Jevtana
Generic Name: cabazitaxel
Dosage Form: injection, solution
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 ≤1,500 cells/mm3. Primary prophylaxis with G-CSF is
recommended in patients with high-risk clinical features [see Contraindications
(4) and Warnings and
Precautions (5.1, 5.2)].
Severe hypersensitivity: Severe hypersensitivity reactions
can occur and may include generalized rash/erythema, hypotension and bronchospasm.
Severe hypersensitivity reactions require immediate discontinuation of the
Jevtana infusion and administration of appropriate therapy. Patients should
receive premedication. Jevtana is contraindicated in patients who have a
history of severe hypersensitivity reactions to cabazitaxel or to other drugs
formulated with polysorbate 80 [see Dosage and Administration (2.1), Contraindications (4), and Warnings and Precautions (5.3)].
Indications and Usage for Jevtana
Jevtana® is indicated in
combination with prednisone for the treatment of patients with metastatic
castration-resistant prostate cancer previously treated with a
docetaxel-containing treatment regimen.
Jevtana Dosage and Administration
Dosing
Information
The recommended dose of Jevtana is based
on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered
as a one-hour intravenous infusion every three weeks in combination with oral
prednisone 10 mg administered daily throughout Jevtana treatment.
A dose of 25 mg/m2 can
be used in select patients at the discretion of the treating healthcare
provider [see Warnings
and Precautions (5.1, 5.2,), Adverse Reactions (6.1), and Clinical Studies (14)].
Premedicate at least 30
minutes prior to each dose of Jevtana with the following intravenous
medications to reduce the risk and/or severity of hypersensitivity [see Warnings and
Precautions (5.3)]:
antihistamine (dexchlorpheniramine 5 mg, or
diphenhydramine 25 mg or equivalent antihistamine),
corticosteroid (dexamethasone 8 mg or equivalent
steroid),
H2 antagonist
(ranitidine 50 mg or equivalent H2antagonist).
Antiemetic prophylaxis is
recommended and can be given orally or intravenously as needed [see Warnings and
Precautions (5.3)].
Jevtana injection single-use
vial requires two dilutions
prior to administration [see Dosage
and Administration (2.5)].
Dose
Modifications for Adverse Reactions
Reduce or discontinue Jevtana
dosing for adverse reactions as described in Table 1.
Table 1: Recommended Dosage Modifications for Adverse Reactions in
Patients Treated with Jevtana
|
|
Toxicity
|
Dosage
Modification
|
|
Prolonged
grade ≥3 neutropenia (greater than 1 week) despite appropriate medication
including granulocyte-colony stimulating factor (G-CSF)
|
Delay treatment
until neutrophil count is >1,500 cells/mm3, then reduce dosage of Jevtana by one dose level.
Use G-CSF for secondary prophylaxis.
|
|
Febrile
neutropenia or neutropenic infection
|
Delay treatment
until improvement or resolution, and until neutrophil count is >1,500
cells/mm3, then reduce dosage of Jevtana by one
dose level. Use G-CSF for secondary prophylaxis.
|
|
Grade ≥3
diarrhea or persisting diarrhea despite appropriate medication, fluid and
electrolytes replacement
|
Delay treatment
until improvement or resolution, then reduce dosage of Jevtana by one dose
level.
|
|
Grade 2
peripheral neuropathy
|
Delay treatment
until improvement or resolution, then reduce dosage of Jevtana by one dose
level.
|
|
Grade ≥3
peripheral neuropathy
|
Discontinue
Jevtana
|
Patients at a 20 mg/m2 dose
who require dose reduction should decrease dosage of Jevtana to 15 mg/m2 [see Adverse Reactions (6.1)].
Patients at a 25 mg/m2 dose
who require dose reduction should decrease dosage of Jevtana to 20 mg/m2. One
additional dose reduction to 15 mg/m2 may
be considered [see Adverse
Reactions (6.1)].
Dose
Modifications for Hepatic Impairment
Mild hepatic impairment (total bilirubin >1 to
≤1.5 × Upper Limit of Normal (ULN) or AST >1.5 × ULN): Administer Jevtana
at a dose of 20 mg/m2.
Moderate hepatic impairment (total bilirubin
>1.5 to ≤3 × ULN and AST = any): Administer Jevtana at a dose of 15
mg/m2 based on
tolerability data in these patients; however, the efficacy of this dose is
unknown.
Severe hepatic impairment (total bilirubin >3 ×
ULN): Jevtana is contraindicated in patients with severe hepatic
impairment [see Warning
and Precautions (5.7) and Clinical
Pharmacology (12.3)].
Dose
Modifications for Use with Strong CYP3A Inhibitors
Concomitant drugs that are
strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel.
Avoid the coadministration of Jevtana with these drugs. If patients require
coadministration of a strong CYP3A inhibitor, consider a 25% Jevtana dose reduction [see Drug Interactions (7.1) and Clinical Pharmacology
(12.3)].
Preparation
and Administration
Jevtana is a cytotoxic anticancer
drug. Follow applicable special handling and disposal procedures [see References (15)]. If Jevtana first diluted
solution, or second (final) dilution for intravenous infusion should come into
contact with the skin or mucous, immediately and thoroughly wash with soap and
water.
Do not use PVC infusion
containers or polyurethane infusions sets for preparation and administration of
Jevtana infusion solution.
Jevtana should not be mixed with
any other drugs.
Preparation
Read this entire section carefully before mixing and
diluting. Jevtana requires two dilutions
prior to administration. Follow the preparation instructions provided below, as
improper preparation may lead to overdose [see Overdosage
(10)].
Note: Both the Jevtana injection and the diluent vials contain
an overfill to compensate for liquid loss during preparation. This overfill
ensures that after dilution with the entire
contents of the accompanying diluent, there is an initial
diluted solution containing 10 mg/mL Jevtana.
Inspect the Jevtana injection
and supplied diluent vials. The Jevtana injection is a clear yellow to
brownish-yellow viscous solution.
Step 1 – First Dilution
Each vial of Jevtana
(cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire
contents of supplied diluent. Once reconstituted, the resultant
solution contains 10 mg/mL of Jevtana.
When transferring the diluent,
direct the needle onto the inside wall of Jevtana vial and inject slowly to
limit foaming. Remove the syringe and needle and gently mix the initial diluted
solution by repeated inversions for at least 45 seconds to assure full mixing
of the drug and diluent. Do not shake.
Let the solution stand for a
few minutes to allow any foam to dissipate, and check that the solution is
homogeneous and contains no visible particulate matter. It is not required that
all foam dissipate prior to continuing the preparation process.
The resulting initial diluted
Jevtana solution (cabazitaxel 10 mg/mL) requires further dilution before
administration. The second dilution should be done immediately (within 30
minutes) to obtain the final infusion as detailed in Step 2.
Step 2 – Second (Final)
Dilution
Withdraw the recommended dose
from the Jevtana solution containing 10 mg/mL as prepared in Step 1 using a
calibrated syringe and further dilute into a sterile 250 mL PVC-free container
of either 0.9% sodium chloride solution or 5% dextrose solution for infusion.
If a dose greater than 65 mg of Jevtana is required, use a larger volume of the
infusion vehicle so that a concentration of 0.26 mg/mL Jevtana is not exceeded.
The concentration of the Jevtana final infusion solution should be between 0.10
mg/mL and 0.26 mg/mL.
Remove the syringe and
thoroughly mix the final infusion solution by gently inverting the bag or
bottle.
As the final infusion solution
is supersaturated, it may crystallize over time. Do not use if this occurs and
discard.
Fully prepared Jevtana
infusion solution (in either 0.9% sodium chloride solution or 5% dextrose
solution) should be used within 8 hours at ambient temperature (including the
one-hour infusion), or for a total of 24 hours (including the one-hour
infusion) under the refrigerated conditions.
Discard any unused portion.
Administration
Inspect visually for
particulate matter, any crystals and discoloration prior to administration. If
the Jevtana first diluted solution or second (final) infusion solution is not
clear or appears to have precipitation, it should be discarded.
Use an in-line filter of 0.22
micrometer nominal pore size (also referred to as 0.2 micrometer) during
administration.
The final Jevtana infusion
solution should be administered intravenously as a one-hour infusion at room
temperature.
Dosage Forms and Strengths
Jevtana (cabazitaxel)
injection is supplied as a kit consisting of the following:
Cabazitaxel injection: 60 mg/1.5 mL; a clear yellow
to brownish-yellow viscous solution
Diluent: 5.7 mL of 13% (w/w) ethanol in water; a
clear colorless solution
Contraindications
Jevtana is contraindicated in
patients with:
neutrophil counts of ≤1,500/mm3 [see Warnings
and Precautions (5.1)]
history of severe hypersensitivity reactions to
cabazitaxel or to other drugs formulated with polysorbate 80 [see Warnings
and Precautions (5.3)]
severe hepatic impairment (total bilirubin >3 ×
ULN) [see Warnings
and Precautions (5.7)]
pregnancy (Jevtana can cause fetal harm
and potential loss of pregnancy) [see Use
in Specific Populations (8.1)
]Warnings and Precautions
Bone Marrow
Suppression
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.
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). All
had grade 4 neutropenia and one had febrile neutropenia. 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 has been observed in 82% of patients treated with Jevtana
in the randomized trial.
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 [see Clinical
Studies (14)].
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. The
effectiveness of primary prophylaxis with G-CSF in patients receiving Jevtana
has not been studied. Therapeutic use of G-CSF and secondary prophylaxis should
be considered in all patients at increased risk for neutropenia complications.
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)].
Increased Toxicities
in Elderly Patients
In a randomized trial (TROPIC), 2% of
patients (3/131) <65 years of age and 6% (15/240) ≥65 years of age died of
causes other than disease progression within 30 days of the last Jevtana dose.
Patients ≥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 ≥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 >60 years of age
In PROSELICA, on the 20 mg/m2 arm,
3% (5/178) of patients <65 years of age and 2% (9/402) ≥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 <65
years of age and 5% (20/420) ≥65 years of age died of causes other than disease
progression within 30 days of the last Jevtana dose [see Adverse Reactions (6) and Use in Specific
Populations (8.5)].
Hypersensitivity
Reactions
Hypersensitivity reactions may
occur within a few minutes following the initiation of the infusion of Jevtana,
thus facilities and equipment for the treatment of hypotension and bronchospasm
should be available. Severe hypersensitivity reactions can occur and may
include generalized rash/erythema, hypotension and bronchospasm.
Premedicate all patients prior
to the initiation of the infusion of Jevtana [see Dosage
and Administration (2.1)]. Observe patients closely for
hypersensitivity reactions, especially during the first and second infusions.
Severe hypersensitivity reactions require immediate discontinuation of the
Jevtana infusion and appropriate therapy. Jevtana is contraindicated in
patients with a history of severe hypersensitivity reactions to cabazitaxel or
to other drugs formulated with polysorbate 80 [see Contraindications
(4)].
Gastrointestinal
Adverse Reactions
Nausea, vomiting and severe
diarrhea, at times, may occur. Deaths related to diarrhea and electrolyte
imbalance occurred in the randomized clinical trials. Intensive measures may be
required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis
is recommended. Treat patients with rehydration, antidiarrheal or antiemetic
medications as needed. Treatment delay or dosage reduction may be necessary if
patients experience Grade ≥3 diarrhea [see Dosage
and Administration (2.2)].
Gastrointestinal (GI)
hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis,
including fatal outcome, have been reported in patients treated with
Jevtana [see Adverse
Reactions (6.2)]. Risk may be increased with neutropenia, age, steroid use,
concomitant use of NSAIDs, antiplatelet therapy or anticoagulants, and patients
with a prior history of pelvic radiotherapy, adhesions, ulceration and GI
bleeding.
Abdominal pain and tenderness,
fever, persistent constipation, diarrhea, with or without neutropenia, may be
early manifestations of serious gastrointestinal toxicity and should be
evaluated and treated promptly. Jevtana treatment delay or discontinuation may
be necessary.
Renal Failure
In the randomized clinical
trial (TROPIC), renal failure of any grade occurred in 4% of the patients being
treated with Jevtana, including four cases with fatal outcome. Most cases
occurred in association with sepsis, dehydration, or obstructive uropathy [see Adverse Reactions (6.1)]. Some deaths due to renal
failure did not have a clear etiology. Appropriate measures should be taken to
identify causes of renal failure and treat aggressively.
Respiratory
Disorders
Interstitial pneumonia/pneumonitis,
interstitial lung disease and acute respiratory distress syndrome have been
reported and may be associated with fatal outcome [see Adverse Reactions (6.2)]. 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.
Use in
Patients with Hepatic Impairment
Cabazitaxel is extensively
metabolized in the liver.
Jevtana is contraindicated in
patients with severe hepatic impairment (total bilirubin >3 × ULN) [see Contraindications (4)]. Dose should be reduced for
patients with mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN)
and moderate (total bilirubin >1.5 to ≤3.0 × ULN and any AST) hepatic
impairment, based on tolerability data in these patients [see Dosage and
Administration (2.3) and Use in Specific
Populations (8.7)]. Administration of Jevtana to patients with mild and moderate
hepatic impairment should be undertaken with caution and close monitoring of
safety.
Adverse Reactions
The following serious adverse
reactions are discussed in greater detail in another section of the label:
Bone Marrow Suppression [see Warnings
and Precautions (5.1)]Use in Elderly Patients [see Warnings
and Precautions (5.2)]Hypersensitivity Reactions [see Warnings
and Precautions (5.3)]Gastrointestinal Adverse Reactions [see Warnings
and Precautions (5.4)]Renal Failure [see Warnings
and Precautions (5.5)]Respiratory Disorders [see Warnings
and Precautions (5.6)]Use in Patients with Hepatic Impairment [see Warnings
and Precautions (5.7)]Clinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, the adverse reaction rates observed
cannot be directly compared to rates in other trials and 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 plus prednisone.
Deaths due to causes other
than disease progression within 30 days of last study drug dose were reported
in 18 (5%) Jevtana-treated patients and 3 (<1%) mitoxantrone-treated
patients. The most common fatal adverse reactions in Jevtana-treated patients
were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients)
of fatal infection-related adverse reactions occurred after a single dose of
Jevtana. Other fatal adverse reactions in Jevtana-treated patients included
ventricular fibrillation, cerebral hemorrhage, and dyspnea.
The most common (≥10%) grade
1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia,
diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain,
hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea,
dysgeusia, cough, arthralgia, and alopecia.
The most common (≥5%) grade
3–4 adverse reactions in patients who received Jevtana were neutropenia,
leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.
Treatment discontinuations due
to adverse drug reactions occurred in 18% of patients who received Jevtana and
8% of patients who received mitoxantrone. The most common adverse reactions
leading to treatment discontinuation in the Jevtana group were neutropenia and
renal failure. Dose reductions were reported in 12% of Jevtana-treated patients
and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of
Jevtana-treated patients and 15% of mitoxantrone-treated patients.
Table 2: Incidence of Adverse Reactions* and Hematologic Abnormalities in
≥5% of Patients Receiving Jevtana in Combination with Prednisone or
Mitoxantrone in Combination with Prednisone in TROPIC
|
|
|
Jevtana 25 mg/m2 every 3 weeks with prednisone 10
mg daily
n=371
|
Mitoxantrone 12 mg/m2 every 3 weeks with prednisone 10
mg daily
n=371
|
|
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
|
*
Graded using NCI
CTCAE version 3
†
Based on
laboratory values, Jevtana: n =369, mitoxantrone: n = 370.
‡
Includes atrial
fibrillation, atrial flutter, atrial tachycardia, atrioventricular block
complete, bradycardia, palpitations, supraventricular tachycardia,
tachyarrhythmia, and tachycardia.
§
Includes
abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal
tenderness, and GI pain.
¶
Includes
gastroesophageal reflux disease and reflux gastritis.
#
Includes urinary
tract infection enterococcal and urinary tract infection fungal.
Þ
Includes peripheral motor neuropathy and peripheral
sensory neuropathy.
|
|
Any Adverse Reaction
|
|
Blood and Lymphatic System Disorders
|
|
Neutropenia†
|
347 (94%)
|
303 (82%)
|
325 (87%)
|
215 (58%)
|
|
Febrile
Neutropenia
|
27 (7%)
|
27 (7%)
|
5 (1%)
|
5 (1%)
|
|
Anemia†
|
361 (98%)
|
39 (11%)
|
302 (82%)
|
18 (5%)
|
|
Leukopenia†
|
355 (96%)
|
253 (69%)
|
343 (93%)
|
157 (42%)
|
|
Thrombocytopenia†
|
176 (48%)
|
15 (4%)
|
160 (43%)
|
6 (2%)
|
|
Cardiac Disorders
|
|
Arrhythmia‡
|
18 (5%)
|
4 (1%)
|
6 (2%)
|
1 (<1%)
|
|
Gastrointestinal Disorders
|
|
Diarrhea
|
173 (47%)
|
23 (6%)
|
39 (11%)
|
1 (<1%)
|
|
Nausea
|
127 (34%)
|
7 (2%)
|
85 (23%)
|
1 (<1%)
|
|
Vomiting
|
83 (22%)
|
6 (2%)
|
38 (10%)
|
0
|
|
Constipation
|
76 (20%)
|
4 (1%)
|
57 (15%)
|
2 (<1%)
|
|
Abdominal
Pain§
|
64 (17%)
|
7 (2%)
|
23 (6%)
|
0
|
|
Dyspepsia¶
|
36 (10%)
|
0
|
9 (2%)
|
0
|
|
General Disorders and Administration Site Conditions
|
|
Fatigue
|
136 (37%)
|
18 (5%)
|
102 (27%)
|
11 (3%)
|
|
Asthenia
|
76 (20%)
|
17 (5%)
|
46 (12%)
|
9 (2%)
|
|
Pyrexia
|
45 (12%)
|
4 (1%)
|
23 (6%)
|
1 (<1%)
|
|
Peripheral
Edema
|
34 (9%)
|
2 (<1%)
|
34 (9%)
|
2 (<1%)
|
|
Mucosal
Inflammation
|
22 (6%)
|
1 (<1%)
|
10 (3%)
|
1 (<1%)
|
|
Pain
|
20 (5%)
|
4 (1%)
|
18 (5%)
|
7 (2%)
|
|
Infections and Infestations
|
|
Urinary
Tract Infection#
|
29 (8%)
|
6 (2%)
|
12 (3%)
|
4 (1%)
|
|
Investigations
|
|
Weight
Decreased
|
32 (9%)
|
0
|
28 (8%)
|
1 (<1%)
|
|
Metabolism and Nutrition Disorders
|
|
Anorexia
|
59 (16%)
|
3 (<1%)
|
39 (11%)
|
3 (<1%)
|
|
Dehydration
|
18 (5%)
|
8 (2%)
|
10 (3%)
|
3 (<1%)
|
|
Musculoskeletal and Connective Tissue Disorders
|
|
Back
Pain
|
60 (16%)
|
14 (4%)
|
45 (12%)
|
11 (3%)
|
|
Arthralgia
|
39 (11%)
|
4 (1%)
|
31 (8%)
|
4 (1%)
|
|
Muscle
Spasms
|
27 (7%)
|
0
|
10 (3%)
|
0
|
|
Nervous System Disorders
|
|
Peripheral
NeuropathyÞ
|
50 (13%)
|
3 (<1%)
|
12 (3.2%)
|
3 (<1%)
|
|
Dysgeusia
|
41 (11%)
|
0
|
15 (4%)
|
0
|
|
Dizziness
|
30 (8%)
|
0
|
21 (6%)
|
2 (<1%)
|
|
Headache
|
28 (8%)
|
0
|
19 (5%)
|
0
|
|
Renal and Urinary Tract Disorders
|
|
Hematuria
|
62 (17%)
|
7 (2%)
|
13 (4%)
|
1 (<1%)
|
|
Dysuria
|
25 (7%)
|
0
|
5 (1%)
|
0
|
|
Respiratory, Thoracic and Mediastinal Disorders
|
|
Dyspnea
|
43 (12%)
|
4 (1%)
|
16 (4%)
|
2 (<1%)
|
|
Cough
|
40 (11%)
|
0
|
22 (6%)
|
0
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Alopecia
|
37 (10%)
|
0
|
18 (5%)
|
0
|
|
Vascular Disorders
|
|
Hypotension
|
20 (5%)
|
2 (<1 %)
|
9 (2%)
|
1 (<1%)
|
|
Median Duration of Treatment
|
6 cycles
|
4 cycles
|
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 ≥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 ≥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/m2group 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 ≥5% of Patients Receiving
Jevtana 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in PROSELICA
|
|
|
Jevtana 20 mg/m2 every 3 weeks with prednisone 10
mg daily
n=580
|
Jevtana 25 mg/m2 every 3 weeks with prednisone 10
mg daily
n=595
|
|
Primary
System Organ Class
Preferred Term
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
|
*
Grade from NCI
CTCAE version 4.03.
†
Based on adverse
event reporting.
‡
Includes urinary
tract infection staphylococcal, urinary tract infection bacterial, urinary
tract infection fungal, and urosepsis.
§
Includes neutropenic sepsis.
|
|
Blood and Lymphatic System Disorders
|
|
Febrile
Neutropenia
|
12 (2%)
|
12 (2%)
|
55 (9%)
|
55 (9%)
|
|
Neutropenia†
|
18 (3%)
|
14 (2%)
|
65 (11%)
|
57 (10%)
|
|
Infections and Infestations
|
|
Urinary
tract infection‡
|
43 (7%)
|
12 (2%)
|
66 (11%)
|
14 (2%)
|
|
Neutropenic
infection§
|
15 (3%)
|
13 (2%)
|
42 (7%)
|
36 (6%)
|
|
Metabolism and Nutrition Disorders
|
|
Decreased
appetite
|
76 (13%)
|
4 (0.7%)
|
110 (19%)
|
7 (1%)
|
|
Nervous System Disorders
|
|
Dysgeusia
|
41 (7%)
|
0
|
63 (11%)
|
0
|
|
Peripheral
sensory neuropathy
|
38 (7%)
|
0
|
63 (11%)
|
4 (0.7%)
|
|
Dizziness
|
24 (4%)
|
0
|
32 (5%)
|
0
|
|
Headache
|
29 (5%)
|
1 (0.2%)
|
24 (4%)
|
1 (0.2%)
|
|
Respiratory, Thoracic and Mediastinal Disorders
|
|
Dyspnea
|
30 (5%)
|
5 (0.9%)
|
46 (8%)
|
4 (0.7%)
|
|
Cough
|
34 (6%)
|
0
|
35 (6%)
|
0
|
|
Gastrointestinal Disorders
|
|
Diarrhea
|
178 (31%)
|
8 (1%)
|
237 (40%)
|
24 (4%)
|
|
Nausea
|
142 (25%)
|
4 (0.7%)
|
191 (32%)
|
7 (1%)
|
|
Vomiting
|
84 (15%)
|
7 (1.2%)
|
108 (18 %)
|
8 (1%)
|
|
Constipation
|
102 (18%)
|
2 (0.3%)
|
107 (18%)
|
4 (0.7%)
|
|
Abdominal
pain
|
34 (6%)
|
3 (0.5%)
|
52 (9%)
|
7 (1%)
|
|
Stomatitis
|
27 (5%)
|
0
|
30 (5%)
|
2 (0.3%)
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Alopecia
|
15 (3%)
|
0
|
36 (6.1%)
|
0
|
|
Musculoskeletal and Connective Tissue Disorders
|
|
Back
pain
|
64 (11%)
|
5 (0.9%)
|
83 (14%)
|
7 (1%)
|
|
Bone
pain
|
46 (8%)
|
10 (2%)
|
50 (8%)
|
13 (2 %)
|
|
Arthralgia
|
49 (8%)
|
3 (0.5%)
|
41 (7%)
|
5 (0.8%)
|
|
Pain
in extremity
|
30 (5%)
|
1 (0.2%)
|
41 (7%)
|
3 (0.5%)
|
|
Renal and Urinary Disorders
|
|
Hematuria
|
82 (14%)
|
11 (2%)
|
124 (21%)
|
25 (4%)
|
|
Dysuria
|
31 (5%)
|
2 (0.3%)
|
24 (4%)
|
0
|
|
General Disorders and Administration Site Conditions
|
|
Fatigue
|
143 (25%)
|
15 (3%)
|
161 (27%)
|
22 (4%)
|
|
Asthenia
|
89 (15%)
|
11 (2%)
|
117 (20%)
|
12 (2%)
|
|
Edema
peripheral
|
39 (7%)
|
1 (0.2%)
|
53 (9%)
|
1 (0.2%)
|
|
Pyrexia
|
27 (5%)
|
1 (0.2%)
|
38 (6 %)
|
1 (0.2%)
|
|
Investigations
|
|
Weight
decreased
|
24 (4%)
|
1 (0.2%)
|
44 (7%)
|
0
|
|
Injury, Poisoning and Procedural Complications
|
|
Wrong
technique in drug usage process
|
2 (0.3%)
|
0
|
32 (5%)
|
0
|
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
|
|
|
Jevtana 20 mg/m2 every 3 weeks with prednisone 10
mg daily
n=577
|
Jevtana 25 mg/m2 every 3 weeks with prednisone 10
mg daily
n=590
|
|
Laboratory
Abnormality
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
Grade 1–4
n (%)
|
Grade 3–4
n (%)
|
|
Neutropenia
|
384 (67%)
|
241 (42%)
|
522 (89%)
|
432 (73%)
|
|
Anemia
|
576 (99.8%)
|
57 (10%)
|
588 (99.7%)
|
81 (14%)
|
|
Leukopenia
|
461 (80%)
|
167 (29%)
|
560 (95%)
|
351 (60%)
|
|
Thrombocytopenia
|
202 (35%)
|
15 (3%)
|
251 (43%)
|
25 (4%)
|
|
|
|
|
|
|
|
|
|
Hematuria
In study TROPIC, adverse
reactions of hematuria, including those requiring medical intervention, were
more common in Jevtana-treated patients. The incidence of grade ≥2 hematuria
was 6% in Jevtana-treated patients and 2% in mitoxantrone-treated patients.
Other factors associated with hematuria were well-balanced between arms and do
not account for the increased rate of hematuria on the Jevtana arm.
In study PROSELICA, hematuria
of all grades was observed in 18% of patients overall.
Hepatic
Laboratory Abnormalities
The incidences of grade 3–4
increased AST, increased ALT, and increased bilirubin were each ≤1%.
Postmarketing
Experience
The following adverse
reactions have been identified from clinical trials and/or postmarketing
surveillance. Because they are reported from a population of unknown size,
precise estimates of frequency cannot be made.
Gastrointestinal: Gastritis,
intestinal obstruction.
Respiratory: Interstitial
pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress
syndrome.
Drug InteractionsCYP3A
Inhibitors
Cabazitaxel is primarily
metabolized through CYP3A [see Clinical
Pharmacology (12.3)]. Strong CYP3A inhibitors
(e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir,
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may
increase plasma concentrations of cabazitaxel. Avoid the coadministration of
Jevtana with strong CYP3A inhibitors. If patients require coadministration of a
strong CYP3A inhibitor, consider a 25% Jevtana dose reduction [see Dosage and
Administration (2.4) and Clinical Pharmacology
(12.3)].
USE IN SPECIFIC POPULATIONSPregnancy
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. In animal
reproduction studies, intravenous administration of cabazitaxel in pregnant
rats during organogenesis caused embryonic and fetal death at doses lower than
the maximum recommended human dose [see Data].
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 ≥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 postimplantation 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 ≥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.
Lactation
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 [see Data].
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.
Females and
Males of Reproductive Potential
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 [see Use in
Specific Populations (8.1)].
Infertility
Males
Based on animal toxicology
studies, cabazitaxel injection may impair human fertility in males of
reproductive potential [see Nonclinical
Toxicology (13.1)].
Pediatric Use
The safety and effectiveness
of Jevtana in pediatric patients have not been established.
Jevtana was evaluated in 39
pediatric patients (ages 3 to 18 years) receiving prophylactic G-CSF. The
maximum tolerated dose (MTD) was 30 mg/m2 intravenously over 1
hour on Day 1 of a 21 day cycle in pediatric patients with solid tumors based
on the dose-limiting toxicity (DLT) of febrile neutropenia. No objective
responses were observed in 11 patients with refractory high grade glioma (HGG)
or diffuse intrinsic pontine glioma (DIPG). One patient had a partial response
among the 9 patients with ependymoma.
Infusion
related/hypersensitivity reactions were seen in 10 patients (26%). Three
patients experienced serious adverse events of anaphylactic reaction. The
incidence of infusion related/hypersensitivity reactions decreased with steroid
pre-medication. The most frequent treatment-emergent adverse events were
similar to those reported in adults.
Based on the population
pharmacokinetics analysis conducted with data from 31 pediatric patients with
cancer (ages 3 to 18 years), the clearances by body surface area were
comparable to those in adults.
Geriatric Use
In the TROPIC study, of the
371 patients with prostate cancer treated with Jevtana every three weeks plus
prednisone, 240 patients (64.7%) were 65 years of age and over, while 70
patients (18.9%) were 75 years of age and over. No overall differences in
effectiveness were observed between patients ≥65 years of age and younger
patients. Elderly patients (≥65 years of age) may be more likely to experience
certain adverse reactions. The incidence of death due to causes other than
disease progression within 30 days of the last cabazitaxel dose were higher in
patients who were 65 years of age or greater compared to younger patients [see Warnings and
Precautions (5.2)]. The incidence of grade 3–4 neutropenia and febrile neutropenia
were higher in patients who were 65 years of age or greater compared to younger
patients. The following grade 1–4 adverse reactions were reported at rates ≥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%).
Based on a population
pharmacokinetic analysis, no significant difference was observed in the
pharmacokinetics of cabazitaxel between patients <65 years (n=100) and older
(n=70).
Renal
Impairment
No dose adjustment is
necessary in patients with renal impairment not requiring hemodialysis.
Patients presenting with end-stage renal disease (creatinine clearance CLCR <15 mL/min/1.73 m2), should be monitored
carefully during treatment [see Clinical
Pharmacology (12.3)].
Hepatic
Impairment
Cabazitaxel is extensively
metabolized in the liver. Patients with mild hepatic impairment (total
bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) should have Jevtana dose of
20 mg/m2. Administration of cabazitaxel to patients with mild hepatic
impairment should be undertaken with caution and close monitoring of
safety [see Clinical
Pharmacology (12.3)]. The maximum tolerated
dose in patients with moderate hepatic impairment (total bilirubin >1.5 to
≤3.0 × ULN and AST = any) was 15 mg/m2, however, the efficacy at this dose level was unknown. Jevtana
is contraindicated in patients with severe hepatic impairment (total bilirubin
>3 × ULN) [see Contraindications
(4)].
Overdosage
There is no known antidote for
Jevtana overdose. Overdose has resulted from improper preparation [see Dosage and
Administration (2.5)]. Read the entire section Dosage and Administration (2) carefully before
mixing or diluting. Complications of overdose include exacerbation of adverse
reactions such as bone marrow suppression and gastrointestinal disorders.
Overdose has led to fatal outcome.
In case of overdose, the
patient should be kept in a specialized unit where vital signs, chemistry and
particular functions can be closely monitored. Patients should receive
therapeutic G-CSF as soon as possible after discovery of overdose. Other
appropriate symptomatic measures should be taken, as needed.
Jevtana Description
Jevtana (cabazitaxel)
injection is an antineoplastic agent belonging to the taxane class that is for
intravenous use. It is prepared by semi-synthesis with a precursor extracted
from yew needles.
The chemical name of
cabazitaxel is
(2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl)
amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl
benzoate–propan-2-one (1:1).
Cabazitaxel has the following
structural formula:
Cabazitaxel is a white to
almost-white powder with a molecular formula of C45H57NO14C3H6O and a molecular weight of
894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is
lipophilic, practically insoluble in water and soluble in alcohol.
Jevtana (cabazitaxel)
injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to
brownish-yellow viscous solution and is available in single-dose vials
containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate
80.
Each mL contains 40 mg
cabazitaxel (anhydrous) and 1.04 g polysorbate 80.
DILUENT for Jevtana is a
clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w)
ethanol in water for injection, approximately 5.7 mL.
Jevtana requires two dilutions
prior to intravenous infusion. Jevtana injection should be diluted only with
the supplied DILUENT for Jevtana, followed by dilution in either 0.9% sodium
chloride solution or 5% dextrose solution.
Jevtana - Clinical PharmacologyMechanism of
Action
Cabazitaxel is a microtubule
inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into
microtubules while simultaneously inhibiting disassembly. This leads to the
stabilization of microtubules, which results in the inhibition of mitotic and
interphase cellular functions.
Pharmacodynamics
Cardiac
Electrophysiology
The effect of cabazitaxel
following a single dose of 25 mg/m2 administered by intravenous infusion on QTc interval was
evaluated in 94 patients with solid tumors. No large changes in the mean QT
interval (i.e., >20 ms) from baseline based on Fridericia correction method
were detected. However, a small increase in the mean QTc interval (i.e., <10
ms) cannot be excluded due to study design limitations.
Pharmacokinetics
A population pharmacokinetic
analysis was conducted in 170 patients with solid tumors at doses ranging from
10 to 30 mg/m2 weekly or every three weeks.
Absorption
Based on the population
pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m2every three weeks, the mean Cmax in patients with
metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end
of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was
991 ng∙h/mL (CV 34%).
No major deviation from the
dose proportionality was observed from 10 to 30 mg/m2 in patients with
advanced solid tumors.
Distribution
The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a
median BSA of 1.84 m2) at steady state.
In
vitro, the binding of cabazitaxel to human
serum proteins was 89 to 92% and was not saturable up to 50,000 ng/mL, which
covers the maximum concentration observed in clinical trials. Cabazitaxel is mainly
bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL,
and 56% for VLDL). The in vitro blood-to-plasma
concentration ratio in human blood ranged from 0.90 to 0.99, indicating that
cabazitaxel was equally distributed between blood and plasma.
Metabolism
Cabazitaxel is extensively
metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to
90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating
moiety in human plasma. Seven metabolites were detected in plasma (including
the 3 active metabolites issued from O-demethylation), with the main one
accounting for 5% of cabazitaxel exposure. Around 20 metabolites of cabazitaxel
are excreted into human urine and feces.
Elimination
After a one-hour intravenous
infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated
within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous
metabolites (76% of the dose); while renal excretion of cabazitaxel and
metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).
Based on the population
pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV
39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic
prostate cancer. Following a one-hour intravenous infusion, plasma
concentrations of cabazitaxel can be described by a three-compartment
pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and
95 hours, respectively.
Renal
Impairment
Cabazitaxel is minimally
excreted via the kidney. A population pharmacokinetic analysis carried out in
170 patients including 14 patients with moderate renal impairment (30 mL/min
≤CLCR <50
mL/min) and 59 patients with mild renal impairment (50 mL/min ≤CLCR <80 mL/min) showed
that mild to moderate renal impairment did not have meaningful effects on the
pharmacokinetics of cabazitaxel. This was confirmed by a dedicated comparative
pharmacokinetic study in patients with solid tumors with normal renal function
(n=8, CLCR >80 mL/min/1.73 m2), or moderate (n=8, 30
mL/min/1.73 m2 ≤CLCR <50 mL/min/1.73 m2) and severe (n=9, CLCR <30 mL/min/1.73 m2) renal impairment, who
received several cycles of cabazitaxel in single IV infusion up to 25 mg/m2. Limited pharmacokinetic data
were available in patients with end-stage renal disease (n=2, CLCR <15 mL/min/1.73 m2).
Hepatic
Impairment
Cabazitaxel is extensively
metabolized in the liver.
A dedicated study in 43 cancer
patients with hepatic impairment showed no influence of mild (total bilirubin
>1 to ≤1.5 × ULN or AST >1.5 × ULN) or moderate (total bilirubin >1.5
to ≤3.0 × ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum
tolerated dose (MTD) of cabazitaxel was 20 and 15 mg/m2, respectively.
In 3 patients with severe
hepatic impairment (total bilirubin >3 × ULN), a 39% decrease in clearance
was observed when compared to patients with mild hepatic impairment
(ratio=0.61, 90% CI: 0.36–1.05), indicating some effect of severe hepatic
impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients
with severe hepatic impairment was not established. Based on safety and
tolerability data, cabazitaxel dose should be maintained at 20 mg/m2 in patients with mild
hepatic impairment and reduced to 15 mg/m2 in patients with
moderate hepatic impairment [see Warnings
and Precautions (5.7) and Use in Specific
Populations (8.7)]. Cabazitaxel is contraindicated in patients with severe hepatic
impairment [see Contraindications
(4) and Use in
Specific Populations (8.7)].
Drug
Interactions
A drug interaction study of
Jevtana in 23 patients with advanced cancers has shown that repeated
administration of ketoconazole (400 mg orally once daily), a strong CYP3A
inhibitor, increased the exposure to cabazitaxel (5 mg/m2 intravenous) by 25%.
A drug interaction study of
Jevtana in 13 patients with advanced cancers has shown that repeated
administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A
inhibitor, did not modify the exposure to cabazitaxel (15 mg/m2 intravenous).
A drug interaction study of
Jevtana in 21 patients with advanced cancers has shown that repeated
administration of rifampin (600 mg once daily), a strong CYP3A inducer,
decreased the exposure to cabazitaxel (15 mg/m2 intravenous) by 17%.
A drug interaction study of
Jevtana in 11 patients with advanced cancers has shown that cabazitaxel (25
mg/m2 administered
as a single 1-hour infusion) did not modify the exposure to midazolam, a probe
substrate of CYP3A.
Prednisone or prednisolone administered
at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
Based on in vitro studies, the potential for
cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes
(1A2,-2B6,-2C9, -2C8, -2C19, -2E1, -2D6, and CYP3A4/5) is low. In addition,
cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro.
In
vitro, cabazitaxel did not inhibit the
multidrug-resistance protein 1 (MRP1), 2 (MRP2) or organic cation transporter
(OCT1). In vitro, cabazitaxel
inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1,
OATP1B3). However the in vivo risk
of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at
the dose of 25 mg/m2.
In
vitro, cabazitaxel is a substrate of P-gp,
but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3.
Nonclinical ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
Long-term animal studies have
not been performed to evaluate the carcinogenic potential of cabazitaxel.
Cabazitaxel was positive for
clastogenesis in the in vivo micronucleus
test, inducing an increase of micronuclei in rats at doses ≥0.5 mg/kg.
Cabazitaxel increased numerical aberrations with or without metabolic
activation in an in vitro test in
human lymphocytes though no induction of structural aberrations was observed.
Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames)
test. The positive in vivo genotoxicity
findings are consistent with the pharmacological activity of the compound
(inhibition of tubulin depolymerization).
In a fertility study performed
in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no
effect of administration of the drug on mating behavior or the ability to
become pregnant. In repeat-dose toxicology studies in rats with intravenous
cabazitaxel administration once every three weeks for up to 6 months, atrophy
of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in
patients with cancer at the recommended human dose) along with necrosis of the
corpora lutea at doses ≥1 mg/kg (approximately 0.2 times the AUC at the
clinically recommended human dose).
In a fertility study in male
rats, cabazitaxel did not affect mating performances or fertility at doses of
0.05, 0.1, or 0.2 mg/kg/day. In repeat-dose toxicology studies with intravenous
cabazitaxel administration once every three weeks for up to 9 months,
degeneration of seminal vesicle and seminiferous tubule atrophy in the testis
were observed in rats at a dose of 1 mg/kg (approximately 0.2 times the AUC in
patients at the recommended human dose), and minimal testicular degeneration
(minimal epithelial single cell necrosis in epididymis) was observed in dogs
treated at a dose of 0.5 mg/kg (approximately 0.1 times the AUC in patients at
the recommended human dose).
Clinical StudiesTROPIC Trial
(Jevtana + prednisone compared to mitoxantrone)
The efficacy and safety of
Jevtana in combination with prednisone were evaluated in a randomized,
open-label, international, multi-center study in patients with metastatic
castration-resistant prostate cancer previously treated with a
docetaxel-containing treatment regimen (TROPIC, NCT00417079).
A total of 755 patients were
randomized to receive either Jevtana 25 mg/m2 intravenously every 3
weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or
to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone
10 mg orally daily (n=377) for a maximum of 10 cycles.
This study included patients
over 18 years of age with hormone-refractory metastatic prostate cancer either
measurable by RECIST criteria or non-measurable disease with rising PSA levels
or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group)
performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000
cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of
normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 ×
ULN. Patients with a history of congestive heart failure, or myocardial
infarction within the last 6 months, or patients with uncontrolled cardiac
arrhythmias, angina pectoris, and/or hypertension were not included in the
study.
Demographics, including age,
race, and ECOG performance status (0–2) were balanced between the treatment
arms. The median age was 68 years (range 46–92) and the racial distribution for
all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the
Jevtana group.
Efficacy results for the Jevtana
arm versus the control arm are summarized in Table 5 and Figure 1.
Table 5: Efficacy of Jevtana in TROPIC in the Treatment of Patients
with Metastatic Castration-Resistant Prostate Cancer (intent-to-treat
analysis)
|
|
|
Jevtana + Prednisone
n=378
|
Mitoxantrone + Prednisone
n=377
|
|
*
Hazard ratio estimated using Cox model; a hazard
ratio of less than 1 favors Jevtana
|
|
Overall Survival
|
|
|
|
Number of deaths
(%)
|
234 (61.9 %)
|
279 (74%)
|
|
Median survival
(month) (95% CI)
|
15.1 (14.1–16.3)
|
12.7 (11.6–13.7)
|
|
Hazard Ratio* (95% CI)
|
0.70 (0.59–0.83)
|
|
p-value
|
<0.0001
|
Figure
1: Kaplan-Meier Overall Survival Curves (TROPIC)
Investigator-assessed tumor
response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the Jevtana arm
compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm,
p=0.0005.
PROSELICA
Trial (comparison of two doses of Jevtana)
In a noninferiority,
multicenter, randomized, open-label study (PROSELICA, NCT01308580), 1200
patients with metastatic castration-resistant prostate cancer, previously
treated with a docetaxel-containing regimen, were randomized to receive either
Jevtana 25 mg/m2 (n=602) or 20 mg/m2(n=598) dose. Overall survival (OS) was the major efficacy
outcome.
Demographics, including age,
race, and ECOG performance status (0–2) were balanced between the treatment
arms. The median age was 68 years (range 45–89) and the racial distribution for
all groups was 87% Caucasian, 6.9% Asian, 2.3% Black, and 3.8% Others in the
Jevtana 20 mg/m2 group. The median age was 69 years (range 45–88) and the
racial distribution for all groups was 88.7% Caucasian, 6.6% Asian, 1.8% Black,
and 2.8% Others in the Jevtana 25 mg/m2 group.
The study demonstrated
noninferiority in overall survival (OS) of Jevtana 20 mg/m2 in comparison with
Jevtana 25 mg/m2 in an intent-to-treat population (see Table
6 and Figure 2). Based on the per-protocol population, the estimated median OS
was 15.1 months on Jevtana 20 mg/m2 and 15.9 months on Jevtana 25 mg/m2, the observed hazard ratio
(HR) of OS was 1.042 (97.78% CI: 0.886, 1.224). Among the subgroup analyses
intended for assessing the heterogeneity, no notable difference in OS was
observed on the Jevtana 25 mg/m2 arm compared to the Jevtana 20 mg/m2 arm in subgroups based
on the stratification factors of ECOG performance status score, measurability
of disease, or region.
Table 6: Overall Survival in PROSELICA for Jevtana 20 mg/m2 versus Jevtana 25
mg/m2 (intent-to-treat analysis)
|
|
|
CBZ20+PRED
n=598
|
CBZ25+PRED
n=602
|
|
CBZ20=Cabazitaxel
20 mg/m2, CBZ25=Cabazitaxel 25 mg/m2, PRED=Prednisone/Prednisolone.
CI=confidence interval.
|
|
*
Hazard ratio is
estimated using a Cox Proportional Hazards regression model. A hazard ratio
<1 indicates a lower risk of death for Cabazitaxel 20 mg/m2 with respect to 25 mg/m2.
†
Adjusted for interim OS analyses. The noninferiority
margin is 1.214.
|
|
Overall Survival
|
|
|
|
Number of
deaths, n (%)
|
497 (83.1 %)
|
501 (83.2%)
|
|
Median survival
(95% CI) (months)
|
13.4 (12.2 to 14.9)
|
14.5 (13.5 to 15.3)
|
|
Hazard Ratio* (97.78% CI†)
|
1.024 (0.886, 1.184)
|
|
Figure
2: Kaplan-Meier Overall Survival Curves (intent-to-treat population) (PROSELICA)
REFERENCES
1. OSHA Hazardous Drugs. OSHA.
http://www.osha.gov/SLTC/hazardousdrugs/index.html
How Supplied/Storage and HandlingHow Supplied
Jevtana is supplied as a kit
consisting of the following:
One single-dose vial of Jevtana (cabazitaxel)
injection: a clear yellow to brownish-yellow viscous solution of 60 mg/1.5
mL in a clear glass vial with a grey rubber closure, aluminum cap, and
light green plastic flip-off capOne single-dose vial of Diluent for Jevtana: a
clear colorless solution of 13% (w/w) ethanol in water for injection in a
clear glass vial with a grey rubber closure, gold-color aluminum cap, and
colorless plastic flip-off cap.
Both items are in a blister
pack in one carton.
NDC 0024-5824-11
Storage
Jevtana injection and Diluent
for Jevtana:
Store at 25°C (77°F);
excursions permitted between 15°–30°C (59°–86°F).
Do not refrigerate.
Handling and
Disposal
Jevtana is a cytotoxic
anticancer drug. Follow applicable special handling and disposable
procedures [see References
(15)].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling
(Patient Information).
Hypersensitivity
Reactions
Educate patients about the
risk of potential hypersensitivity associated with Jevtana. Confirm patients do
not have a history of severe hypersensitivity reactions to cabazitaxel or to
other drugs formulated with polysorbate 80. Instruct patients to immediately
report signs of a hypersensitivity reaction [see Contraindications
(4) and Warnings
and Precautions (5.3)].
Bone
Marrow Suppression
Inform patients that Jevtana
decreases blood count such as white blood cells, platelets and red blood cells.
Thus, it is important that periodic assessment of their blood count be
performed to detect the development of neutropenia, thrombocytopenia, anemia,
and/or pancytopenia [see Contraindications
(4) and Warnings
and Precautions (5.1)]. Instruct patients to monitor
their temperature frequently and immediately report any occurrence of fever to
their healthcare provider.
Increased
Toxicities in Elderly Patients
Inform elderly patients that
certain side effects may be more frequent or severe [see Warnings
and Precautions (5.2) and Use in Specific
Populations (8.5)].
Importance
of Prednisone
Explain that it is important
to take the oral prednisone as prescribed. Instruct patients to report if they
were not compliant with oral corticosteroid regimen [see Dosage
and Administration (2.1)].
Infections,
Dehydration, Renal Failure
Explain to patients that
severe and fatal infections, dehydration, and renal failure have been
associated with cabazitaxel exposure. Patients should immediately report fever,
significant vomiting or diarrhea, decreased urinary output, and hematuria to
their healthcare provider [see Warnings
and Precautions (5.1, 5.4, 5.5)].
Respiratory
Disorders
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 [see Warnings
and Precautions (5.6)].
Drug
Interactions
Inform patients about the risk
of drug interactions and the importance of providing a list of prescription and
non-prescription drugs to their healthcare provider [see Drug
Interactions (7.1)].
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 [see Use in Specific
Populations (8.3)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Jevtana is a registered
trademark of sanofi-aventis © 2017 sanofi-aventis U.S. LLC
|
Patient Information
Jevtana® (JEV-ta-na)
(cabazitaxel)
Injection
|
|
This
Patient Information has been approved by the U.S. Food and Drug Administration
|
Revised:
09/2017
|
|
Read this
Patient Information before you start receiving Jevtana and each time before
you receive your infusion. There may be new information. This information
does not take the place of talking to your healthcare provider about your
medical condition or your treatment.
|
|
What is the most important information I
should know about Jevtana?
Jevtana may cause serious side effects including:
Low white blood cells. Low white blood cells can cause you to get
serious infections, and may lead to death. Men who are 65 years or older may
be more likely to have these problems. Your healthcare provider:
will do blood tests regularly to
check your white blood cell counts during your treatment with Jevtana.may lower your dose of Jevtana,
change how often you receive it, or stop Jevtana until your healthcare
provider decides that you have enough white blood cells.may prescribe a medicine for you
called G-CSF, to help prevent complications if your white blood cell
count is too low.
Tell your healthcare provider right away if you have any of these
symptoms of infection during treatment with Jevtana:
fever. Take your temperature often during
treatment with Jevtana.
|
|
· cough
|
· burning
on urination
|
· muscle
aches
|
|
Also, tell your
healthcare provider if you have any diarrhea during the time that your white
blood cell count is low. Your healthcare provider may prescribe treatment for
you as needed.
Severe allergic reactions. Severe
allergic reactions can happen within a few minutes after your infusion of
Jevtana starts, especially during the first and second infusions. Your
healthcare provider should prescribe medicines before each infusion to help
prevent severe allergic reactions.
Tell your healthcare provider or nurse right away if you
have any of these symptoms of a severe allergic reaction during or soon after
an infusion of Jevtana:
|
|
· rash
or itching
· skin
redness
|
· feeling
dizzy or faint
· breathing
problems
|
· chest
or throat tightness
· swelling
of your face
|
|
Severe stomach and intestine (gastrointestinal) problems. Jevtana can
cause severe stomach and intestine problems, which may lead to death. You may
need to go to a hospital for treatment.
Vomiting and diarrhea can happen
when you receive Jevtana. Severe vomiting and diarrhea with Jevtana can
lead to loss of too much body fluid (dehydration), or too much of your
body salts (electrolytes). Death has happened from having severe
diarrhea and losing too much body fluid or body salts with Jevtana. Your
healthcare provider will prescribe medicines to prevent or treat
vomiting and diarrhea, as needed with Jevtana.
Tell your healthcare provider if:
you have vomiting or diarrheayour symptoms get worse or do not
get better
Jevtana can
cause a leak in the stomach or intestine, intestinal blockage, infection, and
bleeding in the stomach or intestine. This can lead to death. Tell your healthcare provider if you get any of these symptoms:
|
|
· severe
stomach-area (abdomen) pain
|
· constipation
|
· fever
|
|
blood in your stool, or changes in
the color of your stool
Kidney failure. Kidney failure may happen with Jevtana, because of severe
infection, loss of too much body fluid (dehydration), and other reasons,
which may lead to death. Your healthcare provider will check you for this
problem and treat you if needed.
Tell your healthcare provider if you develop these signs
or symptoms:
swelling of your face or bodydecrease in the amount of urine that
your body makes each dayblood in your urine
Lung or breathing problems. Lung or breathing problems may happen with
Jevtana and may lead to death. Men 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 is Jevtana?
Jevtana is a prescription anti-cancer medicine used with the steroid medicine
prednisone. Jevtana is used to treat men with castration-resistant prostate
cancer (prostate cancer that is resistant to medical or surgical treatments
that lower testosterone) that has worsened (progressed) after treatment with
other medicines that included docetaxel.
Jevtana is not for use in females.
It is not known if Jevtana is safe and effective in children.
|
|
Who should not receive Jevtana?
Do not receive Jevtana if:
your white blood cell (neutrophil
count) is too lowyou have had a severe allergic
reaction to cabazitaxel or other medicines that contain polysorbate 80.
Ask your healthcare provider if you are not sure.you have severe liver problemsyou are pregnant. Jevtana can harm your unborn
baby or possibly cause loss of pregnancy.
|
|
Before receiving Jevtana, tell your healthcare provider about all
your medical conditions, including if you:
|
|
· had
allergic reactions in the past
· have
kidney or liver problems
· have
lung problems
|
· are
over the age of 65
|
|
are a male with a female partner who
is able to become pregnant. Males should use effective birth control
(contraception) during treatment with Jevtana and for 3 months after
your final dose of Jevtana.
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements. Jevtana can
interact with many other medicines. Do not take any new medicines without
asking your healthcare provider first. Your healthcare provider will tell you
if it is safe to take the new medicine with Jevtana.
|
|
How will I receive Jevtana?
Jevtana will be given to you by an
intravenous (IV) infusion into your vein.Your treatment will take about 1
hour.Jevtana is usually given every 3
weeks. Your healthcare provider will decide how often you will receive
Jevtana.Your healthcare provider will also prescribe
another medicine called prednisone for you to take by mouth every day
during treatment with Jevtana. Your healthcare provider will tell you
how and when to take your prednisone.
It is important
that you take prednisone exactly as prescribed by your healthcare provider.
If you forget to take your prednisone, or do not take it on schedule, make
sure to tell your healthcare provider or nurse. Before each infusion of
Jevtana, you may receive other medicines to prevent or treat side effects.
|
|
What are the possible side effects of Jevtana?
Jevtana may cause serious side effects including:
See "What is the most important
information I should know about Jevtana?"
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
· tiredness
· nausea
· vomiting
· constipation
|
· weakness
· stomach
(abdominal) pain
· blood
in your urine. Tell your healthcare provider or nurse if you see blood in
your urine.
· back
pain
· decreased
appetite
· shortness
of breath
· hair
loss
· cough
|
|
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 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.
|
|
General information about the safe and effective use of Jevtana
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. You can ask your pharmacist or healthcare
provider for information about Jevtana that is written for health
professionals.
|
|
What are the ingredients in Jevtana?
Active ingredient: cabazitaxel
Inactive ingredient: polysorbate 80
Manufactured by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807 A SANOFI
COMPANY
Jevtana is a registered trademark of sanofi-aventis © 2017 sanofi-aventis
U.S. LLC
For more information, go to www.sanofi-aventis.us or call
1-800-633-1610.
|
PRINCIPAL
DISPLAY PANEL - Kit Carton
NDC 0024-5824-11
Jevtana®
(cabazitaxel)
Injection
60
mg/1.5 mL Before First Dilution*
This carton contains: 1 Jevtana
vial and 1 Diluent vial
*Requires two dilutions before administration-See back panel for details
FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION
CYTOTOXIC AGENT
RX
ONLY
SANOFI
PRINCIPAL
DISPLAY PANEL - 60 mg/1.5 mL Vial Label
Jevtana®
(cabazitaxel) Injection
NDC 0024-5823-15
RX ONLY
60 mg/1.5 mL Before First Dilution*
*FOR INTRAVENOUS INFUSION ONLY
AFTER SECOND DILUTION
CAUTION: Reconstitute this vial using the entire contents
of the diluent
vial (approx. 5.7 mL). Following this first dilution, the resultant solution
contains a concentration of 10 mg/mL. Withdraw
only the required
amount of the first dilution to prepare the final infusion solution prior
to administration. See package insert for full dilution information.
Store
at 25°C (77°F); excursions permitted between 15°-30°C
(59°-86°F). Do not refrigerate.
Single-dose vial.
CYTOTOXIC AGENT
sanofi-aventis U.S. LLC / Origin France 50110242
<MAT>526223
PRINCIPAL
DISPLAY PANEL - 5.7 mL Vial Label
DILUENT
NDC 0024-5822-01
5.7 mL of 13 % (w/w) ethanol
in water for injection.
Use ONLY for dilution of
Jevtana.
See package insert for full
preparation instructions.
Store
at 25°C (77°F); excursions permitted
between 15°-30°C (59°-86°F). Do not refrigerate.
Single-dose vial.
RX ONLY
sanofi-aventis U.S. LLC /
Origin Germany
50110243
<MAT>526222
|
Jevtana cabazitaxel kit
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0024-5824
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0024-5824-11
|
1 KIT in 1 CARTON
|
|
|
|
Quantity of
Parts
|
|
Part #
|
Package
Quantity
|
Total
Product Quantity
|
|
|
|
Part 1
|
1 VIAL, GLASS
|
5.7 mL
|
|
|
|
Part 2
|
1 VIAL, GLASS
|
5.7 mL
|
|
|
|
|
Part
1 of 2
|
|
Jevtana cabazitaxel
injection, solution, concentrate
|
|
|
Product
Information
|
|
Item Code
(Source)
|
NDC:0024-5823
|
|
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
cabazitaxel (cabazitaxel)
|
cabazitaxel
|
60 mg
in 1.5 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
Polysorbate 80
|
1.56 g
in 1.5 mL
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0024-5823-15
|
5.7 mL in 1
VIAL, GLASS
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA201023
|
06/17/2010
|
|
|
|
Part
2 of 2
|
|
DILUENT alcohol
and water injection
|
|
|
Product
Information
|
|
Item Code
(Source)
|
NDC:0024-5822
|
|
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
alcohol
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0024-5822-01
|
5.7 mL in 1
VIAL, GLASS
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA201023
|
06/17/2010
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA201023
|
06/17/2010
|
|
|
|
Labeler - Sanofi-Aventis U.S. LLC (824676584)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Sanofi-Aventis
Deutschland GmbH
|
|
313218430
|
MANUFACTURE(0024-5824),
ANALYSIS(0024-5824), LABEL(0024-5824), PACK(0024-5824)
|
Revised:
09/2017
Sanofi-Aventis U.S. LLC
