2.1 Dosing Information

The recommended dose of Cabazitaxel Injection is based on calculation of the Body Surface Area (BSA), and is 20 mg/m 2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout Cabazitaxel Injection treatment.

A dose of 25 mg/m 2 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)].

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/m 2[see Contraindications (4) and Warnings and Precautions (5.1, 5.2)] .

Premedicate at least 30 minutes prior to each dose of Cabazitaxel Injection 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),
• H 2 antagonist.

Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see Warnings and Precautions (5.3)].

Cabazitaxel Injection single-dose vial requires two dilutions prior to administration [see Dosage and Administration (2.5)] .

2.2 Dose Modifications for Adverse Reactions

Reduce or discontinue Cabazitaxel Injection dosing for adverse reactions as described in Table 1.

Patients at a 20 mg/m 2 dose who require dose reduction should decrease dosage of Cabazitaxel Injection to 15 mg/m 2[see Adverse Reactions (6.1)].

Patients at a 25 mg/m 2 dose who require dose reduction should decrease dosage of Cabazitaxel Injection to 20 mg/m 2. One additional dose reduction to 15 mg/m 2 may be considered [see Adverse Reactions (6.1)].

2.3 Dose Modifications for Hepatic Impairment

• Mild hepatic impairment (total bilirubin > 1 to ≤1.5 x Upper Limit of Normal (ULN) or AST >1.5 x ULN): Administer Cabazitaxel Injection at a dose of 20 mg/m 2.
• Moderate hepatic impairment (total bilirubin >1.5 to ≤3 x ULN and AST = any): Administer Cabazitaxel Injection at a dose of 15 mg/m 2 based on tolerability data in these patients; however, the efficacy of this dose is unknown.
• Severe hepatic impairment (total bilirubin >3 x ULN): Cabazitaxel Injection is contraindicated in patients with severe hepatic impairment [see Warning and Precautions (5.8) and Clinical Pharmacology (12.3)].

2.4 Dose Modifications for Use with Strong CYP3A Inhibitors

2.5 Preparation and Administration

Cabazitaxel Injection is a cytotoxic anticancer drug. Follow applicable special handling and disposal procedures [see References (15)]. If Cabazitaxel Injection 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 Cabazitaxel Injection infusion solution.

Cabazitaxel Injection should not be mixed with any other drugs.

5.1 Bone Marrow Suppression

Cabazitaxel is contraindicated in patients with neutrophils ≤1,500/mm 3[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 (Cabazitaxel 25 mg/m 2)

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/m 2 versus 25 mg/m 2)

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/m 2 arm and 15 patients (3%) on the 25 mg/m 2 arm died from infection; of these, 4 deaths on the 20 mg/m 2 arm and 8 deaths on the 25 mg/m 2 arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m 2 arm and 9.2% on 25 mg/m 2 arm), neutropenic infection/sepsis (2.1% on 20 mg/m 2 arm and 6.4% on 25 mg/m 2 arm), and neutropenic deaths (0.3% on 20 mg/m 2 arm and 0.7% on 25 mg/m 2 arm).

Fewer patients receiving cabazitaxel 20 mg/m 2 were reported to have infectious adverse reactions. Grade 1-4 infections were experienced by 160 patients (28%) on the 20 mg/m 2 arm and 227 patients (38%) on the 25 mg/m 2 arm. Grade 3-4 infections were experienced by 57 patients (10%) on the 20 mg/m 2 arm and 120 patients (20%) on the 25 mg/m 2 arm. Noninferiority for overall survival was demonstrated between these two arms [see Adverse Reactions (6.1)] .

CARD Trial (Cabazitaxel 25 mg/m 2 + primary prophylaxis G-CSF)

In the CARD trial where Cabazitaxel 25 mg/m 2 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/m 2.

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

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 cabazitaxel 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 was 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 cabazitaxel, deaths due to infection within 30 days of starting cabazitaxel occurred in 0.7% (4/580) patients on the 20 mg/m 2 arm and 1.3% (8/595) patients on the 25 mg/m 2 arm; all of these patients were >60 years of age.

In PROSELICA, on the 20 mg/m 2 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 cabazitaxel dose. On the 25 mg/m 2 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 cabazitaxel dose [see Adverse Reactions (6) and Use in Specific Populations (8.5)] .

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.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of cabazitaxel, 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 cabazitaxel [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 cabazitaxel infusion and appropriate therapy. Cabazitaxel is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4)] .

5.4 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, anti-diarrheal or anti-emetic 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 cabazitaxel [see Adverse Reactions (6.2)] . Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, 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. Cabazitaxel treatment delay or discontinuation may be necessary.

The incidence of gastrointestinal adverse reactions is greater in the patients who have received prior radiation. In PROSELICA, diarrhea was reported in 41% (297/732) of patients who had received prior radiation and in 27% (118/443) of patients without prior radiation. Of the patients who had previously received radiation, more patients on the 25 mg/m 2 arm reported diarrhea, compared to patients on the 20 mg/m 2 arm.

5.5 Renal Failure

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.

5.6 Urinary Disorders Including Cystitis

Cystitis, radiation cystitis, and hematuria, including that requiring hospitalization, has been reported with cabazitaxel in patients who previously received pelvic radiation [see Adverse Reactions (6.2)] . In PROSELICA, cystitis and radiation cystitis were reported in 1.2% and 1.5% of patients who received prior radiation, respectively. Hematuria was reported in 19.4% of patients who received prior radiation and in 14.4% of patients who did not receive prior radiation. Cystitis from radiation recall may occur late in treatment with cabazitaxel. Monitor patients who previously received pelvic radiation for signs and symptoms of cystitis while on cabazitaxel. Interrupt or discontinue cabazitaxel in patients experiencing severe hemorrhagic cystitis. Medical and/or surgical supportive treatment may be required to treat severe hemorrhagic cystitis.

5.7 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 cabazitaxel if new or worsening pulmonary symptoms develop. Closely monitor, promptly investigate, and appropriately treat patients receiving cabazitaxel. Consider discontinuation. The benefit of resuming cabazitaxel treatment must be carefully evaluated.

5.8 Use in Patients with Hepatic Impairment

Cabazitaxel is extensively metabolized in the liver.

Cabazitaxel 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 cabazitaxel to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.

5.9 Embryo-Fetal Toxicity

Based on findings in animal reproduction studies and its mechanism of action, cabazitaxel 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 C max in patients at the recommended human dose). Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of cabazitaxel [see Use in Specific Populations (8.1, 8.3)].

6.1 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 (Cabazitaxel 25 mg/m 2 compared to mitoxantrone)

The safety of cabazitaxel 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%) cabazitaxel-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in cabazitaxel-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 cabazitaxel. Other fatal adverse reactions in cabazitaxel-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 cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.

Treatment discontinuations due to adverse reactions occurred in 18% of patients who received cabazitaxel and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the cabazitaxel group were neutropenia and renal failure. Dose reductions were reported in 12% of cabazitaxel-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of cabazitaxel-treated patients and 15% of mitoxantrone-treated patients.

PROSELICA Trial (comparison of two doses of cabazitaxel)

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 cabazitaxel 25 mg/m 2 (n=595) or the 20 mg/m 2 (n=580) dose.

Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m 2 and 32 (5.4%) patients in the 25 mg/m 2 arm. The most common fatal adverse reactions in cabazitaxel-treated patients were related to infections, and these occurred more commonly on the 25 mg/m 2 arm (n=15) than on the 20 mg/m 2 arm (n=8). Other fatal adverse reactions in cabazitaxel-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/m 2 versus 20 mg/m 2 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/m 2 versus 20 mg/m 2 arms were leukopenia, neutropenia, and febrile neutropenia.

Treatment discontinuations due to adverse reactions occurred in 17% of patients in the 20 mg/m 2 group and 20% of patients in the 25 mg/m 2 group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m 2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m 2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m 2 group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m 2, 19 patients (3%) had a dose reduced from 20 to 15 mg/m 2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m 2. In the 20 mg/m 2 group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m 2, and 9 patients (2%) had a dose reduced from 15 to 12 mg/m 2.

CARD Trial (Cabazitaxel 25 mg/m 2 + primary prophylaxis with G-CSF)

The safety of cabazitaxel 25 mg/m 2 in combination with prednisone/prednisolone and primary prophylaxis G-CSF was evaluated in a randomized, open-label study (CARD) in patients with metastatic castration-resistant prostate cancer who progressed after receiving prior docetaxel­ containing regimens and abiraterone acetate or enzalutamide [see Clinical Studies (14.3)] . This study compared cabazitaxel 25 mg/m2 in combination with prednisone/prednisolone and primary prophylaxis with G-CSF to either abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily. Among patients receiving cabazitaxel, 35% remained on treatment at 6 months and 4.7% remained on treatment at 12 months.

Serious adverse reactions occurred in 39% of patients receiving cabazitaxel. Serious adverse reactions in ≥3% of patients included neutropenia (6%), infections (4.8%), and diarrhea, fatigue, pneumonia, and spinal cord compression (3.2% each). Deaths due to causes other than disease progression were reported in 2.4% of cabazitaxel treated patients. Fatal adverse reactions in cabazitaxel-treated patients were septic shock, urinary tract infection (UTI), and aspiration (0.8% each).

Treatment discontinuations due to adverse drug reactions occurred in 20% of patients who received cabazitaxel and 8% of patients who received abiraterone acetate plus prednisone/prednisolone or enzalutamide. The adverse reactions leading to treatment discontinuation in >1% of patients in cabazitaxel arm were nervous system disorders, infections/infestations, and gastrointestinal disorders.

Dose interruptions (alone or in combination with dose reduction) due to an adverse reaction occurred in 31% of patients receiving cabazitaxel. Dose reductions were reported in 18% of cabazitaxel-treated patients. The most frequent adverse reactions leading to dose interruption of cabazitaxel were fatigue (7%) and hypersensitivity reaction (3.2%); the most frequent adverse reaction leading to reduction of cabazitaxel were neutropenia and peripheral neuropathy (3.9% each).

Table 4 summarizes the adverse reactions and laboratory hematologic abnormalities in patients in CARD.

The most common (≥10%) adverse reactions were fatigue, diarrhea, musculoskeletal pain, nausea, infections, peripheral neuropathy, hematuria, constipation, abdominal pain, decreased appetite, vomiting, dysgeusia, edema peripheral and lower urinary tract symptoms.

The most common (≥10%) hematologic abnormalities were anemia, lymphopenia, neutropenia and thrombocytopenia.

Hematuria

In study TROPIC, adverse reactions of hematuria, including those requiring medical intervention, were more common in cabazitaxel-treated patients. The incidence of grade ≥2 hematuria was 6% in cabazitaxel-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 cabazitaxel arm.

In study PROSELICA, hematuria of all grades was observed in 18% of patients overall.

In CARD, hematuria of all grades was observed in 16% of patients receiving cabazitaxel.

Hepatic Laboratory Abnormalities

The incidences of grade 3-4 increased AST, increased ALT, and increased bilirubin were each ≤1%.

6.2 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.

Renal and urinary disorders: Radiation recall hemorrhagic cystitis.

7.1 CYP3A 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 cabazitaxel with strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% cabazitaxel dose reduction [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.3 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 last dose of cabazitaxel [see Use in Specific Populations (8.1)].

Infertility

Males

Based on animal toxicology studies, cabazitaxel may impair human fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of cabazitaxel in pediatric patients have not been established.

Cabazitaxel was evaluated in 39 pediatric patients (ages 3 to 18 years) receiving prophylactic G-CSF. The maximum tolerated dose (MTD) was 30 mg/m 2 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.

8.5 Geriatric Use

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 ≥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%).

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).

8.6 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 <15mL/min/1.73m 2), should be monitored carefully during treatment [see Clinical Pharmacology (12.3)].

8.7 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 cabazitaxel dose of 20 mg/m 2. 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/m 2, however, the efficacy at this dose level was unknown. Cabazitaxel Injection is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see Contraindications (4)].

12.1 Mechanism 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from 10 to 30 mg/m 2 weekly or every three weeks.

13.1 Carcinogenesis, 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).

14.1 TROPIC Trial (Cabazitaxel + prednisone compared to mitoxantrone)

The efficacy and safety of cabazitaxel in combination with prednisone were evaluated in a randomized, open-label, international, multicenter 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 cabazitaxel 25 mg/m 2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m 2 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/mm 3, platelets >100,000 cells/mm 3, 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 cabazitaxel group.

Efficacy results for the cabazitaxel arm versus the control arm are summarized in Table 5 and Figure 1.

Investigator-assessed tumor response of 14.4% (95%CI: 9.6-19.3) was higher for patients in the cabazitaxel arm compared to 4.4% (95%CI: 1.6-7.2) for patients in the mitoxantrone arm, p=0.0005.

14.2 PROSELICA Trial (comparison of two doses of cabazitaxel)

The efficacy and safety of cabazitaxel were evaluated in a noninferiority, multicenter, randomized, open-label study (PROSELICA, NCT01308580). A total of 1200 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen were randomized to receive either cabazitaxel 25 mg/m 2 (n=602) or 20 mg/m 2 (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 cabazitaxel 20 mg/m 2 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 cabazitaxel 25 mg/m 2 group.

The study demonstrated noninferiority in overall survival (OS) of cabazitaxel 20 mg/m 2 in comparison with cabazitaxel 25 mg/m 2 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 cabazitaxel 20 mg/m 2 and 15.9 months on cabazitaxel 25 mg/m 2, 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 cabazitaxel 25 mg/m 2 arm compared to the cabazitaxel 20 mg/m 2 arm in subgroups based on the stratification factors of ECOG performance status score, measurability of disease, or region.

14.3 CARD Trial (Cabazitaxel 25 mg/m 2 + prednisone/prednisolone + primary prophylaxis with G-CSF compared to abiraterone acetate + prednisone/prednisolone or enzalutamide)

The efficacy and safety of cabazitaxel were evaluated in a multinational, randomized, active- controlled, open-label study (CARD: NCT02485691) in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel containing regimen and had progressed within 12 months of initiating either abiraterone or enzalutamide. A total of 255 patients were randomized to receive either cabazitaxel 25 mg/m 2 every 3 week plus prednisone/prednisolone 10 mg daily (n=129), abiraterone 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily depending on prior therapy received (n=126). Primary prophylactic G-CSF was administered at each cycle for patients in the cabazitaxel arm. This study included patients over 18 years of age with ECOG performance status 0-2. Patients had to have neutrophils >1,500 cells/mm 3, platelets >100,000 cells/mm 3, 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. Randomization was stratified by ECOG performance status (0 or 1 vs 2), time from abiraterone acetate or enzalutamide to disease progression, and receipt of abiraterone acetate or enzalutamide before or after docetaxel containing regimen.

The major efficacy outcome measure was radiographic progression free-survival (rPFS) as defined by Prostate Cancer Working Group-2 (PCWG2) assessed by study investigators. Other efficacy outcome measures included overall survival and objective response rate.

Demographics and baseline disease characteristics were balanced between treatment arms. The overall median age was 70 years (range 45 to 88), 95% of patients had an ECOG PS of 0 to 1 and median Gleason score was 8. A majority of the patients (61%) had their prior treatment with abiraterone acetate or enzalutamide after docetaxel. There were 36% of patients on the cabazitaxel arm with visceral disease (liver 8%, lung 8%, other 20%) and 57% with bone-only disease. Race and ethnicity data were not collected. Approximately 92% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy during the first 3 cycles and, overall, 90% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy at each cycle.

Efficacy results from the CARD trial are summarized in Table 7 and Figure 3.

In terms of therapy sequence prior to randomization, rPFS was consistent across the subgroups of patients who received abiraterone acetate/enzalutamide prior to docetaxel (HR=0.61, 95% CI: 0.39, 0.96) and those who received abiraterone acetate/enzalutamide after docetaxel (HR=0.48, 95% CI: 0.32, 0.70).

Objective tumor response rate assessed by study investigators was 36.5% (95% CI: 26.6 to 48.4) for cabazitaxel arm versus 11.5% (95% CI: 2.9 to 20.2) for abiraterone acetate plus prednisone/prednisolone or enzalutamide arm, p=0.004.

16.1 How Supplied

Cabazitaxel Injection is supplied as a kit, NDC 16729-339-50, that contains the following:

• One single-dose vial of Cabazitaxel Injection: a clear colourless to pale yellow or brownish-yellow viscous solution of 60 mg/1.5 mL in a clear glass vial with a grey rubber closure, aluminum cap, and yellow green flip-off cap (Cabazitaxel Injection vial NDC 16729-337-33).
• One single-dose vial of Diluent for Cabazitaxel Injection: a clear colorless solution of 13% (w/w) ethanol in water for injection in a clear glass vial with a grey rubber closure, aluminum cap, and transparent flip-off cap (Diluent vial NDC 16729-338-33).

16.2 Storage

Cabazitaxel Injection and Diluent for Cabazitaxel Injection:

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] excursions permitted between 15°C to 30°C (59°F to 86°F).

Do not refrigerate. Protect from light (keep in outer carton).

16.3 Handling and Disposal

Cabazitaxel Injection is a cytotoxic anticancer drug. Follow applicable special handling and disposable procedures [see References (15)].

Hypersensitivity Reactions

Educate patients about the risk of potential hypersensitivity associated with Cabazitaxel Injection. 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 Cabazitaxel Injection 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)] .

Urinary Disorders Including Cystitis
Inform patients that hematuria may occur during treatment with cabazitaxel. Inform patients that previously received pelvic radiation that cystitis and radiation cystitis may occur during treatment with cabazitaxel. Advise patients to report any occurrence of hematuria, or any signs and symptoms of cystitis or radiation cystitis, to their healthcare provider [see Warnings and Precautions (5.6)] .

Respiratory Disorders
Explain to patients that severe and fatal interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have occurred with cabazitaxel. Instruct patients to immediately report new or worsening pulmonary symptoms to their healthcare provider [see Warnings and Precautions (5.7)] .

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 [see Use in Specific Populations (8.3)] .

Infertility

Advise male patients that cabazitaxel may impair fertility [see Use in Specific Populations (8.3)] .

Manufactured for:
Accord Healthcare, Inc.,
1009, Slater Road,
Suite 210-B,
Durham, NC 27703,
USA

Manufactured by:
Intas Pharmaceuticals Limited,
Plot No.: 457, 458,
Village – Matoda,
Bavla Road, Ta. - Sanand,
Dist. - Ahmedabad – 382 210,
India

10 4944 0 6006506

Issued: October 2021