Included as part of the PRECAUTIONS section.
Risk Of Infections
MAYZENT causes a dose-dependent reduction in peripheral
lymphocyte count to 20%-30% of baseline values because of reversible
sequestration of lymphocytes in lymphoid tissues. MAYZENT may therefore
increase the risk of infections, some serious in nature [see CLINICAL
PHARMACOLOGY]. Life-threatening and rare fatal infections have occurred in
association with MAYZENT.
In Study 1 [see Clinical Studies], the overall
rate of infections was comparable between the MAYZENT-treated patients and
those on placebo (49.0% vs. 49.1% respectively). However, herpes zoster, herpes
infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin
infection were more common in MAYZENT-treated patients. In Study 1, serious
infections occurred at a rate of 2.9% in MAYZENT-treated patients compared to
2.5% of patients receiving placebo.
Before initiating treatment with MAYZENT, results from a
recent complete blood count (i.e., within 6 months or after discontinuation of
prior therapy) should be reviewed.
Initiation of treatment with MAYZENT should be delayed in
patients with severe active infection until resolution. Because residual
pharmacodynamic effects, such as lowering effects on peripheral lymphocyte
count, may persist for up to 3-4 weeks after discontinuation of MAYZENT,
vigilance for infection should be continued throughout this period [see Immune System Effects After Stopping MAYZENT].
Effective diagnostic and therapeutic strategies should be
employed in patients with symptoms of infection while on therapy. Suspension of
treatment with MAYZENT should be considered if a patient develops a serious
Cases of fatal cryptococcal meningitis (CM) and
disseminated cryptococcal infections have been reported with another
sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also
occurred with MAYZENT. Physicians should be vigilant for clinical symptoms or
signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection
should undergo prompt diagnostic evaluation and treatment. MAYZENT treatment
should be suspended until a cryptococcal infection has been excluded. If CM is
diagnosed, appropriate treatment should be initiated.
Herpes Viral Infections
Cases of herpes viral infection, including one case of
reactivation of VZV infection leading to varicella zoster meningitis, have been
reported in the development program of MAYZENT. In Study 1, the rate of
herpetic infections was 4.6% in MAYZENT-treated patients compared to 3.0% of
patients receiving placebo. In Study 1, an increase in the rate of herpes
zoster infections was reported in 2.5% of MAYZENT-treated patients compared to
0.7% of patients receiving placebo. Patients without a healthcare professional
confirmed history of varicella (chickenpox) or without documentation of a full
course of vaccination against VZV should be tested for antibodies to VZV before
initiating MAYZENT (see Vaccinations below).
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (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. 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.
No cases of PML have been reported in MAYZENT-treated
patients in the development program; however, PML has been reported in patients
treated with a S1P receptor modulator and other multiple sclerosis (MS)
therapies and has been associated with some risk factors (e.g.,
immunocompromised patients, polytherapy with immunosuppressants). Physicians
should be vigilant for clinical symptoms or MRI findings that may be suggestive
of PML. MRI findings may be apparent before clinical signs or symptoms. If PML
is suspected, treatment with MAYZENT should be suspended until PML has been
Prior And Concomitant Treatment With Antineoplastic,
Immune-Modulating, Or Immunosuppressive Therapies
Anti-neoplastic, immune-modulating, or immunosuppressive
therapies (including corticosteroids) should be coadministered with caution
because of the risk of additive immune system effects during such therapy [see DRUG
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 MAYZENT
treatment. A full course of vaccination for antibody-negative patients with
varicella vaccine is recommended prior to commencing treatment with MAYZENT,
following which initiation of treatment with MAYZENT should be postponed for 4
weeks to allow the full effect of vaccination to occur.
The use of live attenuated vaccines should be avoided
while patients are taking MAYZENT and for 4 weeks after stopping treatment [see
Vaccinations may be less effective if administered during
MAYZENT treatment. MAYZENT treatment discontinuation 1 week prior to and until
4 weeks after a planned vaccination is recommended.
Macular edema was reported in 1.8% of MAYZENT-treated
patients compared to 0.2% of patients receiving placebo. The majority of cases
occurred within the first four months of therapy.
An ophthalmic evaluation of the fundus, including the
macula, is recommended in all patients before starting treatment and at any
time if there is any change in vision while taking MAYZENT.
Continuation of MAYZENT therapy in patients with macular
edema has not been evaluated. A decision on whether or not MAYZENT should be
discontinued needs to take into account the potential benefits and risks for
the individual patient.
Macular Edema In Patients With A History Of Uveitis Or Diabetes
Patients with a history of uveitis and patients with
diabetes mellitus are at increased risk of macular edema during MAYZENT
therapy. The incidence of macular edema is also increased in MS patients with a
history of uveitis. In the clinical trial experience in adult patients with all
doses of MAYZENT, the rate of macular edema was approximately 10% in MS
patients with a history of uveitis or diabetes mellitus versus 2% in those
without a history of these diseases. In addition to the examination of the
fundus, including the macula, prior to treatment, MS patients with diabetes
mellitus or a history of uveitis should have regular follow-up examinations.
Bradyarrhythmia And Atrioventricular Conduction Delays
Since initiation of MAYZENT treatment results in a
transient decrease in heart rate and atrioventricular conduction delays, an
up-titration scheme should be used to reach the maintenance dosage of MAYZENT [see
DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
MAYZENT was not studied in patients who had:
- In the last 6 months experienced myocardial infarction,
unstable angina, stroke, TIA, or decompensated heart failure requiring
- New York Heart Association Class II-IV heart failure
- Cardiac conduction or rhythm disorders, including
complete left bundle branch block, sinus arrest or sino-atrial block,
symptomatic bradycardia, sick sinus syndrome, Mobitz Type II second degree
AV-block or higher grade AV-block (either history or observed at screening),
unless patient has a functioning pacemaker
- Significant QT prolongation (QTc greater than 500 msec)
- Arrhythmias requiring treatment with Class Ia or Class III
anti-arrhythmic drugs [see DRUG INTERACTIONS].
Reduction In Heart Rate
After the first titration dose of MAYZENT, the heart rate
decrease starts within an hour, and the Day 1 decline is maximal at
approximately 3-4 hours. With continued up-titration, further heart rate
decreases are seen on subsequent days, with maximal decrease from Day
1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute
hourly mean heart rate is observed on Day 1, with the pulse declining on average
5-6 bpm. Post-dose declines on the following days are less pronounced. With
continued dosing, heart rate starts increasing after Day 6 and reaches placebo
levels within 10 days after treatment initiation.
In Study 1, bradycardia occurred in 4.4% of MAYZENT-treated
patients compared to 2.9% of patients receiving placebo. Patients who
experienced bradycardia were generally asymptomatic. Few patients experienced
symptoms, including dizziness or fatigue, and these symptoms resolved within 24
hours without intervention [see ADVERSE REACTIONS]. Heart rates below 40
bpm were rarely observed.
Atrioventricular Conduction Delays
Initiation of MAYZENT treatment has been associated with
transient atrioventricular conduction delays that follow a similar temporal
pattern as the observed decrease in heart rate during dose titration. The AV
conduction delays manifested in most of the cases as first-degree AV block
(prolonged PR interval on ECG), which occurred in 5.1% of MAYZENT-treated
patients and in 1.9 % of patients receiving placebo in Study 1. Second-degree
AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time
of treatment initiation with MAYZENT in less than 1.7% of patients in clinical
trials. The conduction abnormalities typically were transient, asymptomatic,
resolved within 24 hours, rarely required treatment with atropine, and did not
require discontinuation of MAYZENT treatment.
If treatment with MAYZENT is considered, advice from a
cardiologist should be sought:
- In patients with significant QT prolongation (QTc greater
than 500 msec),
- In patients with arrhythmias requiring treatment with
Class Ia or Class III anti-arrhythmic drugs [see DRUG INTERACTIONS].
- In patients with ischemic heart disease, heart failure,
history of cardiac arrest or myocardial infarction, cerebrovascular disease,
and uncontrolled hypertension
- In patients with a history of with second-degree Mobitz
type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see CONTRAINDICATIONS].
- Obtain an ECG in all patients to determine whether
preexisting conduction abnormalities are present.
- In all patients, a dose titration is recommended for
initiation of MAYZENT treatment to help reduce cardiac effects [see DOSAGE
- In patients with sinus bradycardia (HR less than 55 bpm),
first-or second-degree [Mobitz type I] AV block, or a history of myocardial
infarction or heart failure with onset > 6 months prior to initiation, ECG
testing and first-dose monitoring is recommended [see DOSAGE AND
- Since significant bradycardia may be poorly tolerated in
patients with history of cardiac arrest, cerebrovascular disease, uncontrolled
hypertension, or severe untreated sleep apnea, MAYZENT is not recommended in
these patients. If treatment is considered, advice from a cardiologist should
be sought prior to initiation of treatment in order to determine the most
appropriate monitoring strategy.
- Use of MAYZENT in patients with a history of recurrent
syncope or symptomatic bradycardia should be based on an overall benefit-risk
assessment. If treatment is considered, advice from a cardiologist should be
sought prior to initiation of treatment in order to determine the most
- Experience with MAYZENT is limited in patients receiving
concurrent therapy with drugs that decrease heart-rate (e.g., beta-blockers,
calcium channel blockers -diltiazem and verapamil, and other drugs that may
decrease heart rate, such as ivabradine and digoxin). Concomitant use of these
drugs during MAYZENT initiation may be associated with severe bradycardia and
- For patients receiving a stable dose of a beta-blocker,
the resting heart rate should be considered before introducing MAYZENT
treatment. If the resting heart rate is greater than 50 bpm under chronic
beta-blocker treatment, MAYZENT can be introduced. If resting heart rate is
less than or equal to 50 bpm, beta-blocker treatment should be interrupted
until the baseline heart-rate is greater than 50 bpm. Treatment with MAYZENT
can then be initiated and treatment with a beta-blocker can be reinitiated
after MAYZENT has been up-titrated to the target maintenance dosage [see
- For patients taking other drugs that decrease heart rate,
treatment with MAYZENT should generally not be initiated without consultation
from a cardiologist because of the potential additive effect on heart rate [see
DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
Missed Dose During Treatment Initiation And Reinitiation Of
Therapy Following Interruption
If a titration dose is missed or if 4 or more consecutive
daily doses are missed during maintenance treatment, reinitiate Day 1 of the
dose titration and follow titration monitoring recommendations [see DOSAGE
Dose-dependent reductions in absolute forced expiratory
volume over 1 second (FEV1) were observed in MAYZENT-treated patients as early
as 3 months after treatment initiation. In a placebo-controlled trial in adult
patients, the decline in absolute FEV1 from baseline compared to placebo was 88
mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference
between MAYZENT-treated patients and patients receiving placebo in percent
predicted FEV1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient
information to determine the reversibility of the decrease in FEV1 after drug
discontinuation. In Study 1, five patients discontinued MAYZENT because of
decreases in pulmonary function testing. MAYZENT has been tested in MS patients
with mild to moderate asthma and chronic obstructive pulmonary disease. The
changes in FEV1 were similar in this subgroup compared with the overall
population. Spirometric evaluation of respiratory function should be performed
during therapy with MAYZENT if clinically indicated.
Elevations of transaminases may occur in MAYZENT-treated
patients. Recent (i.e., within last 6 months) transaminase and bilirubin levels
should be reviewed before initiation of MAYZENT therapy.
In Study 1, elevations in transaminases and bilirubin
were observed in 10.1% of MAYZENT-treated patients compared to 3.7% of patients
receiving placebo, mainly because of transaminase [alanine
In Study 1, ALT or AST increased to three and five times
the upper limit of normal (ULN) in 5.6% and 1.4% of MAYZENT-treated patients,
respectively, compared to 1.5% and 0.5% of patients receiving placebo,
respectively. ALT or AST increased eight and ten times ULN in MAYZENT-treated
patients (0.5% and 0.2%, respectively) compared to no patients receiving
placebo. The majority of elevations occurred within 6 months of starting
treatment. ALT levels returned to normal within approximately 1 month after
discontinuation of MAYZENT. In clinical trials, MAYZENT was discontinued if the
elevation exceeded a 3-fold increase and the patient showed symptoms related to
Patients who develop symptoms suggestive of hepatic
dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue,
anorexia, rash with eosinophilia, or jaundice and/or dark urine during
treatment, should have liver enzymes checked. MAYZENT should be discontinued if
significant liver injury is confirmed.
Although there are no data to establish that patients
with preexisting liver disease are at increased risk to develop elevated liver
function test values when taking MAYZENT, caution should be exercised when
using MAYZENT in patients with a history of significant liver disease.
Increased Blood Pressure
In Study 1, MAYZENT-treated patients had an average
increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg
in diastolic pressure, which was first detected after approximately 1 month of treatment
initiation and persisted with continued treatment. Hypertension was reported as
an adverse reaction in 12.5% of MAYZENT-treated patients and in 9.2% of
patients receiving placebo. Blood pressure should be monitored during treatment
with MAYZENT and managed appropriately.
Based on animal studies, MAYZENT may cause fetal harm [see
Use In Specific Populations]. Because it takes approximately 10 days to
eliminate MAYZENT from the body, women of childbearing potential should use
effective contraception to avoid pregnancy during and for 10 days after
stopping MAYZENT treatment.
Posterior Reversible Encephalopathy Syndrome
Rare cases of posterior reversible encephalopathy
syndrome (PRES) have been reported in patients receiving a sphingosine
1-phosphate (S1P) receptor modulator. Such events have not been reported for
MAYZENT-treated patients in the development program. However, should a
MAYZENT-treated patient develop any unexpected neurological or psychiatric
symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual
disturbances, or any other neurological cortical symptoms/signs), any
symptom/sign suggestive of an increase of intracranial pressure, or accelerated
neurological deterioration, the physician should promptly schedule a complete
physical and neurological examination and should consider a MRI. 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, MAYZENT should be discontinued.
Unintended Additive Immunosuppressive Effects From Prior
Treatment With Immunosuppressive Or Immune-Modulating Therapies
When switching from drugs with prolonged immune effects,
the half-life and mode of action of these drugs must be considered to avoid
unintended additive immunosuppressive effects while at the same time minimizing
risk of disease reactivation, when initiating MAYZENT.
Initiating treatment with MAYZENT after treatment with
alemtuzumab is not recommended [see DRUG INTERACTIONS].
Severe Increase In Disability After Stopping MAYZENT
Severe exacerbation of disease, including disease
rebound, has been rarely reported after discontinuation of a S1P receptor
modulator. The possibility of severe exacerbation of disease should be
considered after stopping MAYZENT treatment. Patients should be observed for a
severe increase in disability upon MAYZENT discontinuation and appropriate
treatment should be instituted, as required.
Immune System Effects After Stopping MAYZENT
After stopping MAYZENT therapy, siponimod remains in the
blood for up to 10 days. Starting other therapies during this interval will
result in concomitant exposure to siponimod.
Lymphocyte counts returned to the normal range in 90% of
patients within 10 days of stopping therapy [see CLINICAL PHARMACOLOGY ].
However, residual pharmacodynamics effects, such as lowering effects on
peripheral lymphocyte count, may persist for up to 3-4 weeks after the last
dose. Use of immunosuppressants within this period may lead to an additive
effect on the immune system, and therefore caution should be applied 3-4 weeks
after the last dose of MAYZENT [see DRUG INTERACTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Tell patients not to discontinue MAYZENT without first
discussing this with the prescribing physician. Advise patients to contact
their physician if they accidently take more MAYZENT than prescribed.
Risk Of Infections
Inform patients that they may have an increased risk of
infections, some of which could be life-threatening, when taking MAYZENT, and
that they should contact their physician if they develop symptoms of infection
[see WARNINGS AND PRECAUTIONS]. Advise patients that the use of some
vaccines containing live virus (live attenuated vaccines) should be avoided
during treatment with MAYZENT and MAYZENT should be paused 1 week prior and
until 4 weeks after a planned vaccination. Recommend that patients postpone
treatment with MAYZENT for at least 1 month after VZV vaccination. Inform
patients that prior or concomitant use of drugs that suppress the immune system
may increase the risk of infection.
Advise patients that MAYZENT may cause macular edema, and
that they should contact their physician if they experience any changes in
their vision while taking MAYZENT [see WARNINGS AND PRECAUTIONS]. Inform
patients with diabetes mellitus or a history of uveitis that their risk of
macular edema is increased.
Advise patients that initiation of MAYZENT treatment
results in transient decrease in heart rate [see WARNINGS AND PRECAUTIONS].
Inform patients that to reduce this effect, dosage titration is required.
Advise patients that dosage titration is also required if a dose is missed for
more than 24 hours during the titration or if 4 or more consecutive daily
maintenance doses are missed [see DOSAGE AND ADMINISTRATION and WARNINGS
AND PRECAUTIONS]. Inform certain patients with certain pre-existing cardiac
conditions that they will need to be observed in the doctor's office or other
facility for at least 6 hours after the first dose and after reinitiation if
treatment is interrupted or discontinued for certain periods [see DOSAGE AND
Advise patients that they should contact their physician
if they experience new onset or worsening of dyspnea [see WARNINGS AND
Inform patients that MAYZENT may increase liver enzymes. Advise
patient that they should contact their physician if they experience any
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice
and/or dark urine during treatment [see WARNINGS AND PRECAUTIONS].
Pregnancy And Fetal Risk
Inform patients that, based on animal studies MAYZENT may
cause fetal harm [see WARNINGS AND PRECAUTIONS]. Discuss with women of
childbearing age whether they are pregnant, might be pregnant, or are trying to
become pregnant. Advise women of childbearing potential of the need for
effective contraception during treatment with MAYZENT and for 10 days after
stopping MAYZENT. Advise a female patient to immediately inform that prescriber
if she is pregnant or planning to become pregnant [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations].
Posterior Reversible Encephalopathy Syndrome
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].
Severe Increase In Disability After Stopping MAYZENT
Inform patients that severe increase in disability has
been reported after discontinuation of another sphingosine 1phosphate (S1P)
receptor modulator like MAYZENT. Advise patients to contact their physician if
they develop worsening symptoms of MS following discontinuation of MAYZENT [see
WARNINGS AND PRECAUTIONS].
Immune System Effects After Stopping MAYZENT
Advise patients that MAYZENT continues to have effects,
such as lowering effects on peripheral lymphocyte count, for up to 3-4 weeks
after the last dose [see WARNINGS AND PRECAUTIONS].
Storage And Handling
Instruct patients to store any unopened containers of
MAYZENT in a refrigerator. Inform patients that opened starter packs may be
stored at room temperature for 1 week and opened bottles may be stored at room
temperature for 1 month [see HOW SUPPLIED/Storage And Handling].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Oral carcinogenicity studies of spinomod were conducted
in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for
up to 104 weeks, there was an increase in malignant lymphoma in females at all
doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all
doses in males and females. The lowest dose tested is approximately 5 times the
recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m²) basis.
In rats, administration of siponimod (0, 10, 30, or 90
mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to 104 weeks,
there was an increase in thyroid follicular cell adenoma and combined thyroid
follicular cell adenoma and carcinoma in males at the highest dose tested.
These findings are considered secondary to liver enzyme induction in rats and
are not considered relevant to humans. Plasma siponimod exposure (AUC) at the
highest dose tested is approximately 200 times that in humans at the RHD.
Siponimod was negative in a battery of in vitro (Ames,
chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse
and rat) assays.
Impairment Of Fertility
When siponimod was administered orally (0, 2, 20, or 200
mg/kg) to male rats (mated with untreated females) prior to and throughout the
mating period, there was a dose-related increase in precoital interval at all
doses. A decrease in implantation sites, an increase in preimplantation loss,
and a decrease in the number of viable fetuses were observed at the highest
dose tested. The higher no-effect dose for adverse effects on fertility (20
mg/kg) is approximately 100 times the RHD on a mg/m² basis.
When siponimod was administered orally (0, 0.1, 0.3, or 1
mg/kg) to female rats (mated with untreated males) prior to and during mating,
and continuing to Day 6 of gestation, no effects on fertility were observed up
to the highest dose tested (1 mg/kg). Plasma siponimod exposure (AUC) at the
highest dose tested is approximately 16 times that in humans at the RHD.
Use In Specific Populations
There are no adequate data on the developmental risk
associated with the use of MAYZENT in pregnant women. Based on animal data and
its mechanism of action, MAYZENT can cause fetal harm when administered to a
pregnant woman (see Data). Reproductive and developmental studies in
pregnant rats and rabbits have demonstrated MAYZENT-induced embryotoxicity and
fetotoxicity in rats and rabbits and teratogenicity in rats. Increased
incidences of post-implantation loss and fetal abnormalities (external,
urogenital and skeletal) in rat and of embryofetal deaths, abortions and fetal
variations (skeletal and visceral) in rabbit were observed following prenatal
exposure to siponimod starting at a dose 2 times the exposure in humans at the
highest recommended dose of 2 mg/day.
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.
When siponimod (0, 1, 5, or 40 mg/kg) was orally
administered to pregnant rats during the period of organogenesis, post
implantation loss and fetal malformations (visceral and skeletal) were
increased at the lowest dose tested, the only dose with fetuses available for
evaluation. A no-effect dose for adverse effects on embryofetal development in
rats was not identified. Plasma exposure AUC at the lowest dose tested was
approximately 18 times that in humans at the recommended human dose (RHD) of 2
When siponimod (0, 0.1, 1, or 5 mg/kg) was orally
administered to pregnant rabbits during the period of organogenesis,
embryolethality and increased incidences of fetal skeletal variations were
observed at all but the lowest dose tested. Plasma exposure (AUC) at the
no-effect dose (0.1 mg/kg) for adverse effects on embryofetal development in
rabbits is less that than in humans at the RHD.
When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally
administered to female rats throughout pregnancy and lactation, increased
mortality, decreased body weight, and delayed sexual maturation were observed
in the offspring at all but the lowest dose tested. An increase in
malformations was observed at all doses. A no-effect dose for adverse effects
on preand postnatal development in rats was not identified. The lowest dose
tested (0.05 mg/kg) is less than the RHD, on a mg/m² basis.
There are no data on the presence of siponimod in human
milk, the effects of MAYZENT on the breastfed infant, or the effects of the
drug on milk production. A study in lactating rats has shown excretion of
siponimod and/or its metabolites in milk. The developmental and health benefits
of breastfeeding should be considered along with the mother's clinical need for
MAYZENT and any potential adverse effects on the breastfed infant from MAYZENT
or from the underlying maternal condition.
Females And Males Of Reproductive Potential
Before initiation of MAYZENT treatment, women of
childbearing potential should be counselled on the potential for a serious risk
to the fetus and the need for effective contraception during treatment with
MAYZENT [see Use In Specific Populations]. Since it takes approximately
10 days 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 PRECAUTIONS].
Safety and effectiveness in pediatric patients have not
Clinical studies of MAYZENT did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
Before initiation of treatment with MAYZENT, test
patients to determine CYP2C9 genotype. MAYZENT is contraindicated in patients
homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately
0.4%0.5% of Caucasians and less in others, because of substantially elevated
siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients
with CYP2C9 *1/*3 or *2/*3 genotype because of an increase in exposure to
siponimod [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].