Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Liver Injury
Additions and/or
revisions underlined:
Clinically significant liver injury,
including acute liver failure requiring transplant, has occurred
in patients treated
with ZEPOSIA in the postmarketing setting.
Signs of liver
injury, including elevated
serum hepatic enzymes
and elevated total
bilirubin, have occurred as early as ten days after the
first dose.
In
MS Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal
(ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and
1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or
greater occurred in 5.5% of patients
treated with ZEPOSIA
and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%)
of patients continued treatment with ZEPOSIA with values returning to less than
3-fold the ULN within approximately 2-4 weeks. ZEPOSIA was discontinued
for a confirmed elevation greater than 5-fold the ULN. Overall, the
discontinuation rate because of elevations in hepatic enzymes was 1.1% of
patients with MS treated with ZEPOSIA 0.92 mg and 0.8% of patients who received
IFN beta-1a.
In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients
treated with ZEPOSIA 0.92 mg
and 0.5% of patients who received
placebo, and in UC Study 2 elevations occurred in 0.9% of patients and no
patients, respectively. In UC Study 1, elevations of ALT to 3-fold the ULN or greater occurred
in 2.6% of UC patients
treated with ZEPOSIA
0.92 mg and 0.5% of
patients who received placebo, and in UC Study 2 elevations occurred in 2.3% of
patients and no patients, respectively. In controlled and uncontrolled UC
studies, the majority (96%) of patients with ALT greater than 3-fold the ULN
continued treatment with ZEPOSIA with values returning to less than 3-fold the
ULN within approximately 2 to 4 weeks. Overall, the discontinuation rate
because of elevations in hepatic enzymes was 0.4% in patients treated with
ZEPOSIA 0.92 mg, and none in patients who received placebo in the controlled UC
studies.
Individuals with an AST or ALT greater than 1.5-fold
ULN were excluded from MS Study 1 and Study 2 and greater than 2 times the ULN
for UC Study 1 and Study 3. 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 ZEPOSIA. Dosage adjustment in patients with
mild or moderate hepatic impairment (Child-Pugh class
A or B) is required
[see Dosage and Administration (2.3)], and use of ZEPOSIA
in patients with severe
hepatic impairment (Child-Pugh class C) is not recommended [see Use in Specific Populations (8.6)]
Obtain transaminase and bilirubin levels, if not recently available (i.e.,
within 6 months), before initiation of ZEPOSIA. Obtain transaminase levels and total bilirubin levels
periodically during treatment and until two months after
ZEPOSIA discontinuation.
Patients should be monitored for signs and symptoms of
any hepatic injury.
Patients who develop symptoms suggestive of hepatic dysfunction, such as
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice
and/or dark urine, should have hepatic enzymes promptly
checked, and ZEPOSIA
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.
6
Adverse Reactions
6.2 Postmarketing
Experience
Newly added
subsection:
The following adverse
reactions have been identified during
postapproval use of ZEPOSIA. Because
these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish
a causal relationship to drug exposure.
Hepatobiliary Disorders: Liver injury [see Warnings
and Precautions (5.4)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or
revisions underlined:
…
What are the possible side effects of ZEPOSIA? ZEPOSIA may cause serious
side effects, including:
See “What is the most important information I should know about ZEPOSIA?”
liver problems. ZEPOSIA may cause liver
damage. Your healthcare provider will do blood tests to check
your liver before you start
taking ZEPOSIA and periodically during treatment. Call your healthcare
provider right away if you have any of the following symptoms:
…
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
…
Liver Injury
Inform patients
that ZEPOSIA may cause liver injury. Advise
patients that they should contact
their healthcare provider
if they have any unexplained nausea, vomiting, abdominal pain, fatigue,
anorexia, or jaundice and/or dark urine [see
Warnings and Precautions (5.4)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Progressive Multifocal Leukoencephalopathy
Additions and/or
revisions underlined:
…
PML has been reported in patients treated with S1P
receptor modulators, including ZEPOSIA, and other multiple sclerosis (MS) and
UC therapies and has been associated with some risk factors (e.g.,
immunocompromised patients, polytherapy with immunosuppressants, duration of
use). Based on data from patients with MS, longer treatment duration increases
the risk of PML in patients treated with S1P receptor modulators, and the
majority of PML cases have occurred in patients treated with S1P receptor
modulators for at least 18 months. 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 ZEPOSIA should be suspended until PML has been excluded by an
appropriate diagnostic evaluation.
…
5.8 Macular Edema
Additions and/or
revisions underlined:
S1P receptor
modulators, including ZEPOSIA, have been associated with an increased risk of
macular edema. Obtain a baseline evaluation of the fundus, including the
macula, near the start of treatment with ZEPOSIA. Perform an examination of the
fundus, including the macula, periodically while on therapy and any time there
is a change in vision.
…
Continuation of ZEPOSIA therapy in patients with
macular edema has not been evaluated. Macular edema over an extended period
of time (i.e., 6 months) can lead to permanent visual loss. Consider
discontinuing ZEPOSIA if macular edema develops; this decision should
include an assessment of the potential benefits and risks for the individual
patient. The risk of recurrence after rechallenge has not been evaluated.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Macular
Edema
Advise
patients that ZEPOSIA may cause macular edema, and that they should obtain
an eye exam near the start of treatment with ZEPOSIA, have their eyes monitored
periodically by an eye care professional while receiving therapy, and contact
their healthcare provider if they experience any changes in their vision while
taking ZEPOSIA. Inform patients with diabetes mellitus or a history of
uveitis that their risk of macular edema may be increased [see Warnings and Precautions (5.8)].
…
MEDICATION GUIDE
Additions
and/or revisions underlined:
…
What are the
possible side effects of ZEPOSIA?
ZEPOSIA may cause
serious side effects, including:
…
a problem with your vision called macular edema. Macular edema can cause some of the same vision symptoms as a multiple
sclerosis (MS) attack (optic neuritis). You may not
notice any symptoms with macular edema. Your healthcare provider should
test your vision around the time you start taking ZEPOSIA,
periodically while you continue taking ZEPOSIA, and at any time you notice
vision changes during treatment with ZEPOSIA.
Your risk for macular edema is higher if you have
diabetes or have had an inflammation of your eye called uveitis. Call your
healthcare provider right away if you have any of the following symptoms:
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Infections
(Extensive changes; please refer to labeling)
5.2 Bradyarrhythmia
and Atrioventricular Conduction Delays
(Additions and/or revisions underlined)
Reduction in Heart Rate
Initiation of ZEPOSIA may result in
a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg,
the greatest mean decrease from baseline in heart rate occurred at Hour 5 on
Day 1 (decrease of 1.2 bpm in MS Study 1 and Study 2, and 0.7 bpm in UC
Study 1 and Study 3), returning to near baseline at Hour 6. With continued
up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The
utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in
patients with characteristics similar to those studied in the clinical trials
of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation
of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2)].
In MS Study 1 and Study 2,
bradycardia was reported on the day of treatment initiation in 0.6% of patients
treated with ZEPOSIA compared to no patients who received IFN beta-1a. After
Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA
compared to 0.7% of patients who received IFN beta-1a. In UC Study 1 and
Study 3, bradycardia was reported on the day of treatment initiation in 1
patient (0.2%) treated with ZEPOSIA compared to none in patients who received
placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with
ZEPOSIA. In UC Study 2, bradycardia was not reported.
Atrioventricular Conduction
Delays
Initiation of ZEPOSIA may result in
transient atrioventricular conduction delays. At ZEPOSIA exposures higher than
the recommended dosage without dose titration, first- and second-degree type 1
atrioventricular blocks were observed in healthy volunteers; however, in MS
Study 1 and Study 2 and UC Study 1 and Study 3 with dose titration, Mobitz
type 2 second- or third- degree atrioventricular blocks were not reported
in patients treated with ZEPOSIA.
If treatment with ZEPOSIA is
considered, advice from a cardiologist should be sought for those individuals:
5.3 Liver Injury
(Additions and/or revisions underlined)
Obtain transaminase and bilirubin levels15T,15T if
not recently
available (i.e., within 6 months),
before initiation of ZEPOSIA.
In MS Study
1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or
greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of
patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater
occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who
received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6
months. The majority (79%) of patients continued treatment with ZEPOSIA with
values returning to less than 3 times the ULN within approximately 2-4 weeks.
ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN.
Overall, the discontinuation rate because of elevations in hepatic enzymes was
1.1% of patients with MS treated with ZEPOSIA 0.92 mg and 0.8% of
patients who received IFN beta-1a.
In UC Study 1, elevations of ALT
to 5-fold the ULN or greater occurred in 0.9% of patients treated with ZEPOSIA
0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations
occurred in 0.9% of patients and no patients, respectively. In UC Study 1,
elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients
treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in
UC Study 2 elevations occurred in 2.3% of patients and no patients,
respectively. In controlled and uncontrolled UC studies, the majority (96%) of
patients with ALT greater than 3-fold the ULN continued treatment with ZEPOSIA
with values returning to less than 3-fold the ULN within approximately 2 to 4
weeks. Overall, the discontinuation rate because of elevations in hepatic
enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg, and none in patients
who received placebo in the controlled UC studies.
Individuals with an AST or ALT
greater than 1.5 times ULN were excluded from MS Study 1 and Study 2 and
greater than 2 times the ULN for UC Study 1 and Study 3. 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 ZEPOSIA. Use of ZEPOSIA
in patients with hepatic impairment is not recommended [see Use in Specific Populations (8.6)].
5.5 Increased
Blood Pressure
(Additions and/or revisions underlined)
In MS
Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of
approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN
beta-1a, and no effect on diastolic pressure. The increase in systolic pressure
was first detected after approximately 3 months of treatment and persisted
throughout treatment. Hypertension was reported as an adverse reaction in 3.9%
of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received
IFN beta-1a. Two patients treated with ZEPOSIA in MS Study 1 and one
patient treated with interferon (IFN) beta-1a in Study 2 experienced a
hypertensive crisis that was not clearly influenced by a concomitant
medication.
The mean increase in systolic
blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated
with ZEPOSIA is similar to patients with MS. In UC Study 1 and Study 3, the
average increase from baseline in SBP was 3.7 mm Hg in patients treated with
ZEPOSIA and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the
average increase from baseline in SBP was 5.1 mm Hg in patients treated with
ZEPOSIA and 1.5 mm Hg in patients treated with placebo. There was no effect on
DBP.
Hypertension
was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA
0.92 mg and none in patients treated with placebo in UC Study 1 and Study 3, and
in 2.2% and 2.2% of patients in UC Study 2, respectively. Hypertensive crisis
was reported in two patients receiving ZEPOSIA and one patient receiving
placebo.
5.6 Respiratory
Effects
(Additions and/or revisions underlined)
Dose-dependent
reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MS
patients treated with ZEPOSIA as early as 3 months after treatment
initiation. In the MS pooled analyses of Study 1 and Study 2, the
decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who
received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean
difference in percent predicted FEV1 at 12 months between patients treated with
ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9,
-0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value
and %-predicted) were also seen at Month 3 in pooled analyses comparing
patients treated with ZEPOSIA to patients who received IFN beta-1a [60 mL, 95%
CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)], though significant reductions were
not seen at other timepoints.
There is insufficient
information to determine the reversibility of the decrease in FEV1 or FVC after drug
discontinuation. One patient in MS Study 1 discontinued ZEPOSIA
because of dyspnea.
In UC Study 1 the
mean difference in decline in absolute FEV1 from baseline in
patients treated with ZEPOSIA compared to patients who received placebo was 22
mL (95% CI: -84, 39) at 10 weeks. The mean difference in percent predicted
normal (PPN) FEV1 at
10 weeks between patients
treated with ZEPOSIA compared to those who received placebo was 0.8% (95% CI:
-2.6, 1.0). The difference in reductions in FVC (absolute value and
%-predicted) seen at Week 10 in UC Study 1, comparing patients who were treated
with ZEPOSIA to those who received placebo was 44 mL, 95% CI (-114, 26); 0.5%,
95% CI (-2.3, 1.2), respectively. There is insufficient information to determine the
reversibility of observed decreases in FEV1 or FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with
continued use.
5.7 Macular Edema
(Additions and/or revisions underlined)
Sphingosine 1-phosphate (S1P) receptor
modulators, including ZEPOSIA, have been associated with an increased risk of
macular edema.
In MS Study 1 and Study 2,
macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3%
of patients who received IFN beta-1a. Macular edema was reported in a total
of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%) patient in UC
Study 2 treated with ZEPOSIA, and in no patients who received placebo.
5.10 Severe Increase in Multiple Sclerosis Disability
after Stopping ZEPOSIA
(Additions and/or revisions underlined)
In MS, 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 ZEPOSIA treatment.
Patients should be observed for a severe increase in disability upon ZEPOSIA
discontinuation and appropriate treatment should be instituted, as required.
5.11 Immune System Effects after Stopping ZEPOSIA
(Additions and/or revisions underlined)
After discontinuing ZEPOSIA,
the median time for peripheral blood lymphocytes to return to the normal range
was approximately 30 days, with approximately 80% to 90% of
patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Use of immunosuppressants
within this period may lead to an additive effect on the immune system, and
therefore caution should be applied when initiating other drugs 4 weeks after
the last dose of ZEPOSIA [see Drug
Interactions (7)].
6
Adverse Reactions
(Additions and/or revisions underlined)
The
following serious adverse reactions are described elsewhere in the labeling:
6.1 Clinical
Trials Experience
(Additions and/or revisions
underlined)
Ulcerative Colitis
The safety of ZEPOSIA was
evaluated in two randomized, double-blind, placebo-controlled clinical studies
[UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult
patients with moderately to severely active ulcerative colitis [see Clinical Studies (14.2)].
Additional data from the induction period of a randomized, double-blind,
placebo-controlled study (UC Study 3, NCT01647516) included 67 patients who
received ZEPOSIA 0.92 mg once daily.
Common adverse reactions in
UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 3 and 4,
respectively. The most common adverse reactions that occurred in at least 4% of
ZEPOSIA-treated patients and greater than in patients who received placebo were
liver test increased, upper respiratory infection, and headache.
Other Adverse Reactions
Reduction in Heart Rate
Initiation of ZEPOSIA may result in transient
decrease in heart rate in MS and UC patients [see Warnings and Precautions (5.2)].
Respiratory Effects
Dose-dependent reductions
in absolute
FEVR1R and FVC were
observed in MS and UC
patients treated with ZEPOSIA [see Warnings
and Precautions (5.6)].
Malignancies
Malignancies,
such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical
carcinoma, and adenocarcinomas, including rectal adenocarcinoma, were
reported with ZEPOSIA in controlled trials of MS and UC. An increased
risk of cutaneous malignancies has been reported with another S1P receptor
modulator.
Hypersensitivity
Hypersensitivity, including rash
and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical
trials.
Peripheral
Edema
Peripheral
edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients
who received placebo in UC Study 2.
7
Drug Interactions
(Additions and/or revisions underlined)
Tables 5 and 6 include drugs with clinically important
drug, tyramine, and vaccine interactions when administered concomitantly with
ZEPOSIA and instructions for preventing or managing them.
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or revisions underlined)
Clinical studies of ZEPOSIA did not
include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. No clinically significant
differences in the pharmacokinetics of ozanimod and CC112273 were observed
based on age [see Clinical Pharmacology
(12.3)]. Monitor elderly patients for cardiac and hepatic adverse
reactions, because of the greater frequency of reduced cardiac and hepatic
function in the elderly population.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT
COUNSELING INFORMATION
(Additions and/or revisions underlined)
Infections
Inform patients that they may be
more likely to get infections, some of which could be life-threatening, when
taking ZEPOSIA and for 3 months after stopping it, and that they should contact
their healthcare provider if they develop symptoms of infection [see Warnings and Precautions (5.1)]. Inform
patients that prior or concomitant use of drugs that suppress the immune system
may increase the risk of infection. Advise patients that some vaccines
containing live virus (live attenuated vaccines) should be avoided during
treatment with ZEPOSIA. Advise patients that if immunizations are
planned, they should be administered at least 1 month prior to
initiation of ZEPOSIA. Inform patients that the use of live attenuated vaccines should be avoided
during and for 3 months after treatment with ZEPOSIA.
Medication Guide
(Additions and/or revisions underlined)
Before taking ZEPOSIA, tell your healthcare provider about all of your
medical conditions, including if you:
have a fever or infection, or you are unable to fight infections due to
a disease, or take or have taken medicines
that lower your immune system.
received a vaccine in the past 30 days
or are scheduled to receive a vaccine. ZEPOSIA may cause vaccines to be less
effective.
Before you start treatment with
ZEPOSIA, your healthcare provider may give you a chicken pox (Varicella Zoster Virus) vaccine if you have not had
one before.
Tell your healthcare provider
about all the medicines you take or have recently taken, including prescription and
over-the-counter medicines, vitamins, and herbal supplements. Using ZEPOSIA
with other medicines can cause serious side effects. Especially tell your
healthcare provider if you take or have taken:
medicines
that affect your immune system, such as alemtuzumab
medicines
to control your heart rhythm (antiarrhythmics), or heart beat
CYP2C8
inducers such as rifampin
CYP2C8
inhibitors such as gemfibrozil (medicine to treat high fat in your blood)
opioids
(pain medicine)
medicines
to treat depression
medicines
to treat Parkinson’s disease
medicines
to control your heart rate and blood pressure (beta blocker medicines and
calcium channel blocker medicines)
Get Email Alerts |
Guide
