Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
Additions
and/or revisions underlined:
The
following adverse reactions have been identified during post-approval use of
NINLARO. 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.
Immune
system disorders: Angioedema
Skin
and subcutaneous tissue disorders: Toxic epidermal necrolysis
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information
Additions and/or revisions underlined:
NINLARO
may cause serious side effects, including:
…
Swelling. Swelling is common with NINLARO and can sometimes be severe. Tell your
healthcare provider if you develop swelling in your face, arms, hands,
legs, ankles, or feet, or if you gain weight from swelling.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Cutaneous Reactions
Additions
and/or revisions underlined:
…
Stevens-Johnson syndrome and toxic epidermal
necrolysis, including fatal cases, have been reported with NINLARO [see
Adverse Reactions (6.1, 6.2)]. If Stevens-Johnson syndrome or toxic
epidermal necrolysis occurs, discontinue NINLARO and manage as clinically
indicated.
6
Adverse Reactions
6.2 Postmarketing Experience
New
subsection added:
The following adverse reactions have been identified
during post-approval use of NINLARO. 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.
Skin and subcutaneous tissue disorders: Toxic
epidermal necrolysis.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Thrombocytopenia
Additions
and/or revisions underlined
Thrombocytopenia
has been reported with NINLARO with platelet nadirs typically occurring between
Days 14-21 of each 28-day cycle and recovery to baseline by the start of the
next cycle [see Adverse Reactions
(6.1)]. Grade 3 thrombocytopenia was reported in 17% of
patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in
13% in the NINLARO regimen. The rate of platelet transfusions was 10%
in the NINLARO regimen and 7% in the placebo regimen.
…
5.2 Gastrointestinal Toxicities
Additions
and/or revisions underlined
Diarrhea,
constipation, nausea, and vomiting have been reported with NINLARO,
occasionally requiring use of antidiarrheal and antiemetic medications, and
supportive care. Diarrhea was reported in 52% of patients in the NINLARO
regimen and 43% in the placebo regimen, constipation in 35% and 28%,
respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%,
respectively. Diarrhea resulted in discontinuation of one or more of the three
drugs in 3% of patients in the NINLARO regimen and 2% of patients in
the placebo regimen [see Adverse
Reactions (6.1)]. Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].
5.3 Peripheral Neuropathy
Additions
and/or revisions underlined
The
majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the
NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in
the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 adverse reactions of
peripheral neuropathy were reported at 2% in both regimens.
The
most commonly reported reaction was peripheral sensory neuropathy (24% and 17%
in the NINLARO and placebo regimen, respectively). Peripheral motor
neuropathy was not commonly reported in either regimen (< 1%). Peripheral
neuropathy resulted in discontinuation of one or more of the three drugs in 4%
of patients in the NINLARO regimen and <1% of patients in the placebo
regimen. Patients should be monitored for symptoms of neuropathy. Patients
experiencing new or worsening peripheral neuropathy may require dose
modification [see Dosage and
Administration (2.2)].
5.4 Peripheral Edema
Additions and/or
revisions underlined
Peripheral edema was reported in 27% and 21%
of patients in the NINLARO and placebo regimens, respectively. The majority
of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO
regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO
regimen and 6% in the placebo regimen).
Grade 3 peripheral edema was reported in 2% and 1%
of patients in the NINLARO and placebo regimens, respectively [see
Adverse Reactions (6.1)]. Peripheral edema resulted in
discontinuation of one or more of the three drugs in <1% of patients in both
regimens. Evaluate for underlying causes and provide supportive care, as
necessary. Adjust dosing of dexamethasone per its prescribing information or
NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].
5.5 Cutaneous Reactions
Additions
and or revisions underlined
Rash
was reported in 27% of patients in the NINLARO regimen and 16% of
patients in the placebo regimen. The majority of the rash adverse reactions
were Grade 1 (15% in the NINLARO regimen and 9% in the placebo
regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the
placebo regimen) [see Adverse Reactions
(6.1)]. Grade 3 rash was reported in 3% of patients in the NINLARO regimen
and 2% of patients in the placebo regimen. Serious adverse
reactions of rash were reported in <1% of patients in the NINLARO
regimen. The most common type of rash reported in both regimens included
maculo-papular and macular rash.…
Stevens-Johnson
syndrome, including a fatal case, has been reported with NINLARO [see Adverse Reactions (6.1)]. If
Stevens-Johnson syndrome occurs, discontinue NINLARO and manage as clinically
indicated.
5.7 Hepatotoxicity
Additions
underlined
Drug-induced
liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic
and hepatotoxicity have each been reported in < 1% of patients treated with
NINLARO [see Adverse Reactions (6.1)].
Hepatotoxicity has been reported (10% in the NINLARO regimen and 9%
in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing
for Grade 3 or 4 symptoms [see Dosage and
Administration (2.2)].
![]()
5.9 INew subsection addedncreased Mortality in Patients Treated with NINLARO in the Maintenance Setting
New
subsection added
In
two prospective randomized clinical trials in multiple myeloma in the
maintenance setting, treatment with NINLARO resulted in increased deaths.
Treatment of patients with NINLARO for multiple myeloma in the maintenance
setting is not recommended outside of controlled trials [see Clinical Studies (14.2)].
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and or revisions, please refer to label
for complete information.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
underlined
…
Other
Adverse Reactions
Advise
patients to contact their healthcare providers if they experience signs and
symptoms of acute febrile neutrophilic dermatosis (Sweet’s syndrome),
Stevens-Johnson syndrome, transverse myelitis,posterior reversible encephalopathy
syndrome, tumor lysis syndrome, herpes zoster, cataracts, dry eyes, blurred
vision, conjunctivitis and thrombotic thrombocytopenic purpura [see Adverse Reactions
…
PATIENT
INFORMATION
Additions underlined
…
What
is NINLARO?
NINLARO is a prescription medicine used to treat
multiple myeloma in combination with the medicines REVLIMID®
(lenalidomide) and dexamethasone, in people who have received at least one
prior treatment for their multiple myeloma.
NINLARO should not be used to treat people:
who are receiving
maintenance treatment, or
who have been newly
diagnosed with multiple myeloma, unless they are participants in a controlled
clinical trial.
…
What
are the possible side effects of NINLARO?
NINLARO
may cause serious side effects, including:
…
Skin reactions. Rashes are
common with NINLARO. NINLARO can cause rashes and other skin reactions
that can be serious and can lead to death. Tell your healthcare provider right
away if you get a new or worsening rash, severe blistering or peeling of
the skin, or mouth sores.
…
Other common side
effects of NINLARO include:
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Cutaneous Reactions
Additions
and or revisions underlined
Rash
was reported in 27% of patients in the NINLARO regimen and 16% of
patients in the placebo regimen. The majority of the rash adverse reactions
were Grade 1 (15% in the NINLARO regimen and 9% in the placebo
regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the
placebo regimen) [see Adverse Reactions
(6.1)]. Grade 3 rash was reported in 3% of patients in the NINLARO regimen
and 2% of patients in the placebo regimen. Serious adverse
reactions of rash were reported in <1% of patients in the NINLARO regimen.
The most common type of rash reported in both regimens included maculo-papular
and macular rash.…
Stevens-Johnson
syndrome, including a fatal case, has been reported with NINLARO [see Adverse Reactions (6.1)]. If
Stevens-Johnson syndrome occurs, discontinue NINLARO and manage as clinically
indicated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions underlined
…
What
are the possible side effects of NINLARO?
NINLARO
may cause serious side effects, including:
…
- Skin
reactions.
Rashes are common with NINLARO. NINLARO can cause rashes and other skin
reactions that can be serious and can lead to death. Tell your
healthcare provider right away if you get a new or worsening rash, severe
blistering or peeling of the skin, or mouth sores.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.8 Embryo-Fetal Toxicity
Additions underlined
NINLARO can cause fetal harm when administered to a
pregnant woman based on the mechanism of action and findings in animal
studies. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits
at doses resulting in exposures that were slightly higher than those observed
in patients receiving the recommended dose. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to use
effective non-hormonal contraception during treatment with NINLARO and
for 90 days following the final dose. Advise males with female partners of
reproductive potential to use effective contraception during treatment with
NINLARO and for 90 days following the final dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1, 8.3)].
8
Use in Specific Populations
8.3 Females and Males of Reproductive Potential
Additions
underlined
NINLARO
can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy
Testing
Verify
pregnancy status in females of reproductive potential prior to
initiating NINLARO. Contraception
Females
Advise
females of reproductive potential to use effective non-hormonal
contraception during treatment with NINLARO and for 90 days after the
final dose. Dexamethasone is known to be a weak to moderate inducer of
CYP3A4 as well as other enzymes and transporters. Because NINLARO is
administered with dexamethasone, the risk for reduced efficacy of
contraceptives needs to be considered [see
Drug Interactions (7.1)].
Males
Advise
males with female partners of reproductive potential to use effective
contraception during treatment with NINLARO and for 90 days after the final
dose.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
underlined
…
Dosing
Instructions
Instruct
patients to take NINLARO exactly as prescribed.
Advise
patients to take NINLARO once a week on the same day and at approximately the same
time for the first three weeks of a fourweek cycle. The importance of
carefully following all dosage instructions should be discussed with patients
starting treatment. Advise patients to take the recommended dosage as directed,
because overdosage has led to deaths [see
Overdosage (10)].
…
Embryo-Fetal
Toxicity
Advise
pregnant women and females of reproductive potential of the
potential risk to a fetus. Advise females of reproductive potential to inform
their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use
in Specific Populations (8.1)].
Advise
females of reproductive potential to use effective contraception during
treatment
with NINLARO and for 90 days following the final dose. Advise women using
hormonal contraceptives to also use a barrier method of contraception [see Use in Specific Populations (8.1)].
Advise
males with
female partners of reproductive potential to use effective contraception during
treatment with NINLARO and for 90 days following the final dose [see Use in Specific Populations (8.1)].
Lactation
Advise
women not to breastfeed during treatment with NINLARO and for 90 days after the
final dose
[see Use in
Specific Populations (8.2)].
…
PATIENT INFORMATION
Additions
underlined
…
Before taking
NINLARO, tell your healthcare provider about all of your medical conditions,
including if you:
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Thrombotic Microangiopathy
(new subsection
added)
Cases,
sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic
purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who
received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis
is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded,
consider restarting NINLARO. The safety of reinitiating NINLARO therapy in
patients previously experiencing TTP/HUS is not known.
6
Adverse Reactions
(addition
underlined)
…
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions underlined)
…
Thrombotic
Microangiopathy
Advise
patients to seek immediate medical attention if any signs or symptoms of
thrombotic microangiopathy occur.
…
PATIENT INFORMATION
(additions
underlined)
…
What are the
possible side effects of NINLARO?
NINLARO may cause
serious side effects, including:
…
Thrombotic
microangiopathy (TMA). This is a condition involving blood
clots and injury to small blood vessels that may cause harm to your kidneys,
brain, and other organs, and may lead to death. Get medical help right away if
you get any of the following signs or symptoms during treatment with NINLARO:
o fever
o bruising
o nose bleeds
o tiredness
o decreased urination”
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Embryo-Fetal Toxicity (addition underlined)
NINLARO can cause fetal harm
when administered to a pregnant woman based on the mechanism of action and
findings in animals. There are no adequate and well-controlled studies in
pregnant women using NINLARO. Ixazomib caused embryo-fetal toxicity in pregnant
rats and rabbits at doses resulting in exposures that were slightly higher than
those observed in patients receiving the recommended dose.
Females of reproductive potential should be advised
to avoid becoming pregnant while being treated with NINLARO. If NINLARO is used
during pregnancy or if the patient becomes pregnant while taking NINLARO, the
patient should be apprised of the potential hazard to the fetus. Advise females
of reproductive potential that they must use effective contraception during
treatment with NINLARO and for 90 days following the final dose. Women using
hormonal contraceptives should also use a barrier method of contraception.
6
Adverse Reactions
6.1 Clinical Trials Experience (addition underlined)
Herpes Zoster
Herpes zoster was reported
in 4% of patients in the NINLARO regimen and 2% of patients in the placebo
regimen. Antiviral prophylaxis was allowed at the physician’s discretion.
Patients treated in the NINLARO regimen who received antiviral prophylaxis had
a lower incidence (< 1%) of herpes zoster infection compared to patients who
did not receive prophylaxis (6%).
8
Use in Specific Populations
8.1 Pregnancy (addition underlined)
Risk Summary
Based on its
mechanism of action and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a
pregnant woman. There are no human data available regarding the potential
effect of NINLARO on pregnancy or development of the embryo or fetus. Ixazomib
caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in
exposures that were slightly higher then those observed in patients receiving
the recommended dose [see Data]. Advise
women of the potential risk to a fetus and to avoid becoming pregnant while
being treated with NINLARO.
In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In an embryo-fetal development
study in pregnant rabbits there were increases in fetal skeletal
variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae,
and full supernumerary ribs) at doses that were also maternally toxic (greater than or equal to 0.3
mg/kg). Exposures in the rabbit at 0.3 mg/kg were
1.9 times the clinical time
averaged exposures at the recommended dose of 4 mg. In a rat dose range-
finding embryo-fetal development study, at doses that were maternally toxic,
there were decreases in fetal weights, a trend towards decreased fetal
viability, and increased post-implantation losses at 0.6 mg/kg. Exposures in
rats at the dose of 0.6 mg/kg was 2.5 times the clinical time averaged
exposures at the recommended dose of 4 mg.
8.2 Lactation (addition underlined)
Risk Summary
No data are
available regarding the presence of NINLARO
or its metabolites in human milk, the effects of the drug on the breast fed
infant, or the effects of the drug on milk production. Because the
potential for serious adverse reactions from NINLARO in breastfed
infants is unknown, advise nursing women not to breastfeed during
treatment with NINLARO and for 90 days after the last dose.
8.3 Females and Males of Reproductive Potential (addition underlined)
Contraception
Male and female patients of
childbearing potential must use effective contraceptive measures during and for
90 days following treatment. Dexamethasone is known to be a weak to moderate
inducer of CYP3A4 as well as other enzymes and transporters. Because NINLARO is
administered with dexamethasone, the risk for reduced efficacy of
contraceptives needs to be considered. Advise women using hormonal
contraceptives to also use a barrier method of contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNCELING INFORMATION
(addition underlined)
Other Adverse Reactions
Advise patients to
contact their physicians if they experience signs and symptoms of acute febrile
neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome,
transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis
syndrome, and thrombotic thrombocytopenic purpura
Pregnancy
Advise women of the potential
risk to a fetus and to avoid becoming pregnant while being treated with NINLARO
and for 90 days following the final dose. Advise women using hormonal
contraceptives to also use a barrier method of contraception. Advise
patients to contact their physicians immediately if they or their female
partner become pregnant during treatment or within 90 days of the final dose.
PATIENT INFORMATION
Patient Information was updated for consistency with
language in the USPI. Please refer to label.
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