Download a guide to managing adverse reactions - NINLARO

A GUIDE TO MANAGING
ADVERSE REACTIONS
WITH NINLARO® (ixazomib)
NINLARO is indicated in combination with lenalidomide and dexamethasone for the
treatment of patients with multiple myeloma who have received at least one prior therapy.
TOURMALINE-MM1: a global, phase 3, randomized (1:1), double-blind, placebo-controlled study that evaluated the safety and efficacy of
NINLARO (an oral proteasome inhibitor) vs placebo, both in combination with lenalidomide and dexamethasone, until disease progression
or unacceptable toxicity in 722 patients with relapsed and/or refractory multiple myeloma who received 1-3 prior lines of therapy.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
• Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more
frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per
standard medical guidelines. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and
typically recovered to baseline by the start of the next cycle.
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
DOSE MODIFICATION
IMPORTANT
SAFETY INFORMATION
GUIDELINES FOR
(CONTINUED)
THE
NINLARO® (ixazomib) REGIMEN
• Hepatotoxicity has been reported with NINLARO. DrugWARNINGS
ANDTOXICITIES
PRECAUTIONS (CONTINUED)
HEMATOLOGIC
RECOMMENDED ACTIONS
induced liver injury, hepatocellular injury, hepatic steatosis,
• Gastrointestinal Toxicities, including diarrhea, constipation,
Thrombocytopenia
(platelet
hepatitis cholestatic and hepatotoxicity have each been
nausea and vomiting,
werecount)
reported with NINLARO and may
3
3
reported until
in < platelet
1% of patients
NINLARO.
Events
occasionally
use of antidiarrheal
and NINLARO
antiemeticand lenalidomide
• Withhold
count istreated
at leastwith
30,000/mm
Platelet
count require
less thanthe
30,000/mm
of
liver
impairment
have
been
reported
(6%
in
the
medications, and supportive care. Diarrhea
resulted
in
the
• Following recovery, resume lenalidomide at the next lower dose according to its NINLARO
regimen
and 5% in
placebo
regimen).
discontinuation of one or more of the three
drugs Information
in 1% of
Prescribing
and resume
NINLARO
atthe
its most
recent
dose Monitor hepatic
enzymes
regularly
during
treatment
and adjust
dosing
patients in the NINLARO regimen and• <
1% of patients
in the
3
again,
withhold
NINLARO
and lenalidomide
If platelet
count falls
to less than
30,000/mm
as
needed.
placebo regimen. Adjust dosing for severe
symptoms.
3
until platelet count is at least 30,000/mm
• Embryo-fetal Toxicity: NINLARO can cause fetal harm.
• Peripheral Neuropathy (predominantly sensory) was
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide
Women should be advised of the potential risk to a fetus, to
reported with NINLARO. The most commonly reported
at its most recent dose*
avoid becoming pregnant, and to use contraception during
reaction was peripheral sensory neuropathy (19% and 14%
Neutropenia
(absolute
treatment and for an additional 90 days after the final dose
in the NINLARO
and neutrophil
placebo regimens, respectively).
count)
of NINLARO. Women using hormonal contraceptives should
Peripheral motor neuropathy was not commonly reported
also use a barrier method of contraception.
in either regimen (< 1%). Peripheral neuropathy resulted in
Absolute neutrophil count less than • Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3.
discontinuation
of one or more of the three
drugs
in 1% G-CSF
of
3
Consider
adding
as per clinical guidelines
500/mm
patients in both regimens. Monitor patients for symptoms
REACTIONS
• Following
recovery, resumeADVERSE
lenalidomide
at the next lower dose according to its
of peripheral neuropathy and adjust dosing
as needed.
The
most
common
adverse
reactions
(≥ 20%) in the NINLARO
Prescribing
Information
and
resume
NINLARO
at
its most
recent dose
• Peripheral Edema was reported with NINLARO. Monitor
regimen and greater than3 the placebo regimen, respectively,
• If absolute
neutrophil
falls to less than 500/mm again, withhold NINLARO and
for fluid retention. Investigate for underlying
causes
when countwere
diarrhea (42%, 36%), constipation (34%, 25%),
lenalidomide
untilAdjust
absolute neutrophil count is at least 500/mm3
appropriate and provide supportive care
as necessary.
thrombocytopenia (78%, 54%; pooled from adverse events
• Following
recovery, or
resumeand
NINLARO
at the
next peripheral
lower dose neuropathy
and resume (28%,
lenalidomide
dosing of dexamethasone per its prescribing
information
laboratory
data),
21%), at
NINLARO for Grade 3 or 4 symptoms. its most recent dose*
nausea (26%, 21%), peripheral edema (25%, 18%), vomiting
• Cutaneous Reactions: Rash, most commonly maculo-papular
(22%, 11%), and back pain (21%, 16%). Serious adverse reactions
and macular rash, was reported with NINLARO. Rash resulted
reported in ≥ 2% of patients included thrombocytopenia (2%)
in maculo-papular
discontinuation
of one or more of the three drugs in < 1% of and
2
diarrhea
(2%).
Rash
Peripheral
sensory
neuropathy2
patients
in both regimens.
Manage
rash with
supportive
care
Grade
2: macules/papules
covering 10-30%
body surface
area (BSA)
with or without
Grade 1: asymptomatic; loss of deep tendon reflexes or paresthesia.
symptoms
pruritus,
burning,
tightness); limiting instrumental activities of daily
Grade 2: moderate symptoms; limiting instrumental ADL.
or with(eg,
dose
modifi
cation.
DRUG INTERACTIONS: Avoid concomitant administration of
living (ADL).
Grade 3: macules/papules covering >30% BSA with or without associated
symptoms-limiting self-care ADL.
Grade 3: severe symptoms; limiting self-care ADL.
NINLARO
with strong
CYP3Aurgent
inducers.
Grade 4: life-threatening
consequences;
intervention indicated.
For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.
2
6
SPECIAL
POPULATIONS
NONHEMATOLOGIC
TOXICITIES
RECOMMENDED ACTIONS
Rash
3
Grade† 2 orHEPATIC
IMPAIRMENT
• Withhold RENAL
lenalidomide until rash recovers to grade 1 or lower
LACTATION
• Following
recovery, resume lenalidomide
at the next lower dose according to its
IMPAIRMENT
Prescribing Information
• If grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to
grade 1 or lower
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its
most recent dose*
Grade 4
Reduce theNeuropathy
starting dose of
Peripheral
NINLARO to 3 mg in patients
Grade 1 peripheral neuropathy
with moderate or severe hepatic
with pain or grade 2 peripheral
impairment.
neuropathy
• Discontinue treatment regimen
Reduce the starting dose of
Advise nursing women not to
NINLARO to 3 mg in patients
breastfeed during treatment
• Withhold NINLARO until peripheral neuropathy recovers to grade 1 or lower without pain
with severe renal impairment
with NINLARO and for 90 days
or patient’s baseline
or end-stage renal disease
after the
lastmost
dose.recent dose
• Following recovery, resume NINLARO
at its
requiring dialysis.
Grade 2 peripheral neuropathy
• Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s
with pain or grade 3 peripheral
baseline condition or grade 1 or lower prior to resuming NINLARO
neuropathy
• Following recovery, resume NINLARO at the next lower dose
Contraception:
Maleneuropathy
and female patients
of childbearing
potentialregimen
must use effective contraceptive measures
Grade 4 peripheral
• Discontinue
treatment
during, and for 90 days following, treatment.
OTHER NONHEMATOLOGIC
TOXICITIES
RECOMMENDED ACTIONS
is not dialyzable
and
therefore
can be
administered
Other grade 3NINLARO
or 4
• Withhold
NINLARO.
Toxicities
should,
at the physician’s discretion, generally recover to patient’s
nonhematologic
toxicities
baseline
or grade 1 or lower prior to resuming NINLARO
without
regard to the
timingcondition
of dialysis.
• If attributable to NINLARO, resume NINLARO at the next lower dose following recovery
*For additional occurrences, alternate dose modification of lenalidomide and NINLARO.
Grading based on National Cancer Institute Common Terminology Criteria Version 4.03.
Please
Information on
on pages
pages 1-2
1-2 and
and accompanying
accompanying full
full Prescribing
Prescribing Information.
Information.
Please see
see Important
Important Safety
Safety Information
SAFETY PROFILE
PREPARE PATIENTS FOR SIDE EFFECTS
AND DOSING CONCERNS
Nonhematologic ARs occurring in 5% of patients with a 5% difference between the
NINLARO regimen* and the placebo regimen†
Placebo+len+dex
(n=360)
All grades
Grade 3
Difference
(n=360)
Grade 4
All grades
Grade 3
Grade 4
GI toxicity: diarrhea
<1%
0
14%
<1%
0
5%
Peripheral neuropathies
28%
2%
0
21%
2%
0
7%
Diarrhea
42%
6%
0
36%
2%
0
6%
Constipation
34%
<1%
0
25%
<1%
0
9%
Nausea
26%
2%
0
21%
0
0
5%
Vomiting
22%
1%
0
11%
<1%
0
11%
Rash
‡
19%
3%
0
11%
1%
0
8%
Back pain
21%
<1%
0
16%
3%
0
5%
Peripheral edema
25%
2%
0
18%
1%
0
7%
Discontinuation rates of the full regimen due to ARs1
Antidiarrheal (eg, loperamide)
40
GI
toxicity: nausea/vomitingfollowed aProphylaxis
or symptomatic
Thrombocytopenia
cyclical pattern,
3
with platelet nadirs generally occurring between
daysinfection:
14-21 of
a 28-day
Viral
herpes
zoster cycle and recovering to
baseline by
the
start
of the next
cycle. or symptomatic
Prophylaxis
4
(reactivation)
Prophylaxis (subsequent cycles)
or symptomatic
Rash
Additional
Safety information
• NINLARO did not prolong the QTc interval at clinically
5
*NINLARO+lenalidomide
+dexamethasone.
†Placebo+lenalidomide
+dexamethasone.
‡Represents a pooling of
preferred terms.
ARs=adverse reactions.
relevant exposures
• Incidence of eye disorders§ with NINLARO vs placebo: all grades,
26% vs 16%;
grade
3, 2%6 vs 1%, respectively Prophylaxis or symptomatic
Bacterial
infection
• The majority of peripheral neuropathy ARs were grade 1
(18% vs 14%, respectively)
20
0
Antiemetics, antinauseants
(eg, ondansetron)
Direct-acting antivirals
(eg, acyclovir,
13valacyclovir)11
Antihistamines
NINLARO(eg,
regimen
(n=360) or corticosteroids
Placebo+len+dex regimen (n=360)
cetirizine)
(oral or topical; eg, prednisone, betamethasone)
80% of patients Antibacterials
continued at the 4-mg starting
dose of NINLARO without dose reduction.1
• Prophylaxis (eg, sulfonamides, trimethoprim)
• Symptomatic (eg, beta-lactam antibacterials, penicillins)
- Peripheral
neuropathy grade 3 ARs were 2% in both regimens;
The above medications and supportive therapies are examples of appropriate supportive care
no grade
4 or
serious
ARs
reported
that was
permitted
in the
phase
3 trial.
Encourage patients and caregivers to report any side effects
early so appropriate management measures can be taken.
Most commonly reported as blurred vision, dry eye, and conjunctivitis.
Serious ARs
• Serious ARs reported in 2% of patients in the NINLARO regimen included thrombocytopenia (2%) and diarrhea (2%)
§
4
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
SUPPORTIVE
CARE
19%
Recommendation
Symptomatic
3
All grades
Upper respiratory tract infection
‡
placebo regimens: all grades, 78% vs 54%, respectively; grades 3-4,
26% vs 11%, respectively
Condition
Prophylaxis/symptomatic
• Incidence of neutropenia: all grades, 67% vs 66%, respectively;
grades 3-4, 26% vs 30%, respectively
Discontinuation
rates (%)
NINLARO regimen
AR
PooledConcomitant
hematologicmedications
adverse events
data
The NINLARO®
(ixazomib)
regimen represented
mayand
be laboratory
given for prophylaxis
and/or
management
of symptoms
• Incidence of thrombocytopenia in patients in the NINLARO and
a sustainable treatment for patients
PREPARE PATIENTS FOR SIDE EFFECTS
AND DOSING CONCERNS
Concomitant medications may be given for prophylaxis and/or management of symptoms
Recommendation
Symptomatic
Antidiarrheal (eg, loperamide)
GI toxicity: nausea/vomiting3
Prophylaxis or symptomatic
Antiemetics, antinauseants
(eg, ondansetron)
Viral infection: herpes zoster
(reactivation)4
Prophylaxis or symptomatic
Direct-acting antivirals
(eg, acyclovir, valacyclovir)
Prophylaxis (subsequent cycles)
or symptomatic
Antihistamines
(eg, cetirizine) or corticosteroids
(oral or topical; eg, prednisone, betamethasone)
Prophylaxis or symptomatic
Antibacterials
• Prophylaxis (eg, sulfonamides, trimethoprim)
• Symptomatic (eg, beta-lactam antibacterials, penicillins)
GI toxicity: diarrhea3
Rash
5
Bacterial infection6
The above medications and supportive therapies are examples of appropriate supportive care
that was permitted in the phase 3 trial.
Encourage patients and caregivers to report any side effects
early so appropriate management measures can be taken.
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
SUPPORTIVE
CARE
Prophylaxis/symptomatic
Condition
AVAILABLE
IMPORTANT
DOSE MODIFICATION
NINLARO®
SAFETY INFORMATION
(ixazomib)
GUIDELINES
STRENGTHS
(CONTINUED)
FOR THE
NINLARO® (ixazomib) REGIMEN
• Hepatotoxicity has been reported with NINLARO. DrugWARNINGS
AND PRECAUTIONS
(CONTINUED)
HEMATOLOGIC
TOXICITIES
RECOMMENDED ACTIONS
Recommended
induced
injury,
hepatocellular
injury, hepatic
steatosis,
• Gastrointestinal Toxicities, includingFirst
diarrhea,
constipation,
Secondliver
dose
reduction
If toxicities
continue
dose
reduction
Thrombocytopenia
count) with NINLARO and may
starting
dose(platelet
hepatitis cholestatic and hepatotoxicity have each been
nausea
and vomiting,
were reported
3
reported inuntil
< 1%platelet
of patients
with
NINLARO.3 Events
occasionally
require
the 30,000/mm
use of antidiarrheal
and antiemetic
• Withhold
NINLARO and lenalidomide
counttreated
is at least
30,000/mm
Platelet count
less than
of
liver
impairment
have
been
reported
(6%
into
the
medications, and supportive care. Diarrhea
resulted
in
the
• Following recovery, resume lenalidomide at the next lower dose according
itsNINLARO
5% in the
placebo
regimen).
discontinuation of one or more of the three
drugs inInformation
1% of
Prescribing
andregimen
resume and
NINLARO
at its
most recent
dose Monitor hepatic
regularly3 again,
duringwithhold
treatment
and adjust
patients in the NINLARO regimen and <• 1%
of patients
theto lessenzymes
NINLARO
anddosing
lenalidomide
If platelet
countinfalls
than 30,000/mm
as
needed.
placebo regimen. Adjust dosing for severe
symptoms.
3
until platelet count is at least 30,000/mm
• Embryo-fetal Toxicity: NINLARO can cause fetal harm.
• Peripheral Neuropathy (predominantly sensory) was
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide
Women should be advised of the potential risk to a fetus, to
reported with NINLARO. The most commonly reported
at its most recent dose*
avoid becoming pregnant, and to use contraception during
reaction was peripheral sensory neuropathy (19% and 14%
(absolute
neutrophil
treatment and for an additional 90 days after the final dose
inNeutropenia
the NINLARO
and placebo
regimens, respectively).
count)
of NINLARO. Women using hormonal contraceptives should
Peripheral
motor neuropathy was not commonly reported
also use a barrier method of contraception.
in either regimen (< 1%). Peripheral neuropathy resulted in
• Withhold
NINLARO
and lenalidomide until absolute neutrophil count
is at least 500/mm3.
Absolute neutrophil count less than
Discontinue
starting
dose
discontinuation
of one or more ofRecommended
the three
drugs
in 1%
ofG-CSF as per clinical guidelines
Consider
adding
500/mm3
forpatients
patients with:
NINLARO.
patients in both regimens. Monitor
for symptoms
ADVERSE
REACTIONS
• Following
recovery, resume
lenalidomide
at the next lower dose according to its
• Moderate
oras
severe
of peripheral neuropathy and adjust
dosing
needed.
Theresume
most common
adverse
reactions
20%) in the NINLARO
Prescribing
Information and
NINLARO
at its most
recent(≥
dose
hepatic
impairment*
• Peripheral Edema was reported with
NINLARO.
Monitor
regimen and greater than the
placebo regimen, respectively,
3
†
If absolute
neutrophil
count falls to less than 500/mm again, withhold NINLARO and
Severe•renal
impairment
for fluid retention. Investigate for•underlying
causes
when
were diarrhea (42%, 36%), constipation (34%, 25%),
until
absolute neutrophil count is at least 500/mm3
• End-stage
disease,
appropriate and provide supportive
care lenalidomide
asrenal
necessary.
Adjust
thrombocytopenia (78%, 54%; pooled from adverse events
• Following
recovery,
at data),
the next
lower dose
and resume
lenalidomide
at
requiring
dialysis
dosing of dexamethasone per its prescribing
information
or resume
andNINLARO
laboratory
peripheral
neuropathy
(28%,
21%),
NINLARO for Grade 3 or 4 symptoms. its most recent dose*
nausea (26%, 21%), peripheral edema (25%, 18%), vomiting
• Cutaneous Reactions: Rash, most commonly maculo-papular
(22%, 11%), and back pain (21%, 16%). Serious adverse reactions
and macular rash, was reported with NINLARO. Rash resulted
reported in ≥ 2% of patients included thrombocytopenia (2%)
in
discontinuation
and
diarrhea
(2%).
Rash
maculo-papular2 of one or more of the three drugs in < 1% of
Peripheral
sensory
neuropathy2
patients
in both regimens.
Manage
rash
with
Grade 2: macules/papules
covering 10-30%
body
surface
areasupportive
(BSA) with or care
without
Grade 1: asymptomatic; loss of deep tendon reflexes or paresthesia.
symptoms
(eg, pruritus,
burning,
tightness); limiting instrumental activities of daily
Grade 2: moderate symptoms; limiting instrumental ADL.
or
with dose
modifi
cation.
DRUG INTERACTIONS: Avoid concomitant administration of
DOSE
MODIFICATIONS
4mg
3mg
living (ADL).
*Hepatic
impairment: moderate, bilirubin >1.5-3x ULN; severe, bilirubin >3x ULN.
Graderenal
3: macules/papules
coveringclearance
>30% BSA
with
or without associated
†Severe
impairment: Creatinine
<30
mL/min.
symptoms-limiting self-care ADL.
2.3mg
Grade 3: severe symptoms; limiting self-care ADL.
NINLARO
with strong
CYP3A inducers.
Grade 4: life-threatening
consequences;
urgent intervention indicated.
Please see section 2 (Dosing and Administration) of the NINLARO full Prescribing Information.
For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
2 6
SPECIAL POPULATIONS
NONHEMATOLOGIC
TOXICITIES
RECOMMENDED ACTIONS
Rash
Grade† 2 or 3HEPATIC
IMPAIRMENT
• Withhold lenalidomide
RENAL until rash recovers to grade 1 or lower
LACTATION
• Following
recovery, resume lenalidomide at
the next lower dose according to its
IMPAIRMENT
Prescribing Information
• If grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to
grade 1 or lower
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its
most recent dose*
Grade 4
Reduce the
starting dose of
Peripheral
Neuropathy
NINLARO to 3 mg in patients
Grade 1 peripheral neuropathy
with moderate or severe hepatic
with pain or grade 2 peripheral
impairment.
neuropathy
• Discontinue treatment regimen
Reduce the starting dose of
Advise nursing women not to
NINLARO to 3 mg in patients
breastfeed during treatment
• Withhold NINLARO until peripheral neuropathy recovers to grade 1 or lower without pain
with severe renal impairment
with NINLARO and for 90 days
or patient’s baseline
or end-stage renal disease
afteratthe
dose.
• Following recovery, resume NINLARO
its last
most
recent dose
requiring dialysis.
Grade 2 peripheral neuropathy
• Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s
with pain or grade 3 peripheral
baseline condition or grade 1 or lower prior to resuming NINLARO
neuropathy
• Following recovery, resume NINLARO at the next lower dose
Contraception:
and female patients
of childbearing
potential
must use effective contraceptive measures
Grade
4 peripheralMale
neuropathy
• Discontinue
treatment
regimen
during, and for 90 days following, treatment.
OTHER NONHEMATOLOGIC
TOXICITIES
RECOMMENDED ACTIONS
NINLARO
is not dialyzable
and therefore
canshould,
be administered
Other grade 3 or
4
• Withhold NINLARO.
Toxicities
at the physician’s discretion, generally recover to patient’s
nonhematologicwithout
toxicitiesregard to the
baseline
condition
or grade 1 or lower prior to resuming NINLARO
timing
of dialysis.
• If attributable to NINLARO, resume NINLARO at the next lower dose following recovery
*For additional occurrences, alternate dose modification of lenalidomide and NINLARO.
Grading based on National Cancer Institute Common Terminology Criteria Version 4.03.
Please
see
Important
Safety
Information
onon
pages
1-21-2
and
accompanying
fullfull
Prescribing
Information.
Please
see
Important
Safety
Information
pages
and
accompanying
Prescribing
Information.
DOSE
MODIFICATIONS
AVAILABLE NINLARO® (ixazomib) STRENGTHS
Recommended
starting dose
First dose reduction
Second dose reduction
4mg
3mg
2.3mg
If toxicities continue
Recommended starting dose
for patients with:
• Moderate or severe
hepatic impairment*
• Severe renal impairment†
• End-stage renal disease,
requiring dialysis
*Hepatic impairment: moderate, bilirubin >1.5-3x ULN; severe, bilirubin >3x ULN.
†Severe renal impairment: Creatinine clearance <30 mL/min.
Please see section 2 (Dosing and Administration) of the NINLARO full Prescribing Information.
Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information.
Discontinue
NINLARO.
Call 1-844-N1POINT (1-844-617-6468) for information
on access, coverage, and support services.
References: 1. Data on File 117, Takeda Pharmaceuticals International Co. 2. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events
(CTCAE). Version 4.03. Published June 14, 2010. 3. Data on File 113, Takeda Pharmaceuticals International Co. 4. Data on File 109, Takeda Pharmaceuticals International Co.
5. Data on File 114, Takeda Pharmaceuticals International Co. 6. Data on File 115, Takeda Pharmaceuticals International Co.
Please see attached full Prescribing Information above.
Takeda Oncology and
are registered trademarks of Takeda Pharmaceutical Company Limited.
NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc.
is a trademark of Millennium Pharmaceuticals, Inc.
Copyright © 2016, Millennium Pharmaceuticals, Inc.
All rights reserved.
Printed in USA
12/16
USO/IXA/16/0111(1)