Drug Safety-related Labeling Changes (SrLC)
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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
CABAZITAXEL (NDA-207949)
(CABAZITAXEL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/10/2024 (SUPPL-2)
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. Cabazitaxel Injection is contraindicated in patients with neutrophil counts of
Less than or equal to,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.2)].
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5 Warnings and Precautions
5.1 Bone Marrow Suppression
Additions and/or revisions underlined:
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TROPIC Trial (Cabazitaxel 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 cabazitaxel treatment due to neutropenia, febrile neutropenia, infection, or sepsis. Grade 3 - 4 neutropenia occurred in 82% of patients treated with cabazitaxel in the randomized trial [see Adverse Reactions (6.1)].
PROSELICA Trial (comparison of cabazitaxel 20 mg/m2 versus 25 mg/m2)
In the PROSELICA trial comparing two doses of cabazitaxel, 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 cabazitaxel 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 (Cabazitaxel 25 mg/m2 + primary prophylaxis G-CSF)
In the CARD trial where Cabazitaxel 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 were 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 cabazitaxel, 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 cabazitaxel 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 a randomized trial (TROPIC), 2% of patients (3/131) <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 cabazitaxel 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 was 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 cabazitaxel, deaths due to infection within 30 days of starting cabazitaxel 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.
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In CARD, a death due to infection within 30 days of starting cabazitaxel 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 cabazitaxel dose; all of these patients were >75 years of age.
5.5 Renal Failure
Additions and /or revisions underlined:
In the randomized clinical trial (TROPIC), renal failure of any Grade occurred in 4% of the patients being treated with cabazitaxel, 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.
5.9 Embryo-Fetal Toxicity
Additions and/or revisions underlined:
Based on findings in animal reproduction studies and its mechanism of action, Cabazitaxel Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. 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 (approximately 0.06 times the Cmax in patients at the recommended human dose). Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Cabazitaxel Injection [see Use in Specific Populations (8.1, 8.3)].
6 Adverse Reactions
6.1 Clinical Trials ExperienceExtensive additions and/or revisions, please refer to label for complete information.
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
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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 embryo-fetal 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 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
Additions and/or revisions underlined:
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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 of0.08 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
Additions and/or revisions underlined:
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 4 months after the last dose of Cabazitaxel Injection [see Use in Specific Populations (8.1)].
8.5 Geriatric Use
Additions and/or revisions underlined:
In the TROPIC study, of the 371 patients with prostate cancer treated with cabazitaxel 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 greater than or equal to 65 years of age and younger patients. Elderly patients (greater than or equal to 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 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.
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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).
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).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
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Embryo-Fetal Toxicity
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of Cabazitaxel Injection [see Use in Specific Populations (8.3)].
PATIENT INFORMATION
Additions and/or revisions underlined:
What is the most important information I should know about Cabazitaxel Injection?
Cabazitaxel Injection may cause serious side effects including:
Low white blood cell count. Low white blood cell counts are common during treatment with Cabazitaxel Injection and can cause serious infections that may lead to death. Men who are 65 years or older may be more likely to have these problems. Your healthcare provider:
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Before receiving Cabazitaxel Injection, tell your healthcare provider about all your medical conditions, including if you:
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have a history of radiation to the pelvis
have a history of stomach and intestine (gastrointestinal) problems, including scar tissues, inflammation, and bleeding
are pregnant or plan to become pregnant. Cabazitaxel Injection can cause harm to your unborn baby and loss of pregnancy (miscarriage).
are a male with a female partner who is able to become pregnant. Males should use effective birth control (contraception) during treatment with Cabazitaxel Injection and for 4 months after the last dose of Cabazitaxel Injection.
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