JEVTANA 60 mg concentrate and solvent for solution for infusion.

One ml of concentrate contains 40 mg cabazitaxel.

Each vial of 1.5 ml of concentrate contains 60 mg cabazitaxel.

After initial dilution with the entire solvent, each ml of solution contains 10 mg cabazitaxel.

Excipients:

Each vial of solvent contains 573.3 mg of ethanol 96%.

For the full list of excipients, see section 6.1.

Concentrate and solvent for solution for infusion (sterile concentrate).

The concentrate is a clear yellow to brownish-yellow oily solution.

The solvent is a clear and colourless solution.

JEVTANA in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen (see section 5.1).

The use of JEVTANA 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. Facilities and equipment for the treatment of serious hypersensitivity reactions like hypotension and bronchospasm must be available (see section 4.4).

Premedication

The recommended premedication regimen should be performed at least 30 minutes prior to each administration of JEVTANA with the following intravenous medicinal product to mitigate the risk and severity of hypersensitivity:

• antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent),

• corticosteroid (dexamethasone 8 mg or equivalent), and with

• H2 antagonist (ranitidine or equivalent) (see section 4.4).

Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.

Throughout the treatment, adequate hydration of the patient needs to be ensured, in order to prevent complications like renal failure.

Posology

The recommended dose of JEVTANA is 25 mg/m² administered as a 1 hour intravenous infusion every 3 weeks in combination with oral prednisone or prednisolone 10 mg administered daily throughout treatment.

Dose adjustments

Dose modifications should be made if patients experience the following adverse reactions (Grades refer to Common Terminology Criteria for Adverse Events (CTCAE 4.0)):

Table 1 - Recommended dose modifications for adverse reaction in patients treated with cabazitaxel

The treatment should be discontinued if a patient continues to experience any of these reactions at 20 mg/m².

Special populations

Patients with hepatic impairment

Cabazitaxel is extensively metabolised by the liver. No formal studies have been carried out in patients with hepatic impairment. As a precautionary measure, cabazitaxel should not be given to patients with hepatic impairment (bilirubin 1 x Upper Limit of Normal (ULN), or AST and/or ALT 1.5 x ULN) (see sections 4.3, 4.4 and 5.2).

Patients with renal impairment

Cabazitaxel is minimally excreted through the kidney. No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance (CL_CR): 50 to 80 ml/min). Limited data are available for patients with moderate (CL_CR: 30 to 50 ml/min) and no data are available for patients with severe renal impairment (CL_CR <30 ml/min) or end stage renal disease; therefore, these patients should be treated with caution and monitored carefully during treatment (see sections 4.4 and 5.2).

Elderly patients

No specific dose adjustment for the use of cabazitaxel in elderly patients is recommended (see also sections 4.4, 4.8 and 5.2).

Concomitant medicinal products use

Concomitant medicinal products that are strong inducers or inhibitors of CYP3A should be avoided (see sections 4.4 and 4.5).

Paediatric population

The safety and the efficacy of JEVTANA in children and adolescents below 18 years of age have not been established.

Method of administration

For instructions on preparation and administration of the product, see section 6.6.

PVC infusion containers and polyurethane infusion sets should not be used.

• Hypersensitivity to cabazitaxel, to other taxanes, or to any excipients of the formulation including polysorbate 80.

• Neutrophil counts less than 1,500/mm³.

• Hepatic impairment (bilirubin 1 x ULN, or AST and/or ALT1.5 × ULN).

• Concomitant vaccination with yellow fever vaccine (see section 4.5).

Hypersensitivity reactions

All patients should be pre-medicated prior to the initiation of the infusion of cabazitaxel (see section 4.2).

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 with a hypersensitivity reaction must stop treatment with JEVTANA (see section 4.3).

Risk of neutropenia

Patients treated with cabazitaxel may receive prophylactic G-CSF, as per American Society of Clinical Oncology (ASCO) guidelines 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. The use of G-CSF has been shown to limit the incidence and severity of neutropenia.

Neutropenia is the most common adverse reaction of cabazitaxel (see section 4.8). 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.

The dose should be reduced in case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see section 4.2).

Patients should be re-treated only when neutrophils recover to a level 1,500/mm³ (see section 4.3).

Risk of nausea, vomiting, diarrhoea and dehydration

If patients experience diarrhoea following administration of cabazitaxel they may be treated with commonly used anti-diarrhoeal medicinal products. Appropriate measures should be taken to re-hydrate patients. Diarrhoea can occur more frequently in patients that have received prior abdomino-pelvic radiation. Dehydration is more common in patients aged 65 or older. Appropriate measures should be taken to rehydrate patients and to monitor and correct serum electrolyte levels, particularly potassium. Treatment delay or dose reduction may be necessary for grade 3 diarrhoea (see section 4.2). If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics.

Peripheral neuropathy

Cases of peripheral neuropathy, peripheral sensory neuropathy (e.g., paraesthesias, dysaesthesias) and peripheral motor neuropathy have been observed in patients receiving cabazitaxel. Patients under treatment with cabazitaxel should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop. Physicians should assess for the presence or worsening of neuropathy before each treatment. Treatment should be delayed until improvement of symptoms. The dose of cabazitaxel should be reduced from 25 mg/m² to 20 mg/m² for persistent grade >2 peripheral neuropathy (see section 4.2).

Risk of renal failure

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.

Adequate hydration should be ensured throughout treatment with cabazitaxel. The patient should be advised to report any significant change in daily urinary volume immediately. Serum creatinine should be measured at baseline, with each blood count and whenever the patient reports a change in urinary output. Cabazitaxel treatment should be discontinued in case of renal failure CTCAE 4.0 Grade 3.

Risk of cardiac arrhythmias

Cardiac arrhythmias have been reported, most commonly tachycardia and atrial fibrillation (see section 4.8).

Elderly

Elderly patients (65 years of age) may be more likely to experience certain adverse reactions including neutropenia and febrile neutropenia (see section 4.8).

Patients with liver impairment

Treatment with JEVTANA is contraindicated (see sections 4.2 and 4.3).

Patients with anaemia

Caution is recommended in patients with haemoglobin <10 g/dl and appropriate measures should be taken as clinically indicated.

Interactions

Co-administration with strong CYP3A4 inhibitors should be avoided since they may increase the plasma concentrations of cabazitaxel (see sections 4.2 and 4.5).

Co-administration with strong CYP3A4 inducers should be avoided since they may lead to decreased plasma concentrations of cabazitaxel (see sections 4.2 and 4.5).

Excipients

The solvent contains 573.3 mg ethanol 96% (15% v/v), equivalent to 14 ml of beer or 6 ml of wine.

Harmful for those suffering from alcoholism.

To be taken into account in high-risk groups such as patients with liver disease, or epilepsy.

No interaction studies have been performed.

In vitro studies have shown that cabazitaxel is mainly metabolised through CYP3A (80% to 90%) and inhibits CYP3A.

CYP3A inhibitors

Though no formal drug interaction trials have been conducted for cabazitaxel, 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 (see section 5.2).

CYP3A inducers

Though no formal drug interaction trials have been conducted for cabazitaxel, 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 (see section 5.2). In addition, patients should also refrain from taking St. John's Wort.

Vaccinations

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents, may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be avoided in patients receiving cabazitaxel. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Pregnancy

There are no data from the use of cabazitaxel in pregnant women. Studies in animals have shown reproductive toxicity at maternotoxic doses (see section 5.3) and that cabazitaxel crosses the placenta barrier (see section 5.3). As with other cytotoxic medicinal products, cabazitaxel may cause foetal harm in exposed pregnant women.

Cabazitaxel is not recommended during pregnancy and in women of childbearing potential not using contraception.

Lactation

Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites in milk (see section 5.3). A risk to the suckling child cannot be excluded.

Cabazitaxel should not be used during breast-feeding.

Fertility

Animal studies showed that cabazitaxel affected reproductive system in male rats and dogs without any functional effect on fertility (see section 5.3). 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.

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 not to drive or use machines if they experience these adverse reactions during treatment.

Summary of safety profile

The safety of JEVTANA in combination with prednisone or prednisolone was evaluated in 371 patients with hormone refractory metastatic prostate cancer who were treated with 25 mg/m² cabazitaxel once every three weeks in a randomised open label, controlled phase III study. Patients received a median duration of 6 cycles of JEVTANA.

The most commonly (10%) occurring adverse reactions in all grades were anaemia (97.3%), leukopenia (95.6%), neutropenia (93.5%), thrombocytopenia (47.4%), and diarrhoea (46.6%). The most commonly (5%) occurring grade 3 adverse reactions in the JEVTANA group were neutropenia (81.7%, leukopenia (68.2%), anaemia (10.5%), febrile neutropenia (7.5%), diarrhoea (6.2%).

Discontinuation of treatment due to adverse reactions occurred in 68 patients (18.3%) receiving JEVTANA. The most common adverse reactions leading to JEVTANA discontinuation was neutropenia.

Tabulated summary of adverse reactions

Adverse reactions are listed in table 2 according to MedDRA system organ class and frequency categories. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Intensity of the adverse reactions is graded according to CTCAE 4.0 (grade 3 = G3). Frequencies are based on all grades and defined as: very common (1/10), common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 2: Reported adverse reactions and haematological abnormalities with JEVTANA in combination with prednisone or prednisolone in the TROPIC study (n=371)

^a based on laboratory values

* see detailed section below

Description of selected adverse reactions

Neutropenia, and associated clinical events

Incidence of grade 3 neutropenia based on laboratory data was 81.7%. The incidence of grade 3 clinical neutropenia and febrile neutropenia adverse reactions were 21.3% and 7.5% respectively. Neutropenia was the most common adverse reaction leading to medicinal product 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 sections 4.2 and 4.4).

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.

Other laboratory abnormalities

The incidence of grade 3 anaemia, increased AST, ALT, and bilirubin based on laboratory abnormalities were 10.6%, 0.7%, 0.9%, and 0.6%, respectively.

Paediatric population (see section 4.2)

Other special populations

Elderly population

Among the 371 patients treated with JEVTANA 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: fatigue (40.4% versus 29.8%), clinical neutropenia (24.2% versus 17.6%), asthenia (23.8% versus 14.5%), pyrexia (14.6% versus 7.6%), dizziness (10.0% versus 4.6%), urinary tract infection (9.6% versus 3.1%) and dehydration (6.7% versus 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% versus 73.3%), clinical neutropenia (23.8% versus 16.8%) and febrile neutropenia (8.3% versus 6.1%) (see sections 4.2 and 4.4).

There is no known antidote to JEVTANA. The anticipated complications of overdose would consist of exacerbation of adverse reactions as bone marrow suppression and gastrointestinal disorders.

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.

Pharmacotherapeutic group: Antineoplastic agents, Taxanes, ATC code: not yet assigned

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.

Pharmacodynamic effects

Cabazitaxel demonstrated a broad spectrum of antitumour activity against advanced human tumours xenografted in mice. Cabazitaxel is active in docetaxel-sensitive tumours. In addition, cabazitaxel demonstrated activity in tumour models insensitive to chemotherapy including docetaxel.

Clinical efficacy and safety

The efficacy and safety of JEVTANA in combination with prednisone or prednisolone were evaluated in a randomised, open-label, international, multi-center, phase III study, in patients with hormone refractory metastatic prostate cancer previsouly treated with a docetaxel containing regimen.

Overall survival (OS) was the primary efficacy endpoint of the study.

Secondary endpoints included Progression Free Survival [PFS (defined as time from randomization 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 JEVTANA 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 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 Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients had to have neutrophils >1,500/mm³, platelets >100,000/mm³, haemoglobin >10 g/dl, creatinine <1.5 x ULN, total bilirubin <1 x ULN, AST and ALT <1.5 x ULN.

Patients with a history of congestive heart failure, or myocardial infarction within 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 JEVTANA group, the mean age was 68 years, range (46-92) and the racial distribution was 83.9% Caucasian, 6.9% Asian/Oriental, 5.3% Black and 4% Others.

The median number of cycles was 6 in the JEVTANA group and 4 in the mitoxantrone group. The number of patients who completed the study treatment (10 cycles) was respectively 29.4% and. 13.5% in the JEVTANA group and in the comparator group.

Overall survival was significant longer with JEVTANA compared to mitoxantrone (15.1 months versus 12.7 respectively), with a 30% reduction in the risk of death compared to mitoxantrone (see table 3 and figure 1).

A sub-group of 59 patients received prior cumulative dose of docetaxel <225 mg/m² (29 patients in JEVTANA arm, 30 patients in mitoxantrone arm). There was no significant difference in overall survival in this group of patients (HR (95%CI)0.96 (0.49-1.86)).

Table 3 - Efficacy of JEVTANA in the treatment of patients with hormone refractory metastatic prostate cancer

¹HR estimated using Cox model; a hazard ratio of less than 1 favours JEVTANA

Figure1: Kaplan Meier overall survival curves

There was an improvement in PFS in the JEVTANA arm compared to mitoxantrone arm, 2.8 (2.4-3.0) months versus 1.4 (1.4-1.7) respectively, HR (95%CI) 0.74 (0.64-0.86), p<0.0001.

There was a significant higher rate of tumour response of 14.4% (95%CI: 9.6-19.3) in patients in the JEVTANA arm compared to 4.4% (95%CI: 1.6-7.2) for patients in the mitoxantrone arm, p=0.0005.

PSA secondary endpoints were positive in the JEVTANA arm. There was a median PSA progression of 6.4 months (95%CI: 5.1-7.3) for patients in JEVTANA arm, compared to 3.1 months (95%CI: 2.2-4.4) in the mitoxantrone arm, HR 0.75 months (95%CI 0.63-0.90), p=0.0010. The PSA response was 39.2% in patients on JEVTANA arm (95%CI: 33.9-44.5) versus 17.8% of patients on mitoxantrone (95% CI: 13.7-22.0), p=0.0002.

There was no statistical difference between both treatment arms in pain progression and pain response.

Pediatric Population

The European Medicines Agency has waived the obligation to submit the results of studies with JEVTANA in all subsets of the paediatric population in the indication of prostate cancer (see section 4.2)

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 cabazitaxel at doses of 10 to 30 mg/m² weekly or every 3 weeks.

Absorption

After 1-hour intravenous administration at 25 mg/m² cabazitaxel in patients with metastatic prostate cancer (n=67), the C_max was 226 ng/ml (Coefficient of Variation (CV): 107%) and was reached at the end of the 1-hour infusion (T_max). The mean AUC was 991 ng.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 (V_ss) 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 89-92% and was not saturable up to 50,000 ng/ml, which covers the maximum concentration observed in clinical studies. Cabazitaxel is mainly bound to human serum albumin (82.0%) 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.

Biotransformation

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 form O-demethylations), with the main one accounting for 5% of 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 medicinal products that are mainly substrate of CYP3A. However, there is no potential risk of inhibition of medicinal products 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 medicinal products that are substrates of CYP1A, CYP2C9, and CYP3A. Cabazitaxel did not inhibit in vitro the major biotransformation pathway of warfarin into 7-hydroxywarfarin, which is mediated by CYP2C9. Therefore, no pharmacokinetic interaction of cabazitaxel on warfarin is expected in vivo. Potent CYP3A inductor or inhibitor could affect the plasma concentration of cabazitaxel, as cabazitaxel is mainly metabolised by CYP3A. Prednisone or 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 (PgP) (digoxin, vinblastin) and Breast-Cancer-Resistant-Proteins (BRCP) (methotrexate), at concentrations at least 38 fold what is observed in clinical setting. Therefore the risk of interaction, with MRP, PgP and BCRP substrates, is unlikely in vivo at the dose of 25 mg/m².

Elimination

After a 1-hour intravenous 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 medicinal product in urine).

Cabazitaxel had 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.

Special populations

Elderly

In the population pharmacokinetic analysis in 70 patients of 65 years and older (57 from 65 to 75 and 13 patients above 75), no age effect on the pharmacokinetics of cabazitaxel was observed.

Paediatric patients

Safety and effectiveness of JEVTANA have not been established in children and adolescents below 18 years of age.

Hepatic impairment

No formal studies in patients with hepatic impairment have been conducted. However, as cabazitaxel is eliminated primarily via metabolism, increased exposure may be expected.

Renal impairment

Cabazitaxel is minimally excreted via the kidney (2.3% of the dose). 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.

Adverse reactions not observed in clinical studies, but seen in dogs after single dose, 5-day and weekly administation at exposure levels lower than clinical exposure levels and with possible relevance to clinical use were arteriolar/periarterolar necrosis in the liver, bile ductule hyperplasia and/or hepatocellular necrosis (see section 4.2).

Adverse reactions not observed in clinical studies, but seen in rats during repeat-dose toxicity studies at exposure levels higher than clinical exposure levels and with possible relevance to clinical use were eye disorders characterized by subcapsular lens fiber swelling/degeneration. These effects were partially reversible after 8 weeks.

Carcinogenicity studies have not been conducted with cabazitaxel.

Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. It was not clastogenic in an in vitro test in human lymphocytes (no induction of structural chromosomal aberration but it increased number of polyploid cells) and induced an increase of micronuclei in the in vivo test in rats. However these genotoxicity findings are inherent to the pharmacological activity of the compound (inhibition of tubulin depolymerization) and have been observed with medicinal products exhibiting the same pharmacological activity.

Cabazitaxel did not affect mating performances or fertility of treated male rats. However, in repeated-dose toxicity studies, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats, and testicular degeneration (minimal epithelial single cell necrosis in epididymis), was observed in dogs. Exposures in animals were similar or lower than those seen in humans receiving clinically relevant doses of cabazitaxel.

Cabazitaxel induced embryofoetal toxicity in female rats treated intravenously once daily from gestational days 6 through 17 linked with maternal toxicity and consisted of foetal deaths and decreased mean foetal weight associated with delay in skeletal ossification. Exposures in animals were lower than those seen in humans receiving clinically relevant doses of cabazitaxel. Cabazitaxel crossed the placenta barrier in rats.

In rats, cabazitaxel and its metabolites are excreted in maternal milk at a quantity up to 1.5% of administered dose over 24 hours.

Environmental Risk Assessment (ERA)

Results of environmental risk assessment studies indicated that use of JEVTANA will not cause significant risk to the aquatic environment (see section 6.6 for disposal of unused product).

Concentrate

Polysorbate 80

Citric acid

Solvent

Ethanol 96%

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

PVC infusion containers and polyurethane infusion sets should not be used for the preparation and administration of the infusion solution.

Unopened vials: 3 years

After opening:

The concentrate and solvent vials must be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

After initial dilution of the concentrate with the solvent:

Chemical and physical in-use stability has been demonstrated for 1 hour at ambient temperature (15°C-30°C). From a microbiological point of view, the concentrate-solvent mixture should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hour at 2°C – 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

After final dilution in the infusion bag/bottle:

Chemical and physical stability of the infusion solution has been demonstrated for 8 hours at ambient temperature (including the 1-hour infusion time) and for 48 hours at refrigerated conditions.

From a microbiological point of view, the infusion solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hour at 2°C – 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not refrigerate.

For storage conditions of the diluted medicinal product, see section 6.3.

One pack contains one vial of concentrate and one vial of solvent:

• Concentrate: 1.5 ml of concentrate in a 15 ml clear glass vial (type I) closed with a grey chlorobutyl rubber closure sealed by an aluminium cap covered with a light green plastic flip-off cap.

• Solvent: 4.5 ml of solvent in a 15 ml clear glass vial (type I) closed with a grey chlorobutyl rubber closure sealed by a gold colour aluminium cap covered with a colourless plastic flip-off cap.

JEVTANA should only be prepared and administered by personnel trained in handling cytotoxic agents. Pregnant staff should not handle the product. As for any other antineoplastic agent, 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. If JEVTANA, 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.

Always dilute the concentrate for solution for infusion with the supplied solvent before adding to infusion solution.

The following two-step dilution process must be carried out in an aseptic manner for preparing the solution for infusion.

Step 1: Initial dilution of the concentrate for solution for infusion with the supplied solvent.

• Set aside the JEVTANA concentrate vial and the supplied solvent. The solution in the concentrate vial should be clear.

• Withdraw the entire content of the supplied solvent using a syringe, by partially inverting the vial, and inject it into the corresponding vial of JEVTANA concentrate. To limit foaming as much as possible when injecting the solvent, direct the needle onto the inside wall of the vial of concentrate solution and inject slowly.

• Remove the syringe and needle and mix manually and gently by repeated inversions until obtaining a clear and homogeneous solution. It could take approximately 45 seconds.

• Let this solution stand for approximately 5 minutes and then check that the solution is homogeneous and clear. It is normal for foam to persist after this time period.

This resulting concentrate-solvent mixture contains 10 mg/ml of cabazitaxel (at least 6 ml deliverable volume). It should be immediately diluted as detailed in step 2.

Step 2: Preparation of the infusion solution.

• Based on the required dose for the patient, withdraw the corresponding volume of the concentrate-solvent mixture containing 10 mg/ml of JEVTANA, with a graduated syringe. As an example, a dose of 45 mg JEVTANA would require 4.5 ml of the concentrate-solvent mixture prepared following step 1. More than one vial of the concentrate-solvent mixture may be necessary for preparing the appropriate dose.

• Since foam may persist on the wall of the vial of this solution, following its preparation described in step 1, it is preferable to place the needle of the syringe in the middle when extracting.

• Use PVC-free infusion containers and inject the withdrawn volume into either 5% glucose solution or sodium chloride 9 mg/ml (0.9%) 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 content of the infusion bag or bottle manually using a rocking motion.

The JEVTANA infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions mentioned in section 6.3. As with all parenteral products, the resulting infusion solution should be visually inspected prior to use. As the infusion solution is supersaturated, it may crystallize over time. In this case, the solution must not be used and should be discarded.

An in-line filter of 0.22 micrometer nominal pore size is recommended during administration.

Do not use PVC infusion containers and polyurethane infusion sets for the preparation and administration of JEVTANA.

Any unused product or waste material should be disposed of in accordance with local requirements.

sanofi-aventis

174, avenue de France

F - 75013 Paris

France

EU/1/11/676/001

17^th March 2011

27^th October 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

POM