% of the total; less
than 5% is found in feces.
Specific Populations
The effect of
age (range: 2 to 50 years), sex, and
race had no clinically meaningful effect on the pharmacokinetics
of
fenfluramine.
Drug Interaction Studies
Clinical Studies
Effect of a single dose of stiripentol,
clobazam, and
valproic acid combination: Coadministration of
a single 0.7 mg/kg dose of FINTEPLA, with
a single dose of a stiripentol, clobazam, and
valproic acid combination
in health volunteers, increased the
AUC0-INF of fenfluramine
by 69% and the Cmax by 18%,
and decreased
the AUC0-72 hours of norfenfluramine by 41% and the
Cmax by 42%, as
compared to FINTEPLA administered alone.
Effect of steady state stiripentol
plus clobazam, with
or without valproate:
Fenfluramine pharmacokinetic data were collected
from patients after receiving multiple
fenfluramine administrations in Study 1 as well
as Study 2. Population
pharmacokinetic modeling and
simulation were used to assess the
effect of stiripentol
plus clobazam with or without
valproate on fenfluramine
pharmacokinetics.
The
effect of stiripentol plus clobazam,
with or without valproate, on fenfluramine pharmacokinetics
is greater when FINTEPLA is
at steady-state than for
the first dose of FINTEPLA. When initiating
FINTEPLA therapy, coadministration of existing stiripentol plus clobazam
with or without valproate is
expected
to increase the AUC0-24 of the first fenfluramine dose by up to 42% in the patient
population. At steady state in the patient population,
the coadministration of 0.1 mg/kg twice daily (0.2 mg/kg/day), maximum
17 mg/day, of FINTEPLA with
stiripentol plus clobazam
with or without valproate, is expected to result in a 166% increase in
fenfluramine AUC0-24 and a 38% decrease in norfenfluramine AUC0 24, as compared
to 0.2 mg/kg/day,
maximum
26 mg/day, FINTEPLA dose administered alone[see Dosage and Administration
(2.1, 2.2) and Drug
Interactions (7.1)].
Effect of steady state cannabidiol:
Coadministration of a single 0.35 mg/kg dose of FINTEPLA
with
repeated doses of cannabidiol
increased the AUC0-INF of fenfluramine by 59% and
the Cmax by 10%, and
decreased the AUC0-INF of norfenfluramine by 22% and
the
Cmax by 33%, as compared to FINTEPLA administered alone. This interaction is not expected
to be clinically significant.
Effect of FINTEPLA on other drugs: Coadministration of
a single 0.7 mg/kg dose of
FINTEPLA, with
a single dose of a stiripentol, clobazam,
and valproic acid
combination, did not affect
the pharmacokinetics
of stiripentol, nor the pharmacokinetics
of
clobazam or its N‑desmethyl-metabolite norclobazam, nor
the pharmacokinetics of valproic acid, as
compared to the stiripentol, clobazam, and
valproic acid
combination alone.
Coadministration of a single 0.35
mg/kg dose of FINTEPLA,
with repeated
doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as
compared to cannabidiol
alone.
In
Vitro Studies
Fenfluramine is
primarily metabolized by CYP1A2, CYP2B6, and
CYP2D6 in vitro. Other CYP enzymes involved
to a minor extent
are
CYP2C9, CYP2C19, and
CYP3A4/5.
Effect of fenfluramine
and norfenfluramine on CYP
Substrates: fenfluramine and
norfenfluramine
are not inhibitors or inducers
of CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, or CYP3A4
at clinically relevant
concentrations.
Effect of transporters
on fenfluramine and
norfenfluramine:
fenfluramine and
norfenfluramine are not substrates of the P-g, BCRP, OAT1,
OAT3,
OCT2,
MATE1, or MATE2-K transporters.
Effect of FINTEPLA on Transporters: fenfluramine
and norfenfluramine are not inhibitors of P-gp, BCRP, OAT1B1, OATP1B3,
OAT1, OAT3, OCT2, MATE1,
or MATE2-K transporters.
13
NONCLINICA
L TOXICOLOGY
13.1
C
arcinogenesis,
Mutagenesis,
Impairment of Fertility
Carcinogenesis
Studies
to assess the carcinogenic potential of
fenfluramine have not been conducted.
Mutagenesis
Fenfluramine
was negative in an
in vitro bacterial
mutation (Ames) assay and an
in vivo micronucleus
and
comet assay in rats.
Impairment
of Fertility
Studies to assess
for
adverse effects
of fenfluramine on
fertility or reproduction
have not been conducted.
14
CLINICA
L STUDIES
The effectiveness
of FINTEPLA for the treatment of seizures
associated with Dravet syndrome
in patients 2 years of
age and older was established
in two randomized, double-blind,
placebo- controlled trials in patients
2 to 18 years
of age.
Study 1 (N=117) compared a 0.7
mg/kg/day and a 0.2
mg/kg/day dose of FINTEPLA with placebo
in
patients who were not receiving stiripentol (NCT02682927 and NCT02826863).
Study 2 (N=85) compared a 0.4 mg/kg/day dose of FINTEPLA with
placebo in patients who
were receiving stiripentol and either clobazam, valproate,
or both (NCT02926898). In
both studies, patients
had a clinical diagnosis
of Dravet syndrome and
were inadequately controlled on at least
one AED or other antiseizure treatment including
vagal
nerve stimulation
or a ketogenic diet.
Both trials had a 6-week baseline period, during which
patients were required
to have a minimum of 6 convulsive seizures
while on stable AED therapy.
Convulsive seizures
included tonic, clonic,
generalized
tonic-clonic, tonic-atonic,
secondarily generalized
tonic-clonic, hemiclonic,
and focal with
observable motor signs.
The
baseline period
was
followed by randomization into a 2-week (Study 1) or 3-week (Study 2) titration period and
a subsequent
12-week maintenance period, where the dose of FINTEPLA remained stable.
In Study 1,
98% of patients
were taking between 1
and 4 concomitant AEDs.
The
most frequently used concomitant
AEDs (in at least 25% of patients), were valproate (61%), clobazam (59%),
and topiramate (25%). In
Study
2, 100% of patients were taking between
2 and
4 concomitant
AEDs. The most frequently used concomitant
AEDs (in at least 25%
of patients),
were stiripentol
(100%), clobazam (94%), and
valproate (89%).
The primary efficacy endpoint
in both studies was the
change from
baseline in the
frequency
of convulsive seizures
per
28 days during the combined 14-week (Study 1) or 15-week
(Study 2) titration
and maintenance periods
(i.e.,
treatment
period). The median
longest interval between
convulsive seizures was also assessed.
In Study 1
and Study 2, the reduction
in convulsive seizure frequency per 28 days was statistically significantly greater for all dose
groups of FINTEPLA compared
to placebo (Table 4). A reduction in convulsive seizures
was observed within
3 to 4 weeks of starting
FINTEPLA, and the effect remained generally consistent
over
the 14- or 15-week treatment period.
Table
4: Change in Convulsive Seizure Frequency During the Treatment Period in Patients
with
Dravet Syndrome (Study 1 and Study 2)
|
Convulsive Seizure Frequency (per 28 days)
|
Placebo
|
FINTEPLA
0.2 mg/kg/day
|
FINTEPLA
0.7 mg/kg/day
|
FINTEPLA
0.4 mg/kg/day
|
|
Study 1
|
N=39
|
N=38
|
N=40
|
NA
|
|
Baseline Period Median
% Difference Relative to Placebo* p-value compared to placebo
|
29.4
|
18.1
-31.7%
0.043
|
18.7
-70.0%
<0.001
|
NA NA
|
|
Study 2
|
N=42
|
NA
|
NA
|
N=43
|
|
Baseline Period Median
% Difference Relative to Placebo* p-value compared to placebo
|
11.5
|
NA NA
|
NA NA
|
15.0
-59.5%
<0.001
|
*Derived from the primary analysis
model
±All 0.4 mg/kg/day patients were also taking concomitant
stiripentol, which increases the exposure of FINTEPLA.
Figure 1 and Figure 2 display the percentage of patients by category of seizure response from baseline in
convulsive seizure frequency (per 28
days) during the treatment period in Study 1 and Study 2, respectively.
F
igure 1: Proportion of
Patients by
Category of Seizure Response
for FINTEPLA and
Placebo in Patients with Dravet Syndrome (Study
1)
Figure 2: Proportion
of Patients by
Category of Seizure Response
for FINTEPLA and
Placebo in Patients with Dravet Syndrome (Study 2)
In Study 1, 3 of 40 (8%) patients in the FINTEPLA 0.7 mg/kg/day group
and 3 of 38 (8%) patients in the FINTEPLA 0.2
mg/kg/day group reported no convulsive seizures during the
14- week treatment period, compared to 0 patients in the placebo group. In Study 2, 1 of 43 (2%) patients in the FINTEPLA 0.4
mg/kg/day group reported no convulsive seizures during the
15- week treatment period, compared to 0 patients in the placebo group.
In Study 1
and Study 2, FINTEPLA was
associated
with a statistically significant
longer interval
between convulsive seizures
compared to placebo (Figure 3).
F
igure 3: Median Longest Interval Between
Convulsive Seizures
in Patients with Dravet Syndrome (Study
1 and Study 2)
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
FINTEPLA oral
solution is a clear, colorless, cherry flavored liquid containing 2.2
mg/mL fenfluramine and
is supplied in a white
plastic bottle
with a child resistant
closure as follows:
• Carton containing
one 360 mL bottle (NDC 43376-322-36)
• Carton containing
one 30 mL bottle
(NDC 43376-322-30)
Before dispensing,
the pharmacist will
insert a press-in bottle adapter into
the dispensing bottle. The pharmacy will
provide 3 mL or 6 mL calibrated oral
dosing syringes.
16.2
Storage and Handling
Store FINTEPLA at
room
temperature between
20°C to 25°C (68°F to 77°F);
excursions
are
permitted between 15°C
to 30°C (59°F to 86°F)[see USP Controlled Room Temperature].
Do not refrigerate or freeze. Store the bottle
and syringe together.
Discard any unused
portion 3 months after first opening the bottle
or the “Discard
After” date on the
bottle, whichever is sooner.
17
PATIEN
T COUNSELING INFORMATION
Advise the patient
to read the FDA-approved patient
labeling
(Medication
Guide and Instructions
for
Use).
Administration Information
Advise patients who
are prescribed FINTEPLA to use the oral dosing syringes provided
by
the pharmacy[see Dosage and
Administration
(2.5) and Instructions for Use]. Instruct patients to discard any unused
FINTEPLA 3 months after first opening the bottle or if the “discard
after” date on the
dispensing bottle has passed, whichever is sooner[see How
Supplied/Storage and Handling (16.2)].
Valvular Heart
Disease and Pulmonary Arterial
Hypertension
Advise patients that
cardiac monitoring must be
performed
using
echocardiography to monitor for serious heart valve changes or high
blood pressure in the
arteries of the lungs [see Warnings
and Precautions (5.1,5.2)].
FINTEPLA REMS
Program
FINTEPLA is
available only through a restricted program called
the FINTEPLA REMS program
[see Warnings
and Precautions (5.3)]. Inform the patient
of the following notable requirements:
• Patients must enroll in the program and
comply with ongoing
echocardiogram monitoring
requirements[see Warnings and Precautions
(5.1,5.2)].
FINTEPLA is
only
prescribed
by
certified
health care providers and
only
dispensed from certified
pharmacies participating in
the program. Therefore,
provide patients with
the telephone number and
website for information
on how to obtain the product [see Warnings and Precautions
(5.3)].
Decreased Appetite
and Decreased
Weight
Advise patients that
decreased
appetite is
frequent during treatment
with FINTEPLA, which can cause decrease in
weight[see Warnings
and Precautions (5.4)].
Somnolence,
Sedation,
and
Lethargy
Inform
patients that FINTEPLA can cause somnolence, sedation,
and lethargy. Caution
patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that
FINTEPLA does not affect
them adversely (eg, impair judgment,
thinking, or motor skills) [see Warnings
and Precautions (5.5)].
Suicidal
Thinking and Behavior
Counsel patients,
their caregivers,
and their families that
antiepileptic drugs may increase the risk
of suicidal thoughts and behavior
and advise them to be
alert for the emergence or worsening of symptoms of depression,
any unusual changes in mood or behavior,
or the emergence of suicidal thoughts,
behavior, or thoughts
of self-harm. Instruct
patients, caregivers, and families to report behaviors
of concern immediately to
healthcare providers [see Warnings and Precautions (5.6)].
Withdrawal of
Antiepileptic Drugs (AEDs)
Advise patients not to discontinue use of FINTEPLA without
consulting with their healthcare provider. FINTEPLA should
normally be gradually withdrawn
to reduce the potential
for increased seizure frequency and
status epilepticus[see Dosage
and Administration (2.3), Warnings and Precautions (5.7)].
Serotonin Syndrome
Inform
patients about the risk
of serotonin syndrome, which can
be
life-threatening. Advise
patients on the signs and symptoms
of serotonin syndrome and that
certain over-the-counter and herbal supplements can increase this
risk [see Warnings
and Precautions (5.8)].
Increase in Blood Pressure
Inform
patients that FINTEPLA can cause an
increase in blood pressure[see Warnings and Precautions (5.9)].
Glaucoma
Inform
patients that FINTEPLA can cause mydriasis and
can
precipitate angle closure glaucoma. Instruct patients to contact
their healthcare provider if they have any acute decreases
in visual acuity or ocular pain [see Warnings
and Precautions (5.10)].
Pregnancy Registry
Advise patients to notify their healthcare provider if they become pregnant or intend to become
pregnant
during FINTEPLA therapy.
Encourage women
who are taking FINTEPLA to
enroll
in the North American Antiepileptic
Drug (NAAED) Pregnancy Registry if they become pregnant. This
registry is
collecting information about
the safety of antiepileptic drugs during pregnancy [see Use in
Specific Populations
(8.1)].
Marketed
by: Zogenix, Inc.
5959 Horton
Street, Suite 500, Emeryville
CA, 94608
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MEDICATION GUIDE FINTEPLA® (fin-TEP-la)
(fenfluramine) oral solution, C-IV
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Read this Medication Guide before you start taking FINTEPLA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
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What is the most important information I should know about FINTEPLA? FINTEPLA can cause serious side effects, including:
1. Problems with the valves in the heart (valvular heart disease) and high blood pressure in the arteries of the lungs (pulmonary arterial hypertension) have been associated with fenfluramine, the active ingredient in FINTEPLA. Your healthcare provider will do a test called an echocardiogram to check your heart and for high blood pressure in the arteries of the lungs before you start taking FINTEPLA, again every 6 months during treatment, and one time 3 to
6 months after you take your last dose of FINTEPLA.
Call your healthcare provider right away if you develop any of these signs and symptoms of heart or lung problems during treatment with FINTEPLA:
l shortness of breath • chest pain
l tiredness or weakness, • sensations of a rapid, fluttering heartbeat especially with increased activity (palpitations)
l lightheadedness or fainting • irregular pulse
l swollen ankles or feet • bluish color to your lips and skin (cyanosis) Because of the risk of heart valve problems and pulmonary arterial hypertension FINTEPLA is only available through a
restricted program called the FINTEPLA Risk Evaluation and Mitigation (REMS) Program. Before you or your child
receives FINTEPLA, your healthcare provider or pharmacist will make sure you understand how to take FINTEPLA safely. If you have any questions about FINTEPLA, ask your healthcare provider, visit www.FinteplaREMS.com, or call 1-877-964-3649.
2. Decreased appetite and decreased weight. Decreased appetite and decreased weight are both serious and common side effects.
l Your weight should be checked regularly during your treatment with FINTEPLA.
l Your healthcare provider may need to make changes to your FINTEPLA dose if your weight decreases. In some cases, FINTEPLA may need to be stopped.
3. Sleepiness, sedation, and lack of energy (lethargy). These are both serious and common side effects of FINTEPLA. Taking FINTEPLA with central nervous system (CNS) depressants including alcohol may increase sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you.
4. Like all other antiepileptic drugs, FINTEPLA may cause suicidal thoughts or actions in a very small number of people (about 1 in 500).
Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
l thoughts about suicide or dying • new or worse anxiety
l trouble sleeping (insomnia) • acting on dangerous impulses
l attempts to commit suicide • feeling agitated or restless
l new or worse irritability • an extreme increase in activity and talking (mania)
l new or worse depression • panic attacks
l acting aggressive, being angry, or violent • other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
l Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
l Keep all follow-up visits with your healthcare provider as scheduled.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
5. Do not stop taking FINTEPLA without first talking to your healthcare provider. Stopping a seizure medicine such as FINTEPLA suddenly can cause you to have seizures more often or seizures that do not stop (status epilepticus).
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
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1
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What is FINTEPLA?
l FINTEPLA is a prescription medicine used to treat the seizures associated with Dravet syndrome in patients 2 years of age and older.
l FINTEPLA is a federally controlled substance (C-IV) because it contains fenfluramine. Keep FINTEPLA in a safe place to prevent misuse, abuse, and protect it from theft. Never give your FINTEPLA to anyone else, because it may harm them. Selling or giving away this medicine is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines, or street drugs.
l It is not known if FINTEPLA is safe and effective in children less than 2 years of age.
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Do not take FINTEPLA if you:
l are allergic to fenfluramine or any of the ingredients in FINTEPLA. See the end of this Medication Guide for a complete list of ingredients in FINTEPLA.
l are taking or have stopped taking medicines called monoamine oxidase inhibitors (MAOI), serotonin agonists or serotonin reuptake inhibitors in the last 14 days. This may cause a serious or life-threatening problem called serotonin syndrome. If you are not sure whether or not you are taking one of these medicines, contact your healthcare provider.
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Before taking FINTEPLA, tell your healthcare provider about all of your medical conditions, including if you:
l have heart problems
l have or have had weight loss
l have or have had depression, mood problems, or suicidal thoughts or behavior
l have liver problems
l have kidney problems
l are pregnant or plan to become pregnant. Tell your healthcare provider right away if you become pregnant while taking FINTEPLA. You and your healthcare provider will decide if you should take FINTEPLA while you are pregnant.
o If you become pregnant while taking FINTEPLA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 or go to www. aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
l are breastfeeding or plan to breastfeed. It is not known if FINTEPLA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking FINTEPLA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
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How should I take FINTEPLA?
l Read the Instructions for Use at the end of this Medication Guide for information on the right way to use FINTEPLA.
l Take FINTEPLA exactly as your healthcare provider tells you to take it.
l Your healthcare provider will tell you how much FINTEPLA to take and when to take it.
l FINTEPLA may be taken with or without food.
l Measure your dose of FINTEPLA using the dosing syringe that is provided by the pharmacy. Do not use a household teaspoon or tablespoon.
l FINTEPLA can be given through gastric and nasogastric feeding tubes
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What should I avoid while taking FINTEPLA?
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you. FINTEPLA may cause you to feel sleepy.
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What are the possible side effects of FINTEPLA? FINTEPLA may cause serious side effects, including:
• See “What is the most important information I should know about FINTEPLA?”
• serotonin syndrome. Serotonin syndrome is a life-threatening problem that can happen in people taking FINTEPLA, especially if FINTEPLA is taken with certain other medicines to include:
o anti-depressant medicines called SSRIs, SNRIs, TCAs, and MAOIs o St. John’s Wort
o tryptophan o dextromethorphan
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o lithium o tramadol
o antipsychotics
Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome.
o mental status changes such as seeing things that are not o fast heartbeat
there (hallucinations), agitation, or coma o nausea, vomiting, diarrhea
o changes in blood pressure o high body temperature
o tight muscles o trouble walking
• high blood pressure (hypertension). Hypertension is both a serious and common side effect. FINTEPLA can cause your blood pressure to increase even if you have never had high blood pressure before. Your healthcare provider will check your blood pressure while you are taking FINTEPLA.
• increased pressure in your eye (glaucoma). Symptoms of glaucoma may include:
o red eyes o decreased vision
o seeing halos or bright colors around lights o eye pain or discomfort
o nausea or vomiting o blurred vision
If you have any of these symptoms, call your healthcare provider right away.
The most common side effects of FINTEPLA include:
• diarrhea • problems with movement, balance, and walking
• low energy • increased drooling
• respiratory infection • infection
• tiredness • vomiting
• fever • falls
• constipation • seizures that do not stop
• abnormal echocardiogram • weakness
These are not all the possible side effects of FINTEPLA. For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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How should I store FINTEPLA?
l Store FINTEPLA at room temperature between 68°F to 77°F (20°C and 25°C).
l Do not refrigerate or freeze.
l Store the FINTEPLA bottle and syringe together in a clean area.
l Throw away (discard) any unused FINTEPLA 3 months after first opening the bottle or if the Discard After date on the package or bottle has passed. Whichever one comes first.
Keep FINTEPLA and all medicines out of the reach of children.
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General information about the safe and effective use of FINTEPLA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FINTEPLA for a condition for which it was not prescribed. Do not give FINTEPLA to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about FINTEPLA that is written for health professionals.
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What are the ingredients in FINTEPLA? Active ingredient: fenfluramine hydrochloride
Inactive ingredients: cherry flavor, citric acid, ethylparaben, hydroxyethylcellulose, methylparaben, potassium citrate, sucralose, and water.
FINTEPLA contains no ingredient made from gluten-containing grain (wheat, barley, or rye).
Marketed by: Zogenix Inc.
5959 Horton Street, Suite 500, Emeryville CA, 94608
For more information about FINTEPLA, go to www.fintepla.com or call 1-866-964-3649.
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This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 6/2020
3
INSTRUCTIONS FOR USE FINTEPLA TM (fin-TEP-la)
(fenfluramine)
oral solution, C-IV
2.2 mg/mL
Be sure that you read, understand, and follow these instructions before you start using FINTEPLA oral
solution and each time you get a refill. There may be new information.
This Instructions for Use contains
information on how to take FINTEPLA. This information does not take
the place of
talking to your healthcare provider about your medical
condition or treatment.
What is included with FINTEPLA?
The following items are included to prepare and give an oral dose of
FINTEPLA:
•
1 bottle of FINTEPLA oral solution (2.2 mg/mL)
• 
2 reusable oral syringes
1 Bottle of FINTEPLA Oral Solution (2.2 mg/mL)
2 Oral
Syringes
Call the pharmacist at 1-844-288-5007 if you did not
receive the items
listed above, or
if you need
help using them.
Important information about FINTEPLA
• FINTEPLA is an oral medicine (taken by mouth) and is
given 2 times each day.
Follow your
healthcare provider’s instructions for taking or giving doses of FINTEPLA.
• If you have questions about
how
to prepare or give FINTEPLA, contact your healthcare provider or call your pharmacist.
•
Always use the oral
syringes provided with FINTEPLA to make sure the right
dose
is given.
If you need a new syringe contact your pharmacist. Do
not use a household teaspoon or tablespoon.
1
Oral syringes provided with
FINTEPLA by the pharmacy.
With FINTEPLA you will receive 2 reusable oral syringes.
2 oral syringes
that can measure up to 3 mL
OR
2 oral syringes
that can measure up to 6 mL
Call
the pharmacist at 1-844-288-5007 if
you
have any questions about the syringes
provided with
FINTEPLA.
2
Step 1. Make sure you have:
•
The bottle
of
FINTEPLA oral solution, and
• A clean, dry reusable oral syringe that was provided with FINTEPLA.
Step 2. Check the “Discard
After” date (MM/DD/YYYY).
• Do not use the medicine if the “Discard After” (Throw Away) date
has
passed.
• If the date is near, contact your pharmacy or healthcare provider to get a refill or new prescription.
• If the date has passed, dispose
of
any unused FINTEPLA.
Press down and turn
Step 3. Press down and turn the childproof cap to the left (counterclockwise) and remove it from the
bottle.
• 
Set the cap aside (do not throw away).
Plunger is all the way in
Adapter
Step 4. Make sure the adapter is on the
bottle.
• 
If the bottle does not have
an adapter, contact the pharmacist.
• Always leave the adapter in place in the bottle of medicine.
Step 5. Remove an
oral syringe from its packaging, if needed.
Only use the oral syringes provided with
FINTEPLA.
If an oral syringe
is
damaged, or you
cannot read the
dose markings:
•
Use the other oral
syringe
provided, or
•
Contact the pharmacist to get a
new
one.
Step 6. Make sure the plunger is pushed
all
the way into
the
oral syringe.
Step 7. Hold the bottle of medicine firmly on a hard, flat surface.
Step 8. Push the tip
of
the oral
syringe into the opening
of
the adapter until
it
cannot be pushed further.
Turn upside down
Step 9. Hold the oral syringe and bottle together and turn upside down.
Step 10. Slowly pull
the
plunger of the oral
syringe to
withdraw the prescribed dose.
Doses on the 3 mL
syringe:
Dose markings in
0.1 mL increment
Doses on the 6 mL syringe:
Dose markings in
1.5 mL increments
5
Step 11. Line up the end
of
the plunger with the mark for the
prescribed dose on the
oral
syringe.
Tips to Getting the Correct Dose
•
If you draw out too much medicine:
o
Leave the oral syringe in the adapter.
o
Push the plunger slowly back into the syringe until
you
reach the prescribed dose.
•
If you see
air
bubbles in the medicine:
o Leave the oral syringe in the adapter.
o Pull the plunger
further down.
o Allow the bubbles to rise to the tip of the syringe.
o Push the plunger in all the way.
o Slowly pull the plunger out to the
prescribed
dose.
Note: Very small
bubbles in the liquid are
normal.
Turn right side up
Step 12. Hold the oral syringe and bottle together and then turn the bottle right side up.
Step 13. Holding the bottle firmly, gently pull the oral syringe
out of the bottle adapter.
6
Step 14. Make sure the dose in the oral syringe still
matches the prescribed dose.
If the dose
does not match:
•
Put the syringe back into adapter.
•
See steps 9 to 11 to adjust the dose, as needed.
Giving FINTEPLA
Step 15. Place the tip
of
the oral syringe
against the inside of the cheek.
Step 16. Gently push the plunger in until all
the medicine in
the
oral
syringe is given.
• Do not squirt or forcefully push the medicine
into the back
of the throat. This may cause
choking.
Close tightly
Step 17. Place the cap back on the
bottle
tightly by turning
the cap right (clockwise) until
it
stops.
• 
Always leave
the
adapter in
place in the bottle
•
The cap will fit over it.
Cleaning the syringe
• 
Rinse the oral
syringe with clean tap water and allow it to air dry after each use.
• Make sure you rinse the inside of the syringe and the
plunger.
Cleaning Tips:
• Pull clean tap water into the syringe with
the plunger
and push it out several times to clean
the syringe.
• Remove the plunger from the barrel
of
the oral syringe
•
Rinse both parts under tap
water
• Make sure the syringe and
plunger are
completely dry before the next use.
•
The syringe is also safe to clean
in
the dishwasher.
How should I store FINTEPLA?
•
Store FINTEPLA at room temperature between 68°F to 77°F (20°C to 25°C).
• Do not refrigerate
or
freeze.
•
Keep the cap tightly closed and the bottle upright.
•
Store the FINTEPLA bottle
and syringe together in
a clean area.
• Throw away (discard) any unused
FINTEPLA 3
months after first opening the bottle or if the
Discard After date
on
the package or bottle
has
passed. Whichever one comes first.
• Keep FINTEPLA and all medicines out of the reach of children.
Marketed
by: Zogenix Inc.
5959 Horton Street, Suite
500, Emeryville CA, 94608
This “Instructions for Use has been
approved by the
U.S. Food
and
Drug Administration. Approved: 6/2020
8
N Me
HCl