cabazitaxel
Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
Neutropenic deaths have been reported. In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving Jevtana. Jevtana should not be given to patients with neutrophil counts of ≤1,500 cells/mm3.
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 [see Warnings and Precautions (5.2)]. Patients should receive premedication [see Dosage and Administrations (2.3)]. Jevtana must not be given to patients who have a history of severe hypersensitivity reactions to Jevtana or to other drugs formulated with polysorbate 80 [see Contraindications (4)].
1. INDICATIONS AND USAGE
Jevtana® is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
2. DOSAGE AND ADMINISTRATION
General Dosing Information
- The individual dosage of Jevtana is based on calculation of the Body Surface Area (BSA) and is 25 mg/m2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout Jevtana treatment.
- Premedication is recommended prior to treatment [see Dosage and Administration (2.3)].
- Jevtana should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products. Appropriate management of complications is possible only when the adequate diagnostic and treatment facilities are readily available.
- Jevtana Injection single-use vial requires two dilutions prior to administration [see Dosage and Administration (2.5)].
- Do not use PVC infusion containers and polyurethane infusions sets for preparation and administration of Jevtana infusion solution [see Dosage and Administration (2.5)].
- Both the Jevtana Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation.
Dose Modifications
The Jevtana dose should be reduced to 20 mg/m2 if patients experience the following adverse reactions.
| Toxicity | Dosage Modification |
|---|---|
| Prolonged grade ≥ 3 neutropenia (greater than 1 week) despite appropriate medication including G-CSF | Delay treatment until neutrophil count is > 1,500 cells/mm3, then reduce dosage of Jevtana to 20 mg/m2. Use G-CSF for secondary prophylaxis. |
| Febrile neutropenia | Delay treatment until improvement or resolution, and until neutrophil count is > 1,500 cells/mm3, then reduce dosage of Jevtana to 20 mg/m2. 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 to 20 mg/m2. |
Discontinue Jevtana treatment if a patient continues to experience any of these reactions at 20 mg/m2.
Premedication
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:
- 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 H2 antagonist).
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.
Administration Precautions
Jevtana is a cytotoxic anticancer drug and caution should be exercised when handling and preparing Jevtana solutions, taking into account the use of containment devices, personal protective equipment (e.g., gloves), and preparation procedures. Please refer to Handling and Disposal (16.3).
If Jevtana Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Jevtana Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.
Instructions for Preparation
Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of Jevtana infusion solution.
Read this entire section carefully before mixing and diluting. Jevtana requires two dilutions prior to administration. Please follow the preparation instructions provided below. 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.
The following two-step dilution process must be carried out under aseptic conditions to prepare the second (final) infusion solution.
Set aside the Jevtana Injection and supplied diluent vials. The Jevtana Injection is a clear yellow to brownish-yellow viscous solution, if appropriately stored.
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.
Jevtana should not be mixed with any other drugs.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
Jevtana final 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 within a total of 24 hours if refrigerated (including the one-hour infusion).
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
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.
Discard any unused portion.
Administration
The final Jevtana infusion solution should be administered intravenously as a one-hour infusion at room temperature.
Use an in-line filter of 0.22 micrometer nominal pore size during administration.
The final Jevtana infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion) [see Dosage and Administration (2.5)].
3. DOSAGE FORMS AND STRENGTHS
Jevtana (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following:
- –
- Jevtana Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 80,
- –
- Diluent for Jevtana Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection.
4. CONTRAINDICATIONS
Jevtana should not be used in patients with neutrophil counts of ≤ 1,500/mm3.
Jevtana is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80.
5. WARNINGS AND PRECAUTIONS
Neutropenia
Five patients experienced fatal infectious adverse events (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.
G-CSF may be administered to reduce the risks of neutropenia complications associated with Jevtana use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, 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. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be 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)].
Jevtana should not be administered to patients with neutrophils ≤ 1,500/mm3 [see Contraindications (4)].
If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of Jevtana should be reduced [see Dosage and Administration (2.2)]. Patients can restart treatment with Jevtana only when neutrophil counts recover to a level > 1,500/mm3 [see Contraindications (4)].
Hypersensitivity Reactions
All patients should be premedicated prior to the initiation of the infusion of Jevtana [see Dosage and Administration (2.3)]. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. 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. Severe hypersensitivity reactions require immediate discontinuation of the Jevtana infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with Jevtana [see Contraindications (4)].
Gastrointestinal Symptoms
Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Patients should be treated 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)].
Renal Failure
Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. 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.
Elderly Patients
In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 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 [see Adverse Reactions (6) and Use in Specific Populations (8.5)].
Hepatic Impairment
No dedicated hepatic impairment trial for Jevtana has been conducted. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial.
Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase cabazitaxel concentrations.
Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as Jevtana. Jevtana should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN).
Pregnancy
Pregnancy category D.
Jevtana can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level.
There are no adequate and well-controlled studies in pregnant women using Jevtana. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with Jevtana [see Use in Specific Populations (8.1)].
6. ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in another section of the label:
- Neutropenia [see Warnings and Precautions (5.1)].
- Hypersensitivity Reactions [see Warnings and Precautions (5.2)].
- Gastrointestinal Symptoms [see Warnings and Precautions (5.3)].
- Renal Failure [see Warnings and Precautions (5.4)].
Clinical Trial 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.
The safety of Jevtana in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized 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, dysguesia, 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.
| 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 (%) | |
| ||||
| 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 | ||
Neutropenia and Associated Clinical Events:
Five patients experienced fatal infectious adverse events (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%).
Hematuria:
Adverse events 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.
Hepatic Laboratory Abnormalities:
The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤ 1%.
Elderly Population:
The following grade 1–4 adverse reactions were reported at rates ≥ 5% higher in patients 65 years of age or greater 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.
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%) [see Use in Specific Populations (8.5)].
7. DRUG INTERACTIONS
No formal clinical drug-drug interaction trials have been conducted with Jevtana.
Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
Drugs That May Increase Cabazitaxel Plasma Concentrations
CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A [see Clinical Pharmacology (12.3)]. Though no formal drug interaction trials have been conducted for Jevtana, concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore, co-administration with strong CYP3A inhibitors should be avoided. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.
Drugs That May Decrease Cabazitaxel Plasma Concentrations
CYP3A4 Inducers: Though no formal drug interaction trials have been conducted for Jevtana, the concomitant administration of strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co-administration with strong CYP3A inducers should be avoided. In addition, patients should also refrain from taking St. John's Wort.
8. USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy category D. See 'Warnings and Precautions' section.
Jevtana can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Jevtana in pregnant women.
Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic, and abortifacient. Cabazitaxel was shown to cross the placenta barrier within 24 hours of a single intravenous administration of a 0.08 mg/kg dose (approximately 0.02 times the maximum recommended human dose-MRHD) to pregnant rats at gestational day 17.
Cabazitaxel administered once daily to female rats during organogenesis at a dose of 0.16 mg/kg/day (approximately 0.02–0.06 times the Cmax in patients with cancer at the recommended human dose) caused maternal and embryofetal toxicity consisting of increased post-implantation loss, embryolethality, and fetal deaths. Decreased mean fetal birth weight associated with delays in skeletal ossification were observed at doses ≥ 0.08 mg/kg (approximately 0.02 times the Cmax at the MRHD). In utero exposure to cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.
If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Jevtana.
Nursing Mothers
Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats. It is not known whether this drug is excreted in human milk. 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 maximum recommended human dose), radioactivity related to cabazitaxel was detected in the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jevtana, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of Jevtana in pediatric patients have not been established.
Geriatric Use
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).
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 neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection and dehydration occurred at rates ≥ 5% higher in patients who were 65 years of age or greater compared to younger patients [see Adverse Reactions (6.1)].
Renal Impairment
No dedicated renal impairment trial for Jevtana has been conducted. Based on the population pharmacokinetic analysis, no significant difference in clearance was observed in patients with mild (50 mL/min ≤ creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min). No data are available for patients with severe renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)]. Caution should be used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage renal diseases.
Hepatic Impairment
No dedicated hepatic impairment trial for Jevtana has been conducted. The safety of Jevtana has not been evaluated in patients with hepatic impairment [see Warnings and Precautions (5.6)].
As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial.
Overdosage
There is no known antidote for Jevtana overdose. Anticipated complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders.
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) is an antineoplastic agent belonging to the taxane class. 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 off-white powder with a molecular formula of C45H57NO14.C3H6O 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-use 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 Pharmacology
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.
Pharmacodynamics
Cabazitaxel demonstrated antitumor activity against advanced human tumors xenografted in mice. Cabazitaxel is active in docetaxel-sensitive tumors. In addition, cabazitaxel demonstrated activity in tumor models insensitive to chemotherapy including docetaxel.
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/m2 every 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.
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 3A4/5) is low. In addition, cabazitaxel did not induce CYP isozymes in vitro.
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. No formal pharmacokinetic trials have been conducted with cabazitaxel in patients with renal impairment. The 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. No data are available for patients with severe renal impairment or end-stage renal disease [see Use in Special Populations (8.6)].
Hepatic Impairment
No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations [see Warnings and Precautions (5.6), and Use in Special Populations (8.7)].
Drug interactions
As cabazitaxel is mainly metabolized by CYP3A in vitro, strong CYP3A inducers or inhibitors are expected to affect the pharmacokinetics of cabazitaxel.
Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) or 2 (MRP2). In vitro cabazitaxel inhibited the transport of P-gp and BRCP, at concentrations at least 38 fold what is observed in clinical settings. Therefore, the in vivo risk of cabazitaxel to inhibit MRPs, P-gp, or BCRP is unlikely at the dose of 25 mg/m2.
In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, or BCRP.
Nonclinical Toxicology
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).
Cabazitaxel may impair fertility in humans. 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. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses ≥ 0.1 mg/kg/day (approximately 0.02–0.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, 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).
Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of semin
