Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Bone Marrow Suppression
(Additions and/or
revisions underlined)
JEVTANA
is contraindicated in patients with neutrophils ?1,500/mm3 [see Contraindications (4)]. Closely monitor patients with hemoglobin
<10 g/dL.
Bone
marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia
may occur. Neutropenic deaths have been reported.
TROPIC Trial (JEVTANA 25
mg/m2)
In
the TROPIC trial with G-CSF administered only at the investigator’s discretion, 5 patients (1.3%)
died from neutropenic infection
(sepsis or septic shock); 4 of these
patients died in the first
30 days of treatment. One additional patient’s death was
attributed to neutropenia without a documented
infection. Twenty-two (6%) patients discontinued
JEVTANA treatment due to neutropenia,
febrile neutropenia, infection, or sepsis. Grade 3-4 neutropenia occurred in 82% of patients treated
with JEVTANA in the randomized
trial [see Adverse Reactions (6.1)].
PROSELICA Trial (comparison of JEVTANA
20 mg/m2 version 25
mg/m2)
In
the PROSELICA trial comparing two
doses of JEVTANA, primary prophylaxis with G-CSF was
not allowed, but could be administered after development of neutropenia at investigators discretion.
Eight patients (1%) on the 20 mg/m2 arm and
15 patients (3%) on the 25 mg/m2 arm died
from infection; of these,
4 deaths on the 20 mg/m2 arm
and 8 deaths on the 25 mg/m2 arm occurred
within the first 30 days of treatment. Clinically important
neutropenia-related events occurred
and included febrile neutropenia (2.1% on
20 mg/m2 arm
and 9.2% on 25 mg/m2 arm), neutropenic
infection/sepsis (2.1% on 20 mg/m2 arm and
6.4% on 25 mg/m2 arm),
and
neutropenic deaths (0.3% on
20 mg/m2 arm
and 0.7% on 25 mg/m2 arm).
Fewer patients
receiving JEVTANA 20 mg/m2 were
reported to have infectious adverse
reactions. Grade 1-4 infections were experienced by 160 patients
(28%) on the 20 mg/m2 arm and
227 patients (38%) on the 25 mg/m2 arm.
Grade 3-4 infections were experienced
by
57 patients (10%) on the 20 mg/m2 arm
and 120 patients (20%) on the 25 mg/m2 arm. Noninferiority for overall survival
was demonstrated between these two arms [see Adverse Reactions
(6.1)].
CARD Trial (JEVTANA
25 mg/m2 + primary prophylaxis G-CSF)
In
the CARD trial where JEVTANA 25 mg/m2 was administered with primary prophylaxis
of G- CSF, 1 patient (0.8%) died from sepsis within the first 30 days of
treatment. Grade 1-4 neutropenia-related adverse reactions were experienced in
33 patients (26%). Grade 3-4 neutropenias was experienced by 26 patients (21%).
Clinically important neutropenia-related events occurred and included febrile
neutropenia (3.2%), neutropenic infection/sepsis (0.8%) and neutropenic deaths
(0.8%) [see Adverse Reactions (6.1)].
Based
on guidelines for the use of G-CSF and the adverse reactions profile of
JEVTANA, primary prophylaxis with G-CSF is recommended in patients with high-risk
clinical features (older patients, poor performance status, previous episodes
of febrile neutropenia, extensive prior radiation ports, poor nutritional status,
or other serious comorbidities) that predispose them to increased complications
from prolonged neutropenia. Consider primary prophylaxis with G-CSF in all
patients receiving JEVTANA 25 mg/m2.
Monitoring
of complete blood counts is essential on a weekly basis during cycle 1 and before
each treatment cycle thereafter so that the dose can be adjusted, if needed [see Dosage and Administration (2.2)].
5.2 Increased Toxicities in Elderly Patients
(Additions and/or
revisions underlined)
…
In
CARD, a death due to infection within 30 days of starting JEVTANA occurred in
0.8% (1/126) patient who was >75 years of age. There were 2.4% (3/126) of patients
who died of causes other than disease progression within 30 days of the last JEVTANA
dose; all of these patients were >75 years of age.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Extensive
changes; please refer to label)
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or
revisions underlined)
…
In
the CARD study, the grade 1-4 adverse reactions reported at rates of at least
5% higher in patients 65 years of age or older compared to younger patients were
decreased appetite (16% vs 7%), hypertension (5% vs 0), constipation (18% vs 7%),
paresthesia (6% vs 0), stomatitis (10% vs 3%), musculoskeletal pain (5% vs 0), fatigue
(31% vs 23%), asthenia (30% vs 19%), and edema peripheral (11% vs 0).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions and/or
revisions underlined)
…
The most common side
effects of JEVTANA include:
Low
red blood cell count (anemia). Low red blood cell count is common with JEVTANA,
but can sometimes also be serious. Your healthcare provider will regularly check
your red blood cell count. Symptoms of anemia include shortness of breath and tiredness.
Low
blood platelet count. Low platelet count is common with JEVTANA, but can sometimes
also be serious. Tell your healthcare provider if you have any unusual bruising
or bleeding.
diarrhea o blood
in urine
nausea o constipation
tiredness o decreased
appetite
weakness o back
pain
vomiting o stomach
(abdominal) pain
- JEVTANA
may cause fertility problems in males. This may affect your ability to father a
child. Talk to your healthcare provider if you have concerns about fertility.
Tell your healthcare
provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects
of JEVTANA. For more information, ask your healthcare provider or pharmacist.
Call
your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
Approved Drug Label (PDF)
Boxed Warning
Additions
and/or revisions underlined:
WARNING:
NEUTROPENIA AND HYPERSENSITIVITY
Neutropenia:
Neutropenic
deaths have been reported. Monitor
for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with
neutrophil counts of less than or equal to 1,500 cells/mm3. Primary
prophylaxis with G-CSF is recommended in patients with high-risk clinical
features.
4
Contraindications
JEVTANA is contraindicated in patients
with:
Addition
of the following:
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1
Bone Marrow Suppression
JEVTANA is contraindicated in patients
with neutrophils lesss than or equal to 500/mm3. Closely monitor patients with
hemoglobin less than 10 g/dL.
In a randomized trial (TROPIC) in
previously treated patients with metastatic castration-resistant prostate
cancer, five patients (1.3%) died
from infection (sepsis or septic shock).
… One additional patient’s death was attributed
to neutropenia without a documented infection. Twenty-two (6%) patients
discontinued JEVTANA treatment due to neutropenia, febrile neutropenia,
infection, or sepsis. The most common adverse reaction leading to
treatment discontinuation in the JEVTANA group was neutropenia (2%). Grade
3-4 neutropenia …
In a randomized trial (PROSELICA)
comparing two doses
of JEVTANA in previously treated metastatic castration-resistant prostate
cancer, 8 patients (1%) on the 20 mg/m2 arm and 15 patients (3%) on the 25
mg/m2 arm died from infection; of these, 4 deaths on the 20 mg/m2 arm and 8
deaths on the 25 mg/m2 arm occurred within the first 30 days of treatment.
Fewer patients receiving JEVTANA 20
mg/m2 were reported to have infectious adverse reactions. Grade 1-4 infections
were experienced by 160 patients (28%) on the 20 mg/m2 arm and 227 patients
(38%) on the 25 mg/m2 arm. Grade 3-4 infections were experienced by 57 patients
(10%) on the 20 mg/m2 arm and 120 patients (20%) on the 25 mg/m2 arm.
Noninferiority for overall survival was demonstrated between these two arms.
Based on guidelines for the use of G-CSF
and the adverse reactions profile of JEVTANA, primary prophylaxis with
G-CSF is recommended in patients with high-risk clinical features ( older
patients, poor performance status …
… increased complications from prolonged
neutropenia. The effectiveness of primary prophylaxis with G-CSF in patients
receiving JEVTANA has not been studied. Therapeutic use of G-CSF …
Newly
added information:
5.2
Increased Toxicities in Elderly Patients
In a randomized trial (TROPIC), 2% of
patients (3/131) less than 65 years
of age and 6% (15/240) greater than or equal to 65 years of age died of causes
other than disease progression within 30 days of the last JEVTANA dose. Patients greater than or equal to 65 years of
age are more likely to experience certain adverse reactions, including
neutropenia and febrile neutropenia. The
incidence of the following grade 3-4 adverse reactions were higher in patients greater
than or equal to 65 years of age compared to younger patients; neutropenia (87%
vs 74%), and febrile neutropenia (8% vs 6%).
In a randomized clinical trial
(PROSELICA) comparing two doses of JEVTANA, deaths due to infection within 30
days of starting JEVTANA occurred in 0.7% (4/580) patients on the 20 mg/m2 arm
and 1.3% (8/595) patients on the 25 mg/m2 arm; all of these patients were greater
than 60 years of age In PROSELICA, on the 20 mg/m2 arm, 3% (5/178) of patients less
than 65 years of age and 2% (9/402) greater than or equal to 65 years of age
died of causes other than disease progression within 30 days of the last
JEVTANA dose. On the 25 mg/m2 arm, 2%
(3/175) patients less than65 years of age and 5% (20/420) greater than or equal
to 65 years of age died of causes other than disease progression within 30 days
of the last JEVTANA dose.
5.5
Renal Failure
In the randomized clinical trial (TROPIC),
renal failure …
6
Adverse Reactions
Additions
and/or revisions underlined:
6.1
Clinical Trials Experiments
… may not reflect the rates observed in
clinical practice.
TROPIC Trial (JEVTANA + prednisone
compared to mitoxantrone)
The safety of JEVTANA in combination
with prednisone was evaluated in 371 patients with metastatic castration-resistant
prostate cancer treated in the randomized TROPIC trial, compared to
mitoxantrone …
Table 2: Incidence of Adverse Reactions*
and Hematologic Abnormalities in greater than or equal to 5% of Patients
Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in Combination
with Prednisone in TROPIC
Newly added information below:
PROSELICA Trial (comparison of two doses
of JEVTANA)
In a noninferiority, multicenter,
randomized, open-label study (PROSELICA), 1175 patients with metastatic
castration-resistant prostate cancer, previously treated with a
docetaxel-containing regimen, were treated with either JEVTANA 25 mg/m2 (n=595)
or the 20 mg/m2 (n=580) dose.
Deaths within 30 days of last study drug
dose were reported in 22 (3.8%) patients in the 20 mg/m2 and 32 (5.4%) patients
in the 25 mg/m2 arm. The most common fatal adverse reactions in JEVTANA-treated
patients were related to infections, and these occurred more commonly on the 25
mg/m2 arm (n=15) than on the 20 mg/m2 arm (n=8). Other fatal adverse reactions
in JEVTANA-treated patients included cerebral hemorrhage, respiratory failure,
paralytic ileus, diarrhea, acute pulmonary edema, disseminated intravascular
coagulation, renal failure, sudden death, cardiac arrest, ischemic stroke,
diverticular perforation, and cardiorenal syndrome.
Grade 1-4 adverse reactions occurring greater
than or equal to 5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2
arms were leukopenia, neutropenia, thrombocytopenia, febrile neutropenia,
decreased appetite, nausea, diarrhea, asthenia, and hematuria.
Grade 3-4 adverse reactions occurring greater
than or equal to 5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2
arms were leukopenia, neutropenia, and febrile neutropenia.
Treatment discontinuations due to
adverse drug reactions occurred in 17% of patients in the 20 mg/m2 group and
20% of patients in the 25 mg/m2 group. The most common adverse reactions
leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2 group received a
median of 6 cycles (median duration of 18 weeks), while patients in the 25
mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (22%) had
a dose reduced from 25 to 20 mg/m2, 19 patients (3%) had a dose reduced from 20
to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the
20 mg/m2 group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m2, and 9
patients (2%) had a dose reduced from 15 to 12 mg/m2.
Table 3: Incidence of Adverse Reactions*
in greater than or equal to 5% of Patients Receiving JEVTANA 20 mg/m2 or 25
mg/m2 in Combination with Prednisone in PROSELICA Please refer to label for
full information.
Table 4: Incidence of Hematologic
Laboratory Abnormalities in Patients Receiving JEVTANA 20 mg/m2 or 25 mg/m2 in
Combination with Prednisone in Study PROSELICA Please refer to label for full information.
Hematuria
In study TROPIC, adverse reactions of hematuria,
including those requiring medical …
… hematuria on the JEVTANA arm.
In study PROSELICA, hematuria of all
grades was observed in 18% of patients overall.
8
Use in Specific Populations
8.1 Pregnancy
PLLR
conversion; as below:
Risk Summary
JEVTANA is contraindicated for use in
pregnant women because the drug can cause fetal harm and potential loss of
pregnancy. JEVTANA is not indicated for use in female patients. There are no
human data on the use of cabazitaxel injection in pregnant women. Non-clinical
In animal reproduction studies, intravenous administration of cabazitaxel in
pregnant rats Cabazitaxel during organogenesis caused embryonic and fetal death
at doses lower than the maximum recommended human dose.
Data
Animal Data
In an early embryonic developmental
toxicity study in rats, cabazitaxel was administered intravenously for 15 days
prior to mating through Day 6 of pregnancy, which resulted in an increase in
pre-implantation loss at 0.2 mg/kg/day and an increase in early resorptions at
greater than or equal to 0.1 mg/kg/day (approximately 0.06 and 0.02 times the
Cmax in patients at the recommended human dose, respectively).
In an embryo-fetal developmental
toxicity study in rats, cabazitaxel caused maternal and embryofetal toxicity
consisting of increased post implantation loss, embryolethality, and fetal
deaths when administered intravenously at a dose of 0.16 mg/kg/day
(approximately 0.06 times the Cmax in patients at the recommended human dose).
Decreased mean fetal birthweight associated with delays in skeletal
ossification was observed at doses greater than or equal to 0.08 mg/kg.
Cabazitaxel crossed the placenta barrier within 24 hours of a single
intravenous administration of 0.08 mg/kg to pregnant rats at gestational day
17. A dose of 0.08 mg/kg in rats resulted in a Cmax approximately 0.02 times
that observed in patients at the recommended human dose. Administration of
cabazitaxel did not result in fetal abnormalities in rats or rabbits at
exposure levels significantly lower than the expected human exposures.
8.2 Lactation
PLLR
conversion; as below:
Risk Summary
JEVTANA is not indicated for use in
female patients. There is no information available on the presence of
cabazitaxel in human milk, the effects of the drug on the breastfed infant, or
the effects of the drug on milk production. Cabazitaxel or cabazitaxel
metabolites are excreted in maternal milk of lactating rats
Data
Animal Data
In a milk excretion study, radioactivity
related to cabazitaxel was detected in the stomachs of nursing pups within 2
hours of a single intravenous administration of cabazitaxel to lactating rats
at a dose of 0.08 mg/kg (approximately 0.02 times the Cmax in patients at the
recommended human dose). This was detectable 24 hours post dose. Approximately
1.5% of the dose delivered to the mother was calculated to be delivered in the
maternal milk.
8.3 Females and Males of Reproductive Potential
PLLR
conversion; as below:
Contraception Males
Based on findings in animal reproduction
studies, advise male patients with female partners of reproductive potential to
use effective contraception during treatment and for 3 months after the final
dose of JEVTANA.
Infertility Males
Based on animal toxicology studies,
cabazitaxel injection may impair human fertility in males of reproductive
potential.
8.5 Geriatric Use
Additions
and/or revisions underlined:
In the TROPIC study, of the 371
patients with prostate cancer …
… No overall differences in
effectiveness were observed between patients greater than or equal to 65
years of age and younger patients. Elderly patients greater than or equal
to 65 years of may be more likely
to experience certain adverse reactions.
… greater compared to younger patients.
The following grade 1-4 adverse
reactions were reported at rates greater than or equal to 5% higher in
patients 65 years of age or older compared to younger patients: fatigue (40%
vs 30%), neutropenia (97% vs 89%), asthenia (24% vs 15%), pyrexia (15% vs 8%),
dizziness (10% vs 5%), urinary tract infection (10% vs 3%), and dehydration (7%
vs 2%), respectively.
In the PROSELICA study, the grade 1-4
adverse reactions reported at rates of at least 5% higher in patients 65 years
of age or older compared to younger patients were diarrhea (43% vs 33%),
fatigue (30% vs 19%), asthenia (22% vs 13%), constipation (20% vs 13%),
clinical neutropenia (13% vs 6%), febrile neutropenia (11% vs 5%), and dyspnea
(10% vs 3%).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Increased
Toxicities in Elderly Patients
Inform elderly patients that certain
side effects may be more frequent or severe.
Embryo-Fetal
Toxicity
Advise male patients with female partners of reproductive
potential to use effective contraception during treatment and for 3 months
after the last dose of cabazitaxel injection.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Respiratory Disorders (added)
Interstitial
pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress
syndrome have been reported and may be associated with fatal outcome. Patients with underlying lung disease may be at higher risk for these events. Acute respiratory distress syndrome may occur in the setting of infection.
Interrupt JEVTANA if new or worsening pulmonary symptoms develop. Closely monitor, promptly investigate, and appropriately treat patients receiving JEVTANA. Consider discontinuation. The benefit of resuming JEVTANA treatment must be carefully evaluated.
6
Adverse Reactions
6 Respiratory Disorders (added)
6.2 Postmarketing Experience
Respiratory: Interstitial
pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress
syndrome.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Respiratory
Disorders
(added)
Explain to patients that severe
and fatal interstitial pneumonia/pneumonitis, interstitial lung disease and
acute respiratory distress syndrome have occurred with JEVTANA. Instruct
patients to immediately report new or worsening pulmonary symptoms to their
healthcare provider.
Patient
Information
Tell your
healthcare provider if you develop these signs or symptoms:
- swelling of your
face or body
- decrease in the
amount of urine that your body makes each day
Lung or
breathing problems. (added) Lung or
breathing problems may happen with JEVTANA and may lead to death. People who
have lung disease before receiving JEVTANA may have a higher risk for
developing lung or
breathing problems with JEVTANA
treatment. Your healthcare provider will check you for this problem and treat
you if needed.
Tell your
healthcare provider right away if you develop any new or worsening symptoms,
including: trouble breathing, shortness of breath, chest pain cough or fever.
What should I
tell my healthcare provider before receiving JEVTANA?
Before receiving
JEVTANA, tell your healthcare provider if you:
·
have lung problems ( added)
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