1 Name of Medicine
Cabazitaxel.
2 Qualitative and Quantitative Composition
1 mL contains 20 mg cabazitaxel.
1 vial of 3 mL concentrated injection contains 60 mg cabazitaxel.
Excipients with known effect.
Absolute ethanol (50% v/v). For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Cabazitaxel Accord 60 mg/3 mL concentrated injection is a sterile, non-pyrogenic, clear, colourless to pale yellow or brownish-yellow viscous solution.
4.1 Therapeutic Indications
Cabazitaxel Accord in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration resistant prostate cancer previously treated with a docetaxel containing regimen.
4.2 Dose and Method of Administration
The use of Cabazitaxel Accord should be confined to units specialised in the administration of cytotoxics and it should only be administered under the supervision of a physician experienced in the use of anticancer chemotherapy.
Premedication.
Premedicate at least 30 minutes prior to each administration of Cabazitaxel Accord with the following intravenous medications to reduce the risk and severity of a hypersensitivity reaction: antihistamine (equivalent to dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent), corticosteroid (dexamethasone 8 mg or equivalent) and with H2 antagonist (ranitidine or equivalent).
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed (see Section 4.4 Special Warnings and Precautions for Use).
Preparation process.
As for any other antineoplastic agent, caution should be exercised when handling and preparing Cabazitaxel Accord solutions. The use of gloves is recommended.
If Cabazitaxel Accord, at any step of its handling, should come into contact with the skin, wash immediately and thoroughly with soap and water. If it should come into contact with mucous membranes, wash immediately and thoroughly with water.
Cabazitaxel Accord should only be prepared and administered by personnel trained in handling cytotoxic agents. Pregnant staff should not handle it. Cabazitaxel Accord is for single use in one patient only. Discard any residue.
Important.
Cabazitaxel Accord is supplied as a 3 mL vial presentation which does not require an intermediate dilution step. Each vial contains 20 mg/mL of cabazitaxel.
Cabazitaxel Accord can be added directly to the infusion solution (0.9% sodium chloride or 5% glucose) without dilution.
Cabazitaxel Accord should be diluted with 0.9% sodium chloride or 5% glucose to give a final concentration for infusion of 0.10 mg/mL to 0.26 mg/mL.
Preparation of infusion solution.
Inspect the Cabazitaxel Accord 60 mg/3 mL concentrate vial. The concentrate solution should be clear (see Section 3 Pharmaceutical Form).
Calculate the required dose of cabazitaxel (see Recommended dosage below) and withdraw the required volume of Cabazitaxel Accord concentrate (20 mg/mL of cabazitaxel) with a graduated syringe. Note that more than one vial of Cabazitaxel Accord may be required to provide the required dose. Inject the concentrate solution directly into a sterile PVC-free container (bags or bottles) of either 5% glucose solution or 0.9% sodium chloride solution for infusion. The concentration of the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Remove the syringe and mix the contents of the infusion bag or bottle manually using a rocking motion.
As with all parenteral products, the resulting infusion solution should be visually inspected prior to use. Solution containing a precipitate should be discarded.
Table 1 contains examples of Cabazitaxel Accord volumes required over a typical dosage range.
Administration.
Use an in-line filter of 0.22 micrometre (also referred to as 0.2 micrometre) nominal pore size during administration.
Do not use PVC infusion containers (bags or bottles) for the preparation of the infusion solution.
Do not use polyurethane infusion sets (tubing, filter, pumps) for the administration of the infusion solution.
The Cabazitaxel Accord infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions (see Section 6.4 Special Precautions for Storage).
Any unused product or waste material should be disposed of in accordance with local requirements.
Recommended dosage.
The recommended dose of Cabazitaxel Accord is 20 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily throughout Cabazitaxel Accord treatment.
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).
Dosage adjustments.
Dosage modifications should be made if patients experience the following adverse reactions (see Table 2).
Patients at a 20 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel Accord to 15 mg/m2 (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients at a 25 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel Accord to 20 mg/m2. One additional dose reduction to 15 mg/m2 may be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).
Data in patients below the 20 mg/m2 dose are limited.
Special populations.
Patients with hepatic impairment.
Cabazitaxel is extensively metabolised by the liver.
Administer Cabazitaxel Accord at a dose of 20 mg/m2 in patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x Upper Limit of Normal (ULN) or AST > 1.5 x ULN). Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety. Limited efficacy data for cabazitaxel at 15 mg/m2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3.0 x ULN), are available to recommend this dose in this population. (See Section 5.2 Pharmacokinetic Properties).
Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin > 3 x Upper Limit of Normal (ULN), see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Concomitant medicinal products use.
Concomitant medicines that are strong inducers or inhibitors of CYP3A should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). However, if patients require co-administration of a potent CYP3A inhibitor, a cabazitaxel dose reduction should be considered.
Patients with renal impairment.
Cabazitaxel is minimally excreted through the kidney. No dose adjustment is necessary in patients with renal impairment not requiring haemodialysis. Patients presenting end-stage renal disease (CLCR < 15 mL/min/1.73 m2) by their condition and the limited amount of available data; should be treated with caution and monitored carefully during treatment. (See Section 5.2 Pharmacokinetic Properties).
Elderly.
No specific dose adjustment for the use of cabazitaxel in elderly patients is recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Children.
The safety and efficacy of cabazitaxel in children have not been established.4.3 Contraindications
History of severe hypersensitivity reactions to cabazitaxel, any of the excipients of cabazitaxel or other drugs formulated with polysorbate 80.
Neutrophil counts ≤ 1,500/mm3.
Severe hepatic impairment (total bilirubin > 3 x ULN).
Pregnancy and breast-feeding.
Concomitant vaccination with yellow fever vaccine (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
4.4 Special Warnings and Precautions for Use
Bone marrow suppression.
Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia or pancytopenia may occur (see additional information in Neutropenia and Anaemia precautions below).
Neutropenia.
Neutropenic deaths have been reported with cabazitaxel. Neutropenia is the most common adverse reaction of cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitoring of complete blood count 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 Section 4.2 Dose and Method of Administration).
Dose reduction is recommended in the case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see Section 4.2 Dose and Method of Administration).
Restart treatment only when neutrophils recover to a level > 1.5 cells x 109/L (see Section 4.3 Contraindications).
The use of G-CSF has been shown to limit the incidence and severity of neutropenia.
Patients treated with cabazitaxel may receive prophylactic G-CSF as per American Society of Clinical Oncology (ASCO) and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection).
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.
Hypersensitivity reactions.
All patients should be premedicated prior to the initiation of the infusion of cabazitaxel (see Section 4.2 Dose and Method of Administration).
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 cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can occur and may include generalised rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of cabazitaxel and appropriate therapy. Patients who have a history of severe hypersensitivity reactions should not be rechallenged with cabazitaxel (see Section 4.3 Contraindications).
Gastrointestinal symptoms.
Nausea, vomiting and severe diarrhoea may occur. A death related to diarrhoea and electrolyte imbalance occurred with cabazitaxel in the efficacy trial. Intensive measures may be required for severe diarrhoea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrhoeal or antiemetic medications as needed. Monitor and correct serum electrolyte levels, particularly potassium. Delay in cabazitaxel treatment or reduction in dose may be necessary if patients experience Grade ≥ 3 diarrhoea (see Section 4.2 Dose and Method of Administration). Diarrhoea can also occur more frequently in patients who have received prior abdomino-pelvic irradiation. Dehydration is more common in patients aged 65 or older.
Gastrointestinal (GI) haemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with cabazitaxel. Caution is advised with treatment of patients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly, concomitant use of NSAIDs, antiplatelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, gastrointestinal disease, such as ulceration and GI bleeding.
Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with or without neutropenia, maybe be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary.
Peripheral neuropathy.
Cases of peripheral neuropathy, both sensory (e.g. paraesthesia, dysaesthesia) and motor, have been observed in patients treated with cabazitaxel. Patients should be advised to consult their doctor prior to continuing treatment if neuropathy symptoms such as pain, burning, tingling, numbness or weakness develop. Physicians should assess patients for the presence or worsening of neuropathy before each treatment. Treatment should be delayed until improvement of symptoms. For persistent Grade ≥ 2 peripheral neuropathy, the dose of cabazitaxel should be reduced (see Section 4.2 Dose and Method of Administration).
Urinary disorders.
Cystitis due to radiation recall phenomenon has been reported with cabazitaxel therapy in patients who have previously received pelvic radiation therapy and docetaxel containing regimen (see Section 4.8 Adverse Effects (Undesirable Effects)). Appropriate measures should be initiated. Interruption or discontinuation of cabazitaxel therapy may be necessary.
Renal disorders.
Renal disorders have been reported in association with sepsis, severe dehydration due to diarrhoea, vomiting and obstructive uropathy. Renal failure including cases with fatal outcome has been observed. Appropriate measures should be taken to identify the cause and intensively treat the patients if this occurs. Ensure adequate hydration throughout treatment with cabazitaxel. Advise the patient to report any significant change in daily urine volume immediately. Measure serum creatinine at baseline, with each blood count and whenever the patient reports a change in urinary output. Discontinue cabazitaxel in case of renal failure ≥ Grade 3.
Respiratory disorders.
Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)). If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated and appropriately treated. Interruption of cabazitaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may improve the condition. The benefit of resuming cabazitaxel treatment must be carefully evaluated.
Eye disorders.
Subcapsular lens fibre swelling/degeneration was observed in rats during a 10-cycle toxicity study at 10 mg/kg (60 mg/m2 [approximately 2-fold the AUC in cancer patients at the recommended human dose]). The No-Observable Effect Level for microscopic lens findings was 5 mg/kg (30 mg/m2 [approximately the AUC in cancer patients at the recommended human dose]). The clinical relevance of these findings is unknown. Adverse reactions were not observed in clinical studies.
Anaemia.
Anaemia has been observed in patients receiving cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)). Haemoglobin and haematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs or symptoms of anaemia or blood loss. Caution is recommended in patients with haemoglobin < 100 g/L and appropriate measures should be taken as clinically indicated.
Risk of cardiac arrhythmias.
Cardiac arrhythmias have been reported, most commonly tachycardia and atrial fibrillation (see Section 4.8 Adverse Effects (Undesirable Effects)).
Use in hepatic impairment.
Cabazitaxel is contraindicated in patients with severe hepatic impairment [total bilirubin > 3 Upper limit of Normal (ULN)] (see Section 4.3 Contraindications).
Cabazitaxel is extensively metabolised by the liver. Dose should be reduced for patients with mild (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Bile ductule hyperplasia, arteriolar/periarteriolar necrosis, and/or hepatocellular necrosis were observed in dogs after a single dose (0.25 mg/kg [5 mg/m2]) 5-day (0.2 mg/kg [4 mg/m2]) and weekly (0.325 mg/kg [6.5 mg/m2]) administration. Kupffer cell pigmentation and bile duct degeneration/regeneration were observed in the liver at the highest tested dose of 10 mg/kg (60 mg/m2) in a 10-cycle study in rats.
Use in renal impairment.
Cabazitaxel is minimally excreted via the kidney (2.3% of the dose excreted as the unchanged drug). No formal pharmacokinetic studies were conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Use in the elderly.
Elderly patients (≥ 65 years of age) may be more likely to experience certain adverse reactions including neutropenia or febrile neutropenia with cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the randomised 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.
In the population pharmacokinetic analysis in 70 patients of 65 years and older (57 from 65 to 75 and 13 ≥ 75), there was no age effect on the pharmacokinetics of cabazitaxel. No specific dose adjustment is recommended in the elderly.
Paediatric use.
The safety and the efficacy of cabazitaxel in children have not been established.
Effects on laboratory tests.
See Section 4.8 Adverse Effects (Undesirable Effects).4.5 Interactions with Other Medicines and Other Forms of Interactions
No formal clinical drug-drug interaction studies have been performed.
In vitro studies have shown that cabazitaxel is mainly metabolized through CYP3A (80% to 90%).
CYP3A inhibitors.
Though no formal drug interaction trials have been conducted for cabazitaxel, concomitant administration of potent 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 potent CYP3A inhibitors should be avoided.
If co-administration with a potent CYP3A inhibitor cannot be avoided, close monitoring for toxicity and a cabazitaxel dose reduction should be considered. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.
CYP3A inducers.
Though no formal drug interaction trials have been conducted for cabazitaxel, the concomitant administration of CYP3A inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co-administration with CYP3A inducers should be avoided (see Section 5.2 Pharmacokinetic Properties). In addition, patients should also refrain from taking St. John's Wort.
In vitro, cabazitaxel has also been shown to inhibit the transport proteins of the Organic Anion Transport Polypeptides OATP1B1. The risk of interaction with OATP1B1 substrates (e.g. statins, valsartan, repaglinide) is possible notably during the infusion duration (1 hour) and up to 20 minutes after the end of the infusion, and may lead to an increase of exposure of OATP1B1 substrates.
Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
In vitro, cabazitaxel did not inhibit Multidrug Resistant Proteins (MRP): MRP1 and MRP2. Cabazitaxel inhibited the transport of P-glycoprotein (P-gp) (digoxin, vinblastine) and Breast Cancer Resistant Proteins (BRCP) (methotrexate), at concentrations at least 37 fold what is observed in clinical settings. Therefore, the risk of interaction, with MRP, P-gp and BCRP substrates, is unlikely in vivo at the dose of 20 or 25 mg/m2.
Vaccinations.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapy may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be avoided in patients receiving cabazitaxel (see Section 4.3 Contraindications). Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
The effect of cabazitaxel on human fertility is unknown. Cabazitaxel did not affect mating performances or fertility of male or female rats at intravenous cabazitaxel doses of up to 0.2 mg/kg/day (resulting in AUCs below those in patients at the recommended dose). However, in multi-cycle toxicity studies following the clinically recommended dosing schedule in rats and dogs, the male reproductive system was identified as a target organ in both species and the female reproductive system was identified as a target organ in rats. Toxic effects, including seminiferous tubular atrophy and degeneration of seminal vesicles in males, and atrophy of the uterus and necrosis of corpora lutea in females, were observed at exposures (AUC) similar to or less than the AUC in patients at the recommended dose.
Animal studies showed that cabazitaxel affected the reproductive system in male rats and dogs without any functional effect on fertility. Nevertheless, considering the pharmacological activity of taxanes, their genotoxic potential and effect of several compounds of this class on fertility in animal studies, effect on male fertility could not be excluded in human.
Due to potential effects on male gametes and to potential exposure via seminal liquid, men treated with cabazitaxel should use effective contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of cabazitaxel. Due to potential exposure via seminal liquid, men treated with cabazitaxel should prevent contact with the ejaculate by another person throughout treatment. Men being treated with cabazitaxel are advised to seek advice on conservation of sperm prior to treatment.
(Category D)
Cabazitaxel is not recommended during pregnancy.
Due to potential exposure via seminal liquid, men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of cabazitaxel.
There are no adequate and well-controlled studies in pregnant women using cabazitaxel. Cabazitaxel has been shown to be genotoxic by an aneugenic mechanism. 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 foetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with cabazitaxel.
Studies in rats have shown that cabazitaxel crosses the placenta barrier. When female rats were given cabazitaxel intravenously once daily during the period of organogenesis embryofoetal toxicity was observed at a dose of 0.16 mg/kg/day, (resulting in exposures (AUC) well below those in patients at the recommended dose) consisting of foetal deaths and decreased mean foetal weight associated with a delay in skeletal ossification. Similar findings have been reported with docetaxel or paclitaxel.
Cabazitaxel did not produce foetal abnormalities in rats and rabbits.
Cabazitaxel should not be used during breast-feeding.
Data in rats have shown excretion of cabazitaxel and/or its metabolites in milk.4.7 Effects on Ability to Drive and Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile, cabazitaxel may have moderate influence on the ability to drive and use machines as it may cause fatigue and dizziness. Patients should be advised to not drive or use machines if they experience these adverse reactions during treatment.
4.8 Adverse Effects (Undesirable Effects)
The following Council for International Organizations of Medical Sciences (CIOMS) frequency rating is used, when applicable: very common ≥ 10%; common ≥ 1 and < 10%; uncommon ≥ 0.1 and < 1%; rare ≥ 0.01 and < 0.1%; very rare < 0.01%; not known (cannot be estimated from the available data).
The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 371 patients with metastatic castration resistant prostate cancer, in a randomised open label, controlled phase III study (TROPIC). Patients received a median of 6 cycles of cabazitaxel or 4 of mitoxantrone.
The most commonly (≥ 5%) occurring Grade ≥ 3 adverse reactions in the cabazitaxel group were neutropenia (81.7%), febrile neutropenia (7.5%), diarrhoea (6.2%), leukopenia (68.2%), and anaemia (10.5%).
Discontinuation of treatment due to adverse drug reactions occurred in 68 patients (18.3%) in the cabazitaxel group and 31 patients (8.4%) in the mitoxantrone group. The most common adverse reaction leading to treatment discontinuation in the cabazitaxel group was neutropenia. See Table 3.
Neutropenia and associated clinical events.
Incidence of Grade ≥ 3 neutropenia based on laboratory data was 81.7%. The incidence of clinical neutropenia and febrile neutropenia adverse reactions were 21.3% and 7.5%, respectively. Neutropenia was the most common adverse reaction leading to drug discontinuation (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases resulted in a fatal outcome.
The use of G-CSF has been shown to limit the incidence and severity of neutropenia (see Section 4.4 Special Warnings and Precautions for Use).
Cardiac disorders and arrhythmias.
All Grade events among cardiac disorders were more common on cabazitaxel of which 6 patients (1.6%) had Grade ≥ 3 cardiac arrhythmias. The incidence of tachycardia on cabazitaxel was 1.6%, none of which were Grade ≥ 3. The incidence of atrial fibrillation was 1.1% in the cabazitaxel group. Cardiac failure events were more common on cabazitaxel, the event term being reported for 2 patients (0.5%). One patient in the cabazitaxel group died from cardiac failure. Fatal ventricular fibrillation was reported in 1 patient (0.3%), and cardiac arrest in 2 patients (0.5%). None were considered related by the investigator, however an indirect relationship cannot be ruled out (e.g. electrolyte imbalance).
Renal and urinary tract disorders.
Renal failure was observed at 2.2% in all grades and 1.6% in grades ≥ 3 in the cabazitaxel arm. Haematuria all grades was observed at 20.8% in EFC11785 study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Confounding causes such as disease progression, instrumentation, infection or anticoagulation/NSAID/aspirin therapy were identified in nearly two thirds of the cases.
Other laboratory abnormalities.
The incidence of Grade ≥ 3 anaemia, increased AST/SGOT, increased ALT/SGPT, and increased bilirubin based on laboratory abnormalities were 10.6%, 0.9%, 1.1%, and 0.6%, respectively.
Post marketing experience.
The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Gastrointestinal disorders.
Colitis, enterocolitis, gastritis and neutropenic enterocolitis have been observed. Gastrointestinal haemorrhage and perforation, ileus and intestinal obstruction have also been reported.
Respiratory disorders.
Cases of interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome, including cases with fatal outcomes have been reported (see Section 4.4 Special Warnings and Precautions for Use).
Renal and urinary disorders.
Cystitis due to radiation recall phenomenon was reported uncommonly (see Section 4.4 Special Warnings and Precautions for Use).
Elderly population.
Of the 371 patients treated with cabazitaxel in the prostate cancer study, 240 patients were 65 years or over including 70 patients older than 75 years. The following adverse reactions reported at rates ≥ 5% higher in patients 65 years of age or greater compared to younger patients were: fatigue (40.4% vs. 29.8%), clinical neutropenia (24.2% vs. 17.6%), asthenia (23.8% vs. 14.5%), pyrexia (14.6% vs. 7.6%), dizziness (10.0% vs. 4.6%), urinary tract infection (9.6% vs 3.1%) and dehydration (6.7% vs. 1.5%), respectively.
The incidence of the following Grade ≥ 3 adverse reactions were higher in patients ≥ 65 years of age compared to younger patients: neutropenia based on laboratory abnormalities (86.3% vs. 73.3%), clinical neutropenia (23.8% vs. 16.8%) and febrile neutropenia (8.3% vs. 6.1%) (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly). Of the 595 patients treated with cabazitaxel 25 mg/m2 in the prostate cancer EFC 11785 study, 420 patients were 65 years or over. The adverse reactions reported at rates of at least 5% higher in patients 65 years of age or greater compared to younger patients were diarrhoea (42.9% vs. 32.6%), fatigue (30.2% vs. 19.4%), asthenia (22.4% vs. 13.1%), constipation (20.2% vs. 12.6%), clinical neutropenia (12.9% vs. 6.3%), febrile neutropenia (11.2% vs. 4.6%) and dyspnoea (9.5% vs. 3.4%).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.4.9 Overdose
Signs and symptoms.
The anticipated complications of overdose would be exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders.
Management.
There is no known antidote to cabazitaxel. In case of overdose, the patient should be kept in a specialised unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic agent, taxanes, ATC code: L01CD04.
Mechanism of action.
Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells. Cabazitaxel binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their disassembly. This leads to the stabilisation of microtubules, which results in the inhibition of mitotic and interphase cellular functions.
Cabazitaxel demonstrated a broad spectrum of anti-tumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. Cabazitaxel is active in docetaxel sensitive tumours. In addition, cabazitaxel demonstrated activity in some tumour models insensitive to chemotherapy, including docetaxel.
Clinical trials.
The efficacy and safety of cabazitaxel in combination with prednisone or prednisolone were evaluated in a randomised, open-label, international, multi-centre, phase III study (TROPIC), in patients with metastatic castration resistant prostate cancer previously treated with a docetaxel-containing regimen.
Overall survival (OS) was the primary efficacy end-point of the study. Secondary endpoints included Progression Free Survival [PFS (defined as time from randomisation to tumour progression, Prostatic Specific Antigen (PSA) progression, pain progression, or death due to any cause, whichever occurred first], Tumour Response Rate based on Response Evaluation Criteria in Solid Tumours (RECIST), PSA Progression (defined as a ≥ 25% increase or ≥ 50% in PSA non-responders or responders respectively), PSA response (declines in serum PSA levels of at least 50%), pain progression [assessed using the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire and an Analgesic Score (AS)] and pain response (defined as 2 point greater reduction from baseline median PPI with no concomitant increase in AS, or reduction of ≥ 50% in analgesic use from baseline mean AS with no concomitant increase in pain).
A total of 755 patients were randomised to receive either cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=377).
This study included patients over 18 years with metastatic castration resistant prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients had to have neutrophils > 1.5 cells x 109/L, platelets > 100 cells x 109/L, haemoglobin > 100 g/L, creatinine < 1.5 x ULN, total bilirubin < 1 x ULN, AST/SGOT < 1.5 x ULN, and ALT/SGPT < 1.5 x 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 to 2), were balanced between the treatment arms. In the cabazitaxel group, the mean age was 68 years range (46 to 92) and the racial distribution was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others.
The median number of cycles was 6 in the cabazitaxel group and 4 in the mitoxantrone group. The number of patients who completed the study treatment (10 cycles) was 29.4% in the cabazitaxel group and 13.5% in the comparator group.
Overall survival was significantly longer with cabazitaxel compared to mitoxantrone (15.1 months versus 12.7 months, respectively), with a 30% reduction in the risk of death compared to mitoxantrone (see Table 4 and Figure 1).
See Table 5.
There were no significant differences in pain progression or pain response between treatments.
In a non-inferiority, multicentre, multinational, randomised, open label phase III study (EFC11785 study), 1200 patients with metastatic castration resistant prostate cancer, previously treated with a docetaxel containing regimen, were randomized to receive either cabazitaxel 25 mg/m2 (n=602) or 20 mg/m2 (n=598) dose. Overall survival (OS) was the primary efficacy end-point.
The study met its primary objective of demonstrating the non-inferiority of cabazitaxel 20 mg/m2 in comparison with 25 mg/m2 (see Table 6). A statistically significantly higher percentage (p < 0.001) of patients showed a PSA response in the 25 mg/m2 group (42.9%) compared to the 20 mg/m2 group (29.5%). A statistically significantly higher risk of PSA progression in patients with the 20 mg/m2 dose with respect to the 25 mg/m2 dose was observed (HR 1.195; 95% CI: 1.025 to 1.393). There was no statistically significant difference with regards to the other secondary endpoints (PFS, tumour and pain response, tumour and pain progression, and four subcategories of FACT-P).
EFC11785 study demonstrated a better safety profile for the cabazitaxel 20 mg/m2 dose. The safety profile of cabazitaxel 25 mg/m2 observed in this study was qualitatively and quantitatively similar to that observed in the study EFC6193. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (21.5%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3.2%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10.0%) had a dose reduced from 20 to 15 mg/m2 and 9 patients (1.6%) had a dose reduced from 15 to 12 mg/m2. All grade adverse reactions with an incidence higher than 10% were higher in patients treated at 25 mg/m2 than in patients treated at 20 mg/m2. See Table 7.
Grade ≥ 3 adverse reactions with an incidence higher than 5% were observed in patients treated at 25 mg/m2 only. See Table 8.
There were fewer reported hematology abnormalities for patients treated at 20 mg/m2 compared with patients treated at 25 mg/m2 based on laboratory values. See Table 9.
5.2 Pharmacokinetic Properties
A population pharmacokinetic analysis was carried out in 170 patients including patients with advanced solid tumours (n=69), metastatic breast cancer (n=34) and metastatic prostate cancer (n=67). These patients received doses of cabazitaxel ranging from 10 to 30 mg/m2 weekly or every 3 weeks.
Absorption.
After a 1-hour IV administration dose of cabazitaxel at 25 mg/m2, in patients with metastatic prostate cancer (n=67), the mean Cmax was 226 nanogram/mL (coefficient of variation, CV 107%) and was reached at the end of the 1-hour infusion (Tmax). The mean AUC was 991 nanogram.h/mL (CV: 34%).
No major deviation to the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumours (n=126).
Distribution.
The volume of distribution (Vss) was 4870 L (2640 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 nanogram/mL, which covers the maximum concentration observed in clinical studies. Cabazitaxel is mainly bound to human serum albumin (82.1%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). The in vitro blood-to-plasma concentration ratios in human blood ranged from 0.90 to 0.99 indicating that cabazitaxel was equally distributed between blood and plasma.
Metabolism.
Cabazitaxel is extensively metabolised in the liver (≥ 95%), mainly by the CYP3A4 isoenzyme (80% to 90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued from O-demethylation), with the main one accounting for approximately 5% of the parent exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and faeces.
Based on in vitro studies, the potential risk of inhibition by cabazitaxel at clinically relevant concentrations is possible towards drugs that are mainly substrates of CYP3A. However, there is no potential risk of inhibition of drugs that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6) as well as no potential risk of induction by cabazitaxel on drugs that are substrates of CYP1A, CYP2C9, and CYP3A.
Potent CYP3A inducers or inhibitors could affect cabazitaxel, as cabazitaxel is mainly metabolised by CYP3A.
Excretion.
After a 1-hour IV infusion [14C]-cabazitaxel at 25 mg/m2 in patients, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the faeces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for less than 4% of the dose (2.3% as unchanged drug in urine).
Cabazitaxel has a high plasma clearance of 48.5 L/h (26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) and a long terminal half-life of 95 hours.
Cabazitaxel is minimally excreted via the kidney (2.3% of the dose excreted as the unchanged drug). No formal pharmacokinetic studies were conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Hepatic impairment.
Cabazitaxel is eliminated primarily via hepatic metabolism. A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) or moderate (total bilirubin > 1.5 to ≤ 3.0 x ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum tolerated cabazitaxel dose (MTD) was 20 and 15 mg/m2, respectively. In 3 patients with severe hepatic impairment (total bilirubin > 3 x ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment, indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic impairment was not established.
Based on safety and tolerability data, cabazitaxel dose should be reduced in patients with mild hepatic impairment (see Section 4.2 Dose and Method of Administration). Cabazitaxel is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).
Renal impairment.
Cabazitaxel is minimally excreted via the kidney (2.3% of the dose). A population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. This was confirmed by a dedicated comparative pharmacokinetic study in solid cancer patients with normal renal function (8 patients), moderate (8) and severe (9) renal impairment, who received several cycles of cabazitaxel in single IV infusion up to 25 mg/m2.
5.3 Preclinical Safety Data
Genotoxicity.
Cabazitaxel was negative in the bacterial reverse mutation (Ames) test. Cabazitaxel was not clastogenic in an in vitro test in human lymphocytes (no induction of structural chromosomal aberrations) but it increased number of polyploid cells and it induced an increase of micronuclei in the in vivo micronucleus test in rats. However, these genotoxicity (by an aneugenic mechanism) findings are inherent to the pharmacological activity of the compound (inhibition of tubulin depolymerisation) and have been observed with other compounds with the same pharmacological activity.
Carcinogenicity.
Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.6 Pharmaceutical Particulars
6.1 List of Excipients
Absolute ethanol, polysorbate 80.
6.2 Incompatibilities
See Section 4.2 Dose and Method of Administration.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Do not refrigerate undiluted Cabazitaxel Accord concentrate.
After dilution in the infusion bag/bottle, the infusion solution may be stored up to 8 hours below 30°C (including the 1 hour infusion).
To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°-8°C for not more than 24 hours or 8 hours below 30°C (including the 1 hour infusion).
As the infusion solution is supersaturated, it may crystallise over time. In this case, the infusion solution must not be used and should be discarded.
6.5 Nature and Contents of Container
Cabazitaxel Accord 60 mg/3 mL concentrate is available in single-use clear Type I glass vials in single packs.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
CAS number.
183133-96-2.7 Medicine Schedule (Poisons Standard)
S4 - Prescription Only Medicine.
Summary Table of Changes
