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%

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.

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.

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).

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).

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.

Elderly patients

No specific dose adjustment for the use of cabazitaxel in elderly patients is recommended.

Concomitant medicinal products use

Concomitant medicinal products that are strong inducers or inhibitors of CYP3A should be avoided.

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

• 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

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.

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.

Co-administration with strong CYP3A4 inducers should be avoided since they may lead to decreased plasma concentrations of cabazitaxel.

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.

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.

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

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

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%

sanofi-aventis

POM - Prescription Only Medicine

11 April 2011