Included as part of the PRECAUTIONS section.
Bradyarrhythmia And Atrioventricular Blocks
Because of a risk for bradyarrhythmia and AV blocks,
patients should be monitored during GILENYA treatment initiation [see DOSAGE
Reduction In Heart Rate
After the first dose of GILENYA, the heart rate decrease
starts within an hour. On Day 1, the maximum decline in heart rate generally
occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10
hours postdose. Because of physiological diurnal variation, there is a second
period of heart rate decrease within 24 hours after the first dose. In some
patients, heart rate decrease during the second period is more pronounced than the
decrease observed in the first 6 hours. Heart rates below 40 beats per minute
(bpm) in adults, and below 50 bpm in pediatric patients occurred rarely. In
controlled clinical trials in adult patients, adverse reactions of symptomatic
bradycardia following the first dose were reported in 0.6% of patients
receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who
experienced bradycardia were generally asymptomatic, but some patients
experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain
that usually resolved within the first 24 hours on treatment.
Patients with some preexisting conditions (e.g., ischemic
heart disease, history of myocardial infarction, congestive heart failure,
history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension,
history of symptomatic bradycardia, history of recurrent syncope, severe
untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate
the GILENYA-induced bradycardia, or experience serious rhythm disturbances
after the first dose of GILENYA. Prior to treatment with GILENYA, these
patients should have a cardiac evaluation by a physician appropriately trained
to conduct such evaluation, and if treated with GILENYA, should be monitored
overnight with continuous ECG in a medical facility after the first dose.
Since initiation of GILENYA treatment, results in
decreased heart rate and may prolong the QT interval, patients with a prolonged
QTc interval (> 450 msec adult and pediatric males, > 470 msec adult females,
or > 460 msec pediatric females) before dosing or during 6-hour observation,
or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia,
congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs
with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine,
haloperidol, methadone, erythromycin) should be monitored overnight with
continuous ECG in a medical facility
Following the second dose, a further decrease in heart
rate may occur when compared to the heart rate prior to the second dose, but
this change is of a smaller magnitude than that observed following the first
dose. With continued dosing, the heart rate returns to baseline within 1 month
of chronic treatment. Clinical data indicate effects of GILENYA on heart rate
are maximal after the first dose although milder effects on heart rate may
persist for, on average, 2 to 4 weeks after initiation of therapy at which time
heart rate generally returns to baseline. Physicians should continue to be alert
to patient reports of cardiac symptoms.
Initiation of GILENYA treatment has resulted in transient
AV conduction delays. In controlled clinical trials in adult patients,
first-degree AV block after the first dose occurred in 4.7% of patients
receiving GILENYA and 1.6% of patients on placebo. In a study of 697 patients
with available 24-hour Holter monitoring data after their first dose (N = 351
receiving GILENYA and N = 346 on placebo), second-degree AV blocks (Mobitz
Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N = 14) of patients
receiving GILENYA and 2% (N = 7) of patients on placebo. Of the 14 patients
receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6
hours postdose and 2 patients after 6 hours postdose). All second degree AV
blocks on placebo were Mobitz Type I and occurred after the first 12 hours
postdose. The conduction abnormalities were usually transient and asymptomatic,
and resolved within the first 24 hours on treatment, but they occasionally
required treatment with atropine or isoproterenol.
In the postmarketing setting, third-degree AV block and
AV block with junctional escape have been observed during the first-dose 6-hour
observation period with GILENYA. Isolated delayed onset events, including
transient asystole and unexplained death, have occurred within 24 hours of the
first dose. These events were confounded by concomitant medications and/or
preexisting disease, and the relationship to GILENYA is uncertain. Cases of
syncope were also reported after the first dose of GILENYA.
Risk Of Infections
GILENYA causes a dose-dependent reduction in peripheral
lymphocyte count to 20%-30% of baseline values because of reversible
sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore
increase the risk of infections, some serious in nature [see CLINICAL
PHARMACOLOGY]. Life-threatening and fatal infections have occurred in
association with GILENYA.
Before initiating treatment with GILENYA, a recent CBC
(i.e., within 6 months or after discontinuation of prior therapy) should be
available. Consider suspending treatment with GILENYA if a patient develops a
serious infection, and reassess the benefits and risks prior to reinitiation of
therapy. Because the elimination of fingolimod after discontinuation may take
up to 2 months, continue monitoring for infections throughout this period.
Instruct patients receiving GILENYA to report symptoms of infections to a
physician. Patients with active acute or chronic infections should not start
treatment until the infection(s) is resolved.
In MS placebo-controlled trials in adult patients, the
overall rate of infections (72%) with GILENYA was similar to placebo. However,
bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common
in GILENYA-treated patients. Serious infections occurred at a rate of 2.3% in
the GILENYA group versus 1.6% in the placebo group.
In the postmarketing setting, serious infections with
opportunistic pathogens including viruses (e.g., John Cunningham virus (JCV),
herpes simplex viruses 1 and 2, varicella zoster virus), fungi (e.g.,
cryptococci), and bacteria (e.g., atypical mycobacteria) have been reported
with GILENYA. Patients with symptoms and signs consistent with any of these
infections should undergo prompt diagnostic evaluation and appropriate
Herpes Viral Infections
In placebo-controlled trials in adult patients, the rate
of herpetic infections was 9% in patients receiving GILENYA 0.5 mg and 7% on
Two patients died of herpetic infections during
controlled trials. One death was due to disseminated primary herpes zoster and
the other was to herpes simplex encephalitis. In both cases, the patients were
taking a 1.25 mg dose of fingolimod (higher than the recommended 0.5 mg dose)
and had received high-dose corticosteroid therapy to treat suspected MS
Serious, life-threatening events of disseminated
varicella zoster and herpes simplex infections, including cases of encephalitis
and multiorgan failure, have occurred with GILENYA in the postmarketing
setting. Include disseminated herpetic infections in the differential diagnosis
of patients who are receiving GILENYA and present with an atypical MS relapse
or multiorgan failure.
Cases of Kaposi’s sarcoma have been reported in the
postmarketing setting. Kaposi’s sarcoma is an angioproliferative disorder that
is associated with infection with human herpes virus 8 (HHV-8). Patients with
symptoms or signs consistent with Kaposi’s sarcoma should be referred for
prompt diagnostic evaluation and management.
Cryptococcal infections, including cases of fatal
cryptococcal meningitis and disseminated cryptococcal infections, have been
reported with GILENYA in the postmarketing setting. Cryptococcal infections
have generally occurred after approximately 2 years of GILENYA treatment, but
may occur earlier. The relationship between the risk of cryptococcal infection
and the duration of treatment is unknown. Patients with symptoms and signs
consistent with a cryptococcal infection should undergo prompt diagnostic
evaluation and treatment.
Prior And Concomitant Treatment With Antineoplastic,
Immunosuppressive, Or Immune-Modulating Therapies
In clinical studies, patients who received GILENYA did
not receive concomitant treatment with antineoplastic, non-corticosteroid
immunosuppressive, or immune-modulating therapies used for treatment of MS.
Concomitant use of GILENYA with any of these therapies, and also with
corticosteroids, would be expected to increase the risk of immunosuppression [see
When switching to GILENYA from immune-modulating or
immunosuppressive medications, consider the duration of their effects and their
mode of action to avoid unintended additive immunosuppressive effects.
Varicella Zoster Virus Antibody Testing/Vaccination
Patients without a healthcare professional confirmed
history of chickenpox or without documentation of a full course of vaccination
against VZV should be tested for antibodies to VZV before initiating GILENYA.
VZV vaccination of antibody-negative patients is recommended prior to
commencing treatment with GILENYA, following which initiation of treatment with
GILENYA should be postponed for 1 month to allow the full effect of vaccination
to occur [see DRUG INTERACTIONS, Use In Specific Populations].
Progressive Multifocal Leukoencephalopathy
Cases of progressive multifocal leukoencephalopathy (PML)
have occurred in patients with MS who received GILENYA in the postmarketing
setting. PML is an opportunistic viral infection of the brain caused by the JC
virus (JCV) that typically only occurs in patients who are immunocompromised,
and that usually leads to death or severe disability. PML has occurred in
patients who had not been treated previously with natalizumab, which has a
known association with PML, were not taking any other immunosuppressive or
immunomodulatory medications concomitantly, and did not have any ongoing
systemic medical conditions resulting in compromised immune system function.
The majority of cases have occurred in patients treated with GILENYA for at
least 2 years. The relationship between the risk of PML and the duration of
treatment is unknown.
At the first sign or symptom suggestive of PML, withhold
GILENYA and perform an appropriate diagnostic evaluation. Typical symptoms
associated with PML are diverse, progress over days to weeks, and include
progressive weakness on one side of the body or clumsiness of limbs,
disturbance of vision, and changes in thinking, memory, and orientation leading
to confusion and personality changes.
MRI findings may be apparent before clinical signs or
symptoms. Cases of PML, diagnosed based on MRI findings and the detection of
JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms
specific to PML, have been reported in patients treated with MS medications
associated with PML, including GILENYA. Many of these patients subsequently
became symptomatic with PML. Therefore, monitoring with MRI for signs that may
be consistent with PML may be useful, and any suspicious findings should lead
to further investigation to allow for an early diagnosis of PML, if present.
Lower PML-related mortality and morbidity have been reported following
discontinuation of another MS medication associated with PML in patients with
PML who were initially asymptomatic compared to patients with PML who had
characteristic clinical signs and symptoms at diagnosis. It is not known
whether these differences are due to early detection and discontinuation of MS
treatment or due to differences in disease in these patients.
Fingolimod increases the risk of macular edema. Perform
an examination of the fundus including the macula in all patients before
starting treatment, again 3 to 4 months after starting treatment, and again at
any time after a patient reports visual disturbances while on GILENYA therapy.
A dose-dependent increase in the risk of macular edema
occurred in the GILENYA clinical development program.
In 2-year double-blind, placebo-controlled studies in
adult patients with multiple sclerosis, macular edema with or without visual
symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg,
0.5% of patients (4/783) treated with GILENYA 0.5 mg, and 0.4% of patients
(3/773) treated with placebo. Macular edema occurred predominantly during the
first 3 to 4 months of therapy. These clinical trials excluded patients with
diabetes mellitus, a known risk factor for macular edema (see below Macular
Edema in Patients with History of Uveitis or Diabetes Mellitus). Symptoms
of macular edema included blurred vision and decreased visual acuity. Routine
ophthalmological examination detected macular edema in some patients with no
visual symptoms. Macular edema generally partially or completely resolved with
or without treatment after drug discontinuation. Some patients had residual
visual acuity loss even after resolution of macular edema. Macular edema has
also been reported in patients taking GILENYA in the postmarketing setting,
usually within the first 6 months of treatment.
Continuation of GILENYA in patients who develop macular
edema has not been evaluated. A decision on whether or not to discontinue
GILENYA therapy should include an assessment of the potential benefits and
risks for the individual patient. The risk of recurrence after rechallenge has
not been evaluated.
Macular Edema In Patients with History Of Uveitis Or
Patients with a history of uveitis and patients with diabetes
mellitus are at increased risk of macular edema during GILENYA therapy. The
incidence of macular edema is also increased in MS patients with a history of
uveitis. In the combined clinical trial experience in adult patients with all
doses of fingolimod, the rate of macular edema was approximately 20% in MS
patients with a history of uveitis versus 0.6% in those without a history of
uveitis. GILENYA has not been tested in MS patients with diabetes mellitus. In
addition to the examination of the fundus including the macula prior to
treatment and at 3 to 4 months after starting treatment, MS patients with
diabetes mellitus or a history of uveitis should have regular follow-up
Clinically significant liver injury has occurred in
patients treated with Gilenya in the postmarketing setting. Signs of liver
injury, including markedly elevated serum hepatic enzymes and elevated total
bilirubin, have occurred as early as ten days after the first dose and have
also been reported after prolonged use. Cases of acute liver failure requiring
liver transplant have been reported.
In 2-year placebo-controlled clinical trials in adult
patients, elevation of liver enzymes (ALT, AST and GGT) to 3fold the upper
limit of normal (ULN) or greater occurred in 14% of patients treated with
GILENYA 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or
greater occurred in 4.5% of patients on GILENYA and 1% of patients on placebo.
The majority of elevations occurred within 6 to 9 months. In clinical trials,
GILENYA was discontinued if the elevation exceeded 5 times the ULN. Serum
transaminase levels returned to normal within approximately 2 months after
discontinuation of GILENYA. Recurrence of liver transaminase elevations
occurred with rechallenge in some patients.
Prior to starting treatment with GILENYA (within 6
months), obtain serum transaminases (ALT and AST) and total bilirubin levels.
Obtain transaminase levels and total bilirubin levels periodically until two
months after GILENYA discontinuation.
Patients should be monitored for signs and symptoms of
any hepatic injury. Measure liver transaminase and bilirubin levels promptly in
patients who report symptoms that may indicate liver injury, including new or
worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, or
jaundice. In this clinical context, if the patient is found to have an alanine
aminotransferase (ALT) greater than three times the reference range with serum
total bilirubin greater than two times the reference range, treatment with
GILENYA treatment should be interrupted. Treatment should not be resumed if a
plausible alternative etiology for the signs and symptoms cannot be
established, because these patients are at risk for severe drug-induced liver injury.
Because GILENYA exposure is doubled in patients with
severe hepatic impairment, these patients should be closely monitored, as the
risk of adverse reactions is greater [see Use In Specific Populations, CLINICAL
Posterior Reversible Encephalopathy Syndrome
There have been rare cases of posterior reversible
encephalopathy syndrome (PRES) reported in adult patients receiving GILENYA.
Symptoms reported included sudden onset of severe headache, altered mental
status, visual disturbances, and seizure. Symptoms of PRES are usually
reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in
diagnosis and treatment may lead to permanent neurological sequelae. If PRES is
suspected, GILENYA should be discontinued.
Dose-dependent reductions in forced expiratory volume
over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO)
were observed in patients treated with GILENYA as early as 1 month after
treatment initiation. In 2-year placebo-controlled trials in adult patients,
the reduction from baseline in the percent of predicted values for FEV1 at the
time of last assessment on drug was 2.8% for GILENYA 0.5 mg and 1.0% for
placebo. For DLCO, the reduction from baseline in percent of predicted values
at the time of last assessment on drug was 3.3% for GILENYA 0.5 mg and 0.5% for
placebo. The changes in FEV1 appear to be reversible after treatment
discontinuation. There is insufficient information to determine the
reversibility of the decrease of DLCO after drug discontinuation. In MS
placebo-controlled trials in adult patients, dyspnea was reported in 9% of
patients receiving GILENYA 0.5 mg and 7% of patients receiving placebo. Several
patients discontinued GILENYA because of unexplained dyspnea during the extension
(uncontrolled) studies. GILENYA has not been tested in MS patients with
compromised respiratory function.
Spirometric evaluation of respiratory function and
evaluation of DLCO should be performed during therapy with GILENYA if
Based on animal studies, GILENYA may cause fetal harm.
Because it takes approximately 2 months to eliminate GILENYA from the body,
women of childbearing potential should use effective contraception to avoid
pregnancy during and for 2 months after stopping GILENYA treatment.
Severe Increase In Disability After Stopping GILENYA
Severe increase in disability accompanied by multiple new
lesions on MRI has been reported after discontinuation of GILENYA in the
postmarketing setting. Patients in most of these reported cases did not return
to the functional status they had before stopping GILENYA. The increase in
disability generally occurred within 12 weeks after stopping GILENYA, but was
reported up to 24 weeks after GILENYA discontinuation.
Monitor patients for development of severe increase in
disability following discontinuation of GILENYA and begin appropriate treatment
Increased Blood Pressure
In adult MS controlled clinical trials, patients treated
with GILENYA 0.5 mg had an average increase over placebo of approximately 3
mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure,
first detected after approximately 1 month of treatment initiation, and
persisting with continued treatment. Hypertension was reported as an adverse
reaction in 8% of patients on GILENYA 0.5 mg and in 4% of patients on placebo.
Blood pressure should be monitored during treatment with GILENYA.
The risk of basal cell carcinoma (BCC) and melanoma is
increased in patients treated with GILENYA. In two-year placebo-controlled
trials in adult patients, the incidence of BCC was 2% in patients on GILENYA
0.5 mg and 1% in patients on placebo [see ADVERSE REACTIONS]. Melanoma
and Merkel cell carcinoma have been reported with GILENYA in the postmarketing
setting. Periodic skin examination is recommended for all patients,
particularly those with risk factors for skin cancer. Providers and patients
are advised to monitor for suspicious skin lesions. If a suspicious skin lesion
is observed, it should be promptly evaluated. As usual for patients with
increased risk for skin cancer, exposure to sunlight and ultraviolet light
should be limited by wearing protective clothing and using a sunscreen with a high
Cases of lymphoma, including both T-cell and B-cell types
and CNS lymphoma, have occurred in patients receiving GILENYA. The reporting
rate of non-Hodgkin lymphoma with GILENYA is greater than that expected in the
general population adjusted by age, gender, and region. Cutaneous T-cell
lymphoma (including mycosis fungoides) has also been reported with GILENYA in
the postmarketing setting.
Immune System Effects Following GILENYA Discontinuation
Fingolimod remains in the blood and has pharmacodynamic
effects, including decreased lymphocyte counts, for up to 2 months following
the last dose of GILENYA. Lymphocyte counts generally return to the normal
range within 1-2 months of stopping therapy [see CLINICAL PHARMACOLOGY].
Because of the continuing pharmacodynamic effects of fingolimod, initiating
other drugs during this period warrants the same considerations needed for
concomitant administration (e.g., risk of additive immunosuppressant effects) [see
Hypersensitivity reactions, including rash, urticaria,
and angioedema have been reported with GILENYA in the postmarketing setting.
GILENYA is contraindicated in patients with history of hypersensitivity to
fingolimod or any of its excipients [see CONTRAINDICATIONS].
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Tell patients not to
discontinue GILENYA without first discussing this with the prescribing
physician. Advise patients to contact their physician if they accidently take
more GILENYA than prescribed.
Advise patients that initiation
of GILENYA treatment results in a transient decrease in heart rate. Inform
patients that they will need to be observed in the doctor's office or other
facility for at least 6 hours after the first dose, after reinitiation if
treatment is interrupted or discontinued for certain periods, and after the
dosage is increased [see DOSAGE AND ADMINISTRATION, WARNINGS
Risk Of Infections
Inform patients that they may
have an increased risk of infections, some of which could be life-threatening,
when taking GILENYA, and that they should contact their physician if they
develop symptoms of infection. Advise patients that the use of some vaccines
should be avoided during treatment with GILENYA and for 2 months after discontinuation. Recommend to patients that they delay
treatment with GILENYA until after VZV vaccination if they have not had
chickenpox or a previous VZV vaccination. Inform patients that prior or
concomitant use of drugs that suppress the immune system may increase the risk
of infection [see WARNINGS AND PRECAUTIONS].
Inform patients that cases of
progressive multifocal leukoencephalopathy (PML) have occurred in patients who
received GILENYA. Inform the patient that PML is characterized by a progression
of deficits and usually leads to death or severe disability over weeks or
months. Instruct the patient of the importance of contacting their doctor if
they develop any symptoms suggestive of PML. Inform the patient that typical
symptoms associated with PML are diverse, progress over days to weeks, and
include progressive weakness on one side of the body or clumsiness of limbs,
disturbance of vision, and changes in thinking, memory, and orientation leading
to confusion and personality changes [see WARNINGS AND PRECAUTIONS].
Advise patients that GILENYA
may cause macular edema, and that they should contact their physician if they
experience any changes in their vision. Inform patients with diabetes mellitus
or a history of uveitis that their risk of macular edema is increased [see WARNINGS
Inform patients that GILENYA
may cause liver injury. Advise patients that they should contact their
physician if they have any unexplained nausea, vomiting, abdominal pain,
fatigue, anorexia, or jaundice and/or dark urine [see WARNINGS AND
Advise patients to immediately
report to their healthcare provider any symptoms involving sudden onset of
severe headache, altered mental status, visual disturbances, or seizure. Inform
patients that delayed treatment could lead to permanent neurological sequelae [see
WARNINGS AND PRECAUTIONS].
Advise patients that they
should contact their physician if they experience new onset or worsening of
dyspnea [see WARNINGS AND PRECAUTIONS].
Inform patients that, based on
animal studies, GILENYA may cause fetal harm. Discuss with women of
childbearing age whether they are pregnant, might be pregnant or are trying to
become pregnant. Advise women of childbearing age of the need for effective
contraception during GILENYA treatment and for 2 months after stopping GILENYA.
Advise the patient that if she should nevertheless become pregnant, she should
immediately inform her physician [see WARNINGS AND PRECAUTIONS].
Severe Increase In Disability
After Stopping GILENYA
Inform patients that severe
increase in disability has been reported after discontinuation of GILENYA.
Advise patients to contact their physician if they develop worsening symptoms
of MS following discontinuation of GILENYA [see WARNINGS AND
Advise patients that basal cell
carcinoma and melanoma are associated with use of GILENYA. Advise patients that
any suspicious skin lesions should be promptly evaluated. Advise patients to
limit exposure to sunlight and ultraviolet light by wearing protective clothing
and using a sunscreen with a high protection factor. Inform patients that
lymphoma has also occurred in patients receiving GILENYA [see WARNINGS
Persistence Of GILENYA Effects
After Drug Discontinuation
Advise patients that GILENYA
remains in the blood and continues to have effects, including decreased blood
lymphocyte counts, for up to 2 months following the last dose [see WARNINGS
Advise patients that GILENYA may cause hypersensitivity
reactions including rash, urticaria, and angioedema. Advise patients to contact
their physician if they have any symptoms associated with hypersensitivity [see
WARNINGS AND PRECAUTIONS].
Pregnancy And Pregnancy Registry
Instruct patients that if they are pregnant or plan to
become pregnant while taking GILENYA they should inform their physician.
Encourage patients to enroll in the GILENYA Pregnancy Registry if they become
pregnant while taking GILENYA [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Oral carcinogenicity studies of fingolimod were conducted
in mice and rats. In mice, fingolimod was administered at oral doses of 0,
0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant
lymphoma was increased in males and females at the mid and high dose. The lowest
dose tested (0.025 mg/kg/day) is less than the RHD of 0.5 mg/day on a body
surface area (mg/m²) basis. In rats, fingolimod was administered at oral doses
of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed.
The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a
Fingolimod was negative in a battery of in vitro (Ames,
mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and
in vivo (micronucleus in mouse and rat) assays.
When fingolimod was administered orally (0, 1, 3, and 10
mg/kg/day) to male and female rats prior to and during mating, and continuing
to Day 7 of gestation in females, no effect on fertility was observed up to the
highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure
registry that monitors pregnancy outcomes in women exposed to GILENYA during
pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant
women may register themselves in the GILENYA pregnancy registry by calling
1-877-598-7237, sending an email to [email protected], or visiting
There are no adequate data on the developmental risk
associated with the use of GILENYA in pregnant women. In oral studies conducted
in rats and rabbits, fingolimod demonstrated developmental toxicity, including
an increase in malformations (rats) and embryolethality, when given to pregnant
animals. In rats, the highest no-effect dose was less than the recommended
human dose of 0.5 mg/day on a body surface area (mg/m²) basis. The most common
fetal visceral malformations in rats were persistent truncus arteriosus and
ventricular septal defect. The receptor affected by fingolimod (sphingosine
1-phosphate receptor) is known to be involved in vascular formation during
In the US general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The
background risk of major birth defects and miscarriage for the indicated
population is unknown.
The possibility of severe
increase in disability should be considered in women who discontinue or are
considering discontinuation of GILENYA because of pregnancy or planned
pregnancy. In many of the cases in which increase in disability was reported
after stopping GILENYA, patients had stopped GILENYA because of pregnancy or
planned pregnancy [see WARNINGS AND PRECAUTIONS]. For females planning to
become pregnant, GILENYA should be stopped 2 months before conception [See Pregnancy]
When fingolimod was orally administered to pregnant rats
during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3,
and 10 mg/kg/day), increased incidences of fetal malformations and embryo-fetal
deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which
is less than the recommended human dose (RHD) on a mg/m² basis. Oral
administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5
mg/kg/day) resulted in increased incidences of embryo-fetal mortality and fetal
growth retardation at the mid and high doses. The no-effect dose for these
effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m²
When fingolimod was orally administered to female rats
during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival
was decreased at all doses and a neurobehavioral (learning) deficit was seen in
offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to
the RHD on a mg/m² basis
There are no data on the
presence of fingolimod in human milk, the effects on the breastfed infant, or
the effects of the drug on milk production. Fingolimod is excreted in the milk
of treated rats. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for GILENYA and any
potential adverse effects on the breastfed infant from GILENYA or from the
underlying maternal condition.
Females And Males Of Reproductive
Before initiation of GILENYA
treatment, women of childbearing potential should be counseled on the potential
for a serious risk to the fetus and the need for effective contraception during
treatment with GILENYA [see Use In Specific Populations]. Since it takes
approximately 2 months to eliminate the compound from the body after stopping
treatment, the potential risk to the fetus may persist and women should use
effective contraception during this period [see WARNINGS AND
Safety and effectiveness of
GILENYA for the treatment of relapsing forms of multiple sclerosis in pediatric
patients 10 to less than 18 years of age were established in one randomized,
double-blind clinical study in 215 patients (GILENYA n = 107; intramuscular
interferon (IFN) beta-1a n = 108) [see Clinical Studies].
In the controlled pediatric
study, the safety profile in pediatric patients (10 to less than 18 years of
age) receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in
adult patients. In the pediatric study, cases of seizures were reported in 5.6%
of GILENYA treated patients and 0.9% of interferon beta-1a treated patients.
It is recommended that
pediatric patients if possible, complete all immunizations in accordance with
current immunization guidelines prior to initiating GILENYA therapy.
Safety and effectiveness of
GILENYA in pediatric patients below the age of 10 years have not been
Juvenile Animal Toxicity Data
In a study in which fingolimod
(0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning
through sexual maturity, changes in bone mineral density and persistent
neurobehavioral impairment (altered auditory startle) were observed at all
doses. Delayed sexual maturation was noted in females at the highest dose
tested and in males at all doses. The bone changes observed in
fingolimod-treated juvenile rats are consistent with a reported role of S1P in
the regulation of bone mineral homeostasis.
When fingolimod (0.5 or 5
mg/kg/day) was orally administered to rats from the neonatal period through
sexual maturity, a marked decrease in T-cell dependent antibody response was
observed at both doses. This effect had not fully recovered by 6-8 weeks after
the end of treatment.
Overall, a no-effect dose for
adverse developmental effects in juvenile animals was not identified.
Clinical MS studies of GILENYA
did not include sufficient numbers of patients aged 65 years and over to
determine whether they respond differently than younger patients. GILENYA should
be used with caution in patients aged 65 years and over, reflecting the greater
frequency of decreased hepatic, or renal, function and of concomitant disease
or other drug therapy.
Because fingolimod, but not
fingolimod-phosphate, exposure is doubled in patients with severe hepatic
impairment, patients with severe hepatic impairment should be closely
monitored, as the risk of adverse reactions may be greater [see WARNINGS
AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
No dose adjustment is needed in
patients with mild or moderate hepatic impairment.
The blood level of some GILENYA
metabolites is increased (up to 13-fold) in patients with severe renal
impairment [see CLINICAL PHARMACOLOGY]. The toxicity of these
metabolites has not been fully explored. The blood level of these metabolites
has not been assessed in patients with mild or moderate renal impairment.