Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Serotonin Syndrome
(Additions and/or
revisions underlined)
The
development of a potentially life-threatening serotonin syndrome has been
reported in patients on concomitant treatment with MAOIs (including
selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants,
cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate,
amphetamine, and their derivatives . Concomitant use of XADAGO with these drugs
is contraindicated.
In
clinical trials, serotonin syndrome was reported in a patient treated with
XADAGO and a selective serotonin reuptake inhibitor (SSRI). Use the
lowest effective dose of SSRIs in patients treated with concomitant XADAGO.
Serotonin
syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia,
labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia),
neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia,
incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea,
vomiting, diarrhea).
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
Clinical
trials are conducted under widely varying conditions; therefore, adverse
reactions observed in the clinical trials of a drug cannot be directly compared
to the incidence in the clinical trials of another drug and may not reflect the
incidence observed in clinical practice.
Common
Adverse Reactions in Placebo-Controlled PD Studies
Table
1 shows the incidence of adverse reactions with an incidence of at least 2% on
XADAGO 100 mg/day and greater than placebo in controlled studies in PD
(Study 1 and Study 2). The most common adverse reactions associated with XADAGO
treatment in which the incidence for XADAGO 100 mg/day was at least 2% greater
than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.
Adverse
Reactions Reported as Reason for Discontinuation from Study
In
pooled placebo-controlled studies (Study 1 and Study 2) in patients with PD taking
a stable dose of carbidopa/levodopa with or without other PD medications, there
was an increase in the incidence of XADAGO-treated patients who discontinued
from the study because of adverse reactions. The incidence of patients
discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for
XADAGO 50 mg/day, 6% for XADAGO 100 mg/day, and 4% for placebo. The most
frequently reported adverse reaction causing study discontinuation was
dyskinesia (1% of patients treated with XADAGO 50 mg/day or XADAGO 100 mg/day
vs. 0% for placebo).
7
Drug Interactions
7.1 MAO Inhibitors (MAOIs)
(Subsection title
revised; Additions and/or revisions underlined)
XADAGO
is contraindicated for use with other drugs in the MAOIs class or other
drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid, an
oxazolidinone antibacterial, which also has reversible nonselective MAO
inhibition activity). Co-administration increases the risk of nonselective MAO
inhibition, which may lead to hypertensive crisis. At least 14 days should elapse between discontinuation of XADAGO
and initiation of treatment with other MAOIs.
Isoniazid
has some monoamine oxidase inhibiting activity. Monitor for hypertension and
reaction to dietary tyramine in patients treated concomitantly with isoniazid
and XADAGO.
7.2 Opioid Drugs
(Additions and/or
revisions underlined)
Because
serious, sometimes fatal reactions have been precipitated with concomitant use
of opioid drugs (e.g., meperidine and
its derivatives, methadone, propoxyphene, or tramadol) and MAOIs,
including selective MAO-B inhibitors, concomitant use of these drugs is
contraindicated. At least 14 days
should elapse between discontinuation of XADAGO and initiation of treatment
with these drugs.
7.3 Serotonergic Drugs
(Additions and/or
revisions underlined)
Concomitant
use of XADAGO with SNRIs; triazolopyridine, tricyclic or tetracyclic antidepressants;
cyclobenzaprine (a skeletal muscle
relaxant that is a tricyclic antidepressant derivative); or St. John’s
wort is contraindicated. At least 14
days should elapse between discontinuation of XADAGO and initiation of
treatment with these drugs.
Monitor
patients for symptoms of serotonin syndrome if SSRIs are used by
patients treated with XADAGO.
7.4 Dextromethorphan
(Additions and/or
revisions underlined)
The
combination of MAOIs and dextromethorphan has been reported to cause
episodes of psychosis or bizarre behavior. Therefore, in view of XADAGO’s MAO
inhibitory activity, dextromethorphan is
contraindicated for use with XADAGO.
7.5 Sympathomimetic Medications
(Additions and/or
revisions underlined)
Severe
hypertensive reactions have followed the administration of sympathomimetics and
nonselective MAOIs. Hypertensive crisis has been reported in patients
taking the recommended doses of selective MAO-B inhibitors and sympathomimetic
medications. Concomitant use of XADAGO with methylphenidate, amphetamine, and
their derivatives is contraindicated.
Monitor
patients for hypertension if XADAGO is prescribed concomitantly with
prescription or nonprescription sympathomimetic medications, including nasal,
oral, or ophthalmic decongestants and cold remedies.
7.7 Dopaminergic Antagonists
(Additions and/or
revisions underlined)
Dopamine
antagonists, such as antipsychotics or metoclopramide, may decrease the
effectiveness of XADAGO and exacerbate the symptoms of PD.
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion)
Risk
Summary
There
are no adequate data on the developmental risk associated with the use of
XADAGO in pregnant women. In animals,
developmental toxicity, including teratogenic effects, was observed when
safinamide was administered during pregnancy at clinically relevant doses.
Developmental
toxicity was observed at doses lower than those used clinically when safinamide
was administered during pregnancy in combination with levodopa/carbidopa.
The
background risk of major birth defects and miscarriage for the indicated
population is unknown. 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.
Data
Animal Data
In
an embryofetal development study in rats, oral administration of safinamide (0,
50, 100, or 150 mg/kg/day) throughout organogenesis resulted in dose-related
increases in fetal abnormalities (primarily urogenital malformations) at all
doses. A no-effect dose for adverse effects on embryofetal development was not
established. The lowest dose tested (50 mg/kg/day) is approximately 5 times the
maximum recommended human dose (MRHD) of 100 mg on a body surface area (mg/m^2)
basis. In a combination embryofetal
development study of safinamide and
levodopa (LD)/carbidopa (CD) in rats (80/20 mg/kg/day LD/CD in
combination with 0, 25, 50, or 100
mg/kg/day safinamide or 100 mg/kg/day safinamide alone), increased incidences
of fetal visceral and skeletal malformations
and variations were observed at all doses of safinamide in combination with CD/LD and with safinamide
alone. The lowest dose of safinamide tested (25 mg/kg/day) is approximately 2
times the MRHD on a mg/m^2 basis.
In
embryofetal development studies in rabbits, no developmental toxicity was
observed at up to the highest oral dose of safinamide tested (100 mg/kg/day).
However, when safinamide (0, 4, 12, or 40 mg/kg/day) was administered
throughout organogenesis in a combination study of safinamide with LD/CD (80/20
mg/kg/day LD/CD), there was an increased incidence of embryofetal death and
cardiac and skeletal malformations, compared to LD/CD alone. A no- effect dose for safinamide was not
established; the lowest effect dose of safinamide tested (4 mg/kg/day) is less
than the MRHD on a mg/m^2 basis.
In
a rat pre- and postnatal development study, oral administration of safinamide
(0, 4, 12.5, or 37.5
mg/kg/day) throughout pregnancy and lactation resulted in skin discoloration of
the offspring, presumed to be due to hepatobiliary toxicity, at the mid and
high doses and decreased body weight and increased postnatal mortality in
offspring at the highest dose tested. The no effect dose (4 mg/kg/day) for
adverse developmental effects is less than the MRHD on a mg/m^2 basis.
8.2 Lactation
(PLLR conversion)
Risk
Summary
There
is no information regarding the presence of XADAGO 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 mothers’ clinical need for XADAGO and any potential adverse effects on
the breastfed infant from XADAGO or from the underlying maternal condition.
Data
Animal Data
Skin
discoloration, presumed to be caused by hyperbilirubinemia resulting from
hepatobiliary toxicity, was observed in rat pups indirectly exposed to
safinamide through the milk during the lactation period.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions and/or revisions underlined)
…
Before taking
XADAGO, tell your healthcare provider about all of your medical conditions,
including if you:
have high or low
blood pressure
have a sleep
disorder, have unexpected or unpredictable daytime sleepiness or take a
medicine to help you sleep
drink alcoholic
beverages. This may increase your chances of becoming drowsy or sleepy while
taking XADAGO.
have a history of
abnormal movement (dyskinesia)
have or have had a
mental health problem such as schizophrenia, bipolar disorder or psychosis
have or have had
unusual urges
have or have had
problems with the retina in your eye or have a family history of problems with
the retina
are pregnant or
plan to become pregnant. It is not known if XADAGO will harm your unborn baby.
- are breastfeeding
or plan to breastfeed. It is not known if XADAGO passes into breast milk or
if it can cause side effects in a breastfed baby. Talk to your healthcare
provider about the best way to feed your baby if you take XADAGO.
…
What should I
avoid while taking XADAGO?
Avoid certain foods and
beverages that are high in tyramine such as aged, fermented, cured, smoked and
pickled foods.
- Do not drive,
operate heavy machinery, work in high places or do other dangerous activities
until you know how XADAGO affects you.
…
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