JEVTANA 60mg concentrate+solvent for solution for infusion medication leaflet

JEVTANA 60 mg concentrate and solvent for solution for infusion.

One ml of concentrate contains 40 mg cabazitaxel.

One vial of 1.5 ml (nominal volume) of concentrate contains 60 mg cabazitaxel.

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

Note: Both the JEVTANA 60 mg/1.5 ml concentrate vial (fill volume: 73.2 mg of cabazitaxel/1.83 ml)and the solvent vial (fill volume: 5.67 ml) contain an overfill to compensate for liquid loss duringpreparation. This overfill ensures that after dilution with the ENTIRE contents of the accompanyingsolvent, there is solution containing 10 mg/ml cabazitaxel.

One 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 adultpatients with metastatic castration resistant prostate cancer previously treated with adocetaxel-containing regimen (see section 5.1).

The use of JEVTANA should be confined to units specialised in the administration of cytotoxics and itshould only be administered under the supervision of a physician experienced in the use of anticancerchemotherapy. Facilities and equipment for the treatment of serious hypersensitivity reactions likehypotension and bronchospasm must be available (see section 4.4).

Premedication

The recommended premedication regimen should be performed at least 30 minutes prior to eachadministration of JEVTANA with the following intravenous medicinal products to mitigate the riskand severity of hypersensitivity:

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

* corticosteroid (dexamethasone 8 mg or equivalent), and

* 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 preventcomplications like renal failure.

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

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

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

Adverse reactions Dose modification

Prolonged grade ≥3 neutropenia (longer than Delay treatment until neutrophil count is1 week) despite appropriate treatment including >1,500 cells/mm3, then reduce cabazitaxel dose

G-CSF from 25 mg/m2 to 20 mg/m2.

Febrile neutropenia or neutropenic infection Delay treatment until improvement or resolution,and until neutrophil count is >1,500 cells/mm3,then reduce cabazitaxel dose from 25 mg/m2 to20 mg/m2.

Grade ≥3 diarrhoea or persisting diarrhoea Delay treatment until improvement or resolution,despite appropriate treatment, including fluid and then reduce cabazitaxel dose from 25 mg/m2 toelectrolytes replacement 20 mg/m2.

Grade >2 peripheral neuropathy Delay treatment until improvement, then reducecabazitaxel dose from 25 mg/m2 to 20 mg/m2.

If patients continue to experience any of these reactions at 20 mg/m2, further dose reduction to 15mg/m2 or discontinuation of JEVTANA may be considered. Data in patients below the 20 mg/m2 doseare limited.

Cabazitaxel is extensively metabolised by the liver. Patients with mild hepatic impairment (totalbilirubin >1 to ≤1.5 x upper limit of normal (ULN) or Aspartate Aminotransferase (AST)>1.5 x ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel topatients with mild hepatic impairment should be undertaken with caution and close monitoring ofsafety.

In patients with moderate hepatic impairment (total bilirubin >1.5 to ≤ 3.0 x ULN), the maximumtolerated dose (MTD) was 15 mg/m2. If the treatment is envisaged in patients with moderate hepaticimpairment the dose of cabazitaxel should not exceed 15 mg/m2. However, limited efficacy data areavailable at this dose.

Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin >3 x ULN)(see sections pct. 4.3, pct. 4.4 and 5.2).

Cabazitaxel is minimally excreted through the kidney. No dose adjustment is necessary in patientswith renal impairment, not requiring hemodialysis. Patients presenting end stage renal disease(creatinine clearance (CLCR< 15 mL/min/1.73 m2), by their condition and the limited amount of dataavailable should be treated with caution and monitored carefully during treatment (see sections 4.4 and5.2).

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

Concomitant medicinal products use

Concomitant medicinal products that are strong inducers or strong inhibitors of CYP3A should beavoided. However, if patients require co-administration of a strong CYP3A inhibitor, a 25%cabazitaxel dose reduction should be considered (see sections 4.4 and 4.5).

There is no relevant use of JEVTANA in the paediatric population.

The safety and the efficacy of JEVTANA in children and adolescents below 18 years of age have notbeen established (see section 5.1).

JEVTANA is for intravenous use.

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

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

JEVTANA must not be mixed with any other medicinal products than those mentioned in section 6.6.

* Hypersensitivity to cabazitaxel, to other taxanes, to polysorbate 80 or to any of the excipientslisted in section 6.1.

* Neutrophil counts less than 1,500/mm3.

* Severe hepatic impairment (total bilirubin >3 x ULN).

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

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

Patients should be observed closely for hypersensitivity reactions especially during the first andsecond infusions. Hypersensitivity reactions may occur within a few minutes following the initiationof the infusion of cabazitaxel, thus facilities and equipment for the treatment of hypotension andbronchospasm should be available. Severe reactions can occur and may include generalisedrash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediatediscontinuation of cabazitaxel and appropriate therapy. Patients with a hypersensitivity reaction muststop treatment with JEVTANA (see section 4.3).

Bone marrow suppression

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia, or pancytopeniamay occur (see “Risk of neutropenia” and “Anaemia” in section 4.4 below).

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 manageneutropenia 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 radiationports, poor nutritional status, or other serious comorbidities) that predispose them to increasedcomplications from prolonged neutropenia. The use of G-CSF has been shown to limit the incidenceand severity of neutropenia.

Neutropenia is the most common adverse reaction of cabazitaxel (see section 4.8). Monitoring ofcomplete blood counts is essential on a weekly basis during cycle 1 and before each treatment cyclethereafter so that the dose can be adjusted, if needed.

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

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

Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with orwithout neutropenia, may be early manifestations of serious gastrointestinal toxicity and should beevaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary.

Risk of nausea, vomiting, diarrhoea and dehydration

If patients experience diarrhoea following administration of cabazitaxel they may be treated withcommonly used anti-diarrhoeal medicinal products. Appropriate measures should be taken tore-hydrate patients. Diarrhoea can occur more frequently in patients that have received priorabdomino-pelvic radiation. Dehydration is more common in patients aged 65 or older. Appropriatemeasures 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 usedanti-emetics.

Risk of serious gastrointestinal reactions

Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have beenreported in patients treated with cabazitaxel (see section 4.8). Caution is advised with treatment ofpatients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly,concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior historyof pelvic radiotherapy or gastrointestinal disease, such as ulceration and GI bleeding.

Cases of peripheral neuropathy, peripheral sensory neuropathy (e.g., paraesthesias, dysaesthesias) andperipheral motor neuropathy have been observed in patients receiving cabazitaxel. Patients undertreatment with cabazitaxel should be advised to inform their doctor prior to continuing treatment ifsymptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop. Physiciansshould assess for the presence or worsening of neuropathy before each treatment. Treatment should bedelayed until improvement of symptoms. The dose of cabazitaxel should be reduced from 25 mg/m2 to20 mg/m2 for persistent grade >2 peripheral neuropathy (see section 4.2).

Anaemia has been observed in patients receiving cabazitaxel (see section 4.8). Haemoglobin andhaematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs orsymptoms of anaemia or blood loss. Caution is recommended in patients with haemoglobin <10 g/dland appropriate measures should be taken as clinically indicated.

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 beenobserved. Appropriate measures should be taken to identify the cause and intensively treat the patientsif this occurs.

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

Interstitial pneumonia/pneumonitis and interstitial lung disease have been reported and may beassociated with fatal outcome (see section 4.8).

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptlyinvestigated, and appropriately treated. Interruption of cabazitaxel therapy is recommended untildiagnosis is available. Early use of supportive care measures may help improve the condition. Thebenefit of resuming cabazitaxel treatment must be carefully evaluated.

Risk of cardiac arrhythmias

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

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

Patients with liver impairment

Treatment with JEVTANA is contraindicated in patients with severe hepatic impairment (totalbilirubin > 3 x ULN) (see sections 4.3 and 5.2).

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 sections 4.2 and 5.2).

Co-administration with strong CYP3A inhibitors should be avoided since they may increase theplasma concentrations of cabazitaxel (see sections 4.2 and 4.5). If co-administration with a strong

CYP3A inhibitor cannot be avoided, close monitoring for toxicity and a cabazitaxel dose reductionshould be considered (see sections 4.2 and 4.5).

Co-administration with strong CYP3A inducers should be avoided since they may decrease plasmaconcentrations of cabazitaxel (see sections 4.2 and 4.5).

This medicine contains 573 mg of alcohol (ethanol) in each solvent vial. The amount in the dose ofthis medicine is equivalent to less than 11 ml beer or 5 ml wine. The small amount of alcohol in thismedicine will not have any noticeable effects. However, special precaution needs to be taken inhigh-risk groups such as patients with liver disease, epilepsy and patients with the history ofalcoholism.

Contraception measure

Men should use contraceptive measures during treatment and for 4 months after cessation of treatmentwith cabazitaxel (see section 4.6).

In vitro studies have shown that cabazitaxel is mainly metabolised through CYP3A (80% to 90%) (seesection 5.2).

Repeated administration of ketoconazole (400 mg once daily), a strong CYP3A inhibitor, resulted in a20% decrease in cabazitaxel clearance corresponding to a 25% increase in AUC. Thereforeconcomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole,clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)should be avoided as an increase of plasma concentrations of cabazitaxel may occur (see sections 4.2and 4.4).

Concomitant administration of aprepitant, a moderate CYP3A inhibitor, had no effect on cabazitaxelclearance.

Repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, resulted in anincrease in cabazitaxel clearance of 21% corresponding to a decrease in AUC of 17%.

Therefore concomitant administration of strong CYP3A inducers (e.g., phenytoin, carbamazepine,rifampin, rifabutin, rifapentin, phenobarbital) should be avoided as a decrease of plasmaconcentrations of cabazitaxel may occur (see sections 4.2 and 4.4). In addition, patients should alsorefrain from taking St. John’s Wort.

OATP1B1

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 minutesafter the end of the infusion. A time interval of 12 hours is recommended before the infusion and atleast 3 hours after the end of infusion before administering the OATP1B1 substrates.

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

Contraception measure

Due to the genotoxic risk of cabazitaxel (see section 5.3), men should use effective method ofcontraception during treatment and for 4 months after cessation of treatment with cabazitaxel.

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

Cabazitaxel is not indicated for use in women.

Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites inmilk (see section 5.3).

Animal studies showed that cabazitaxel affected reproductive system in male rats and dogs withoutany functional effect on fertility (see section 5.3). Nevertheless, considering the pharmacologicalactivity of taxanes, their genotoxic potential by an aneugenic mechanism and effect of severalcompounds of this class on fertility in animal studies, effect on male fertility could not be excluded inhuman.

Men being treated with cabazitaxel are advised to seek advice on conservation of sperm prior totreatment.

Cabazitaxel has a moderate influence on the ability to drive and use machines as it may cause fatigueand dizziness. Patients should be advised not to drive or use machines if they experience these adversereactions during treatment.

The safety of JEVTANA in combination with prednisone or prednisolone was evaluated in 3randomized, open label, controlled studies (TROPIC, PROSELICA and CARD), totaling 1092patients with metastatic castration resistant prostate cancer who were treated with 25 mg/m²cabazitaxel once every 3 weeks. Patients received a median of 6 to 7 cycles of cabazitaxel.

The incidences from the pooled analysis of these 3 trials are presented below and in the tabulated list.

The most common all grades adverse reactions were anaemia (99.0%), leukopenia (93.0%),neutropenia (87.9%), thrombocytopenia (41.1%), diarrhoea (42.1%), fatigue (25.0%) and asthenia(15.4%).The most common grade ≥3 adverse reactions occurring in at least 5% of patients wereneutropenia (73.1%), leukopenia (59.5%), anaemia (12.0%), febrile neutropenia (8.0%) and diarrhoea(4.7%).

Discontinuation of treatment due to adverse reactions occurred with similar frequencies across the 3studies (18.3% in TROPIC, 19.5% in PROSELICA and 19.8% in CARD) in patients receivingcabazitaxel. The most common adverse reactions (> 1.0%) leading to cabazitaxel discontinuation werehematuria, fatigue and neutropenia.

Adverse reactions are listed in table 2 according to MedDRA system organ class and frequencycategories. Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness. Intensity of the adverse reactions is graded according to CTCAE 4.0 (grade ≥3 = G≥3).

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 cabazitaxel in combinationwith prednisone or prednisolone from pooled analysis (n=1092)

System Organ Adverse reaction All grades Grade>3

Class n (%) n (%)

Very Common Uncommoncommon

Neutropenic 48 (4.4) 42 (3.8)infection/sepsis*

Septic shock 10 (0.9) 10 (0.9)

Sepsis 13 (1.2) 13 (1.2)

Cellulitis 8 (0.7) 3 (0.3)

Urinary tract infection 103 (9.4) 19 (1.7)

Infections andinfestations

Influenza 22 (2.0) 0

Cystitis 22 (2.0) 2 (0.2)

Upper respiratory tract 23 (2.1) 0infection

Herpes zoster 14 (1.3) 0

Candidiasis 11 (1.0) 1 (<0.1)

Neutropeniaa* 950 (87.9) 790 (73.1)

Blood and Anaemia a 1073 (99.0) 130 (12.0)lymphatic system Leukopeniaa 1008 (93.0) 645 (59.5)disorders Thrombocytopeniaa 478 (44.1) 44 (4.1)

Febrile neutropenia 87 (8.0) 87 (8.0)

Immune system Hypersensitivity 7 (0.6) 0disorders

System Organ Adverse reaction All grades Grade>3

Class n (%) n (%)

Very Common Uncommoncommon

Decreased appetite 192 (17.6) 11 (1.0)

Metabolism and Dehydration 27 (2.5) 11 (1.0)nutrition disorders Hyperglycaemia 11 (1.0) 7 (0.6)

Hypokalemia 8 (0.7) 2 (0.2)

Psychiatric Insomnia 45 (4.1) 0disorders Anxiety 13 (1.2) 0

Confusional state 12 (1.1) 2 (0.2)

Dysgeusia 64 (5.9) 0

Taste disorder 56 (5.1) 0

Neuropathy peripheral 40 (3.7) 2 (0.2)

Peripheral sensory 89 (8.2) 6 (0.5)

Nervous system neuropathydisorders Polyneuropathy 9 (0.8) 2 (0.2)

Paraesthesia 46 (4.2) 0

Hypoaesthesia 18 (1.6) 1 (<0.1)

Dizziness 63 (5.8) 0

Headache 56 (5.1) 1 (<0.1)

Lethargy 15 (1.4) 1 (<0.1)

Sciatica 9 (0.8) 1 (<0.1)

Eye disorders Conjunctivitis 11 (1.0) 0

Lacrimation increased 22 (2.0) 0

Ear and labyrinth Tinnitus 7 (0.6) 0disorders Vertigo 15 (1.4) 1 (<0.1)

Cardiac disorders* Atrial fibrillation 14 (1.3) 5 (0.5)

Tachycardia 11 (1.0) 1 (<0.1)

Hypotension 38 (3.5) 5 (0.5)

Deep vein thrombosis 12 (1.1) 9 (0.8)

Hypertension 29 (2.7) 12 (1.1)

Vascular disorders Orthostatic 6 (0.5) 1 (<0.1)hypotension

Hot flush 23 (2.1) 1 (<0.1)

Flushing 9 (0.8) 0

Dyspnoea 97 (8.9) 9 (0.8)

Respiratory,thoracic and Cough 79 (7.2) 0mediastinal Oropharyngeal pain 26 (2.4) 1 (< 0.1)disorders Pneumonia 26 (2.4) 16 (1.5)

Pulmonary embolism 30 (2.7) 23 (2.1)

Diarrhoea 460 (42.1) 51 (4.7)

Nausea 347 (31.8) 14 (1.3)

Vomiting 207 (19.0) 14 (1.3)

Constipation 202 (18.5) 8 (0.7)

Gastrointestinal Abdominal pain 105 (9.6) 15 (1.4)disorders Dyspepsia 53 (4.9) 0

Abdominal pain upper 46 (4.2) 1 (< 0.1)

Haemorrhoids 22 (2.0) 0

Gastroesophageal 26 (2.4) 1 (< 0.1)reflux disease

Rectal haemorrhage 14 (1.3) 4 (0.4)

System Organ Adverse reaction All grades Grade>3

Class n (%) n (%)

Very Common Uncommoncommon

Dry mouth 19 (1.7) 2 (0.2)

Abdominal distension 14 (1.3) 1 (< 0.1)

Stomatitis 46 (4.2) 2 (0.2)

Ileus* 7 (0.6) 5 (0.5)

Gastritis 10 (0.9)

Colitis* 10 (0.9) 5 (0.5)

Gastrointestinal 3 (0.3) 1 (<0.1)perforation

Gastrointestinal 2 (0.2) 1 (<0.1)haemorrhage

Skin and Alopecia 80 (7.3) 0subcutaneous tissue Dry skin 23 (2.1) 0disorders Erythema 8 (0.7) 0

Nail disorder 18 (1.6) 0

Back pain 166 (15.2) 24 (2.2)

Arthralgia 88 (8.1) 9 (0.8)

Pain in extremity 76 (7.0) 9 (0.8)

Musculoskeletal Muscle spasms 51 (4.7) 0and connective Myalgia 40 (3.7) 2 (0.2)tissue disorders Musculoskeletal chest 34 (3.1) 3 (0.3)pain

Muscular weakness 31 (2.8) 1 (0.2)

Flank pain 17 (1.6) 5 (0.5)

Acute renal failure 21 (1.9) 14 (1.3)

Renal failure 8 (0.7) 6 (0.5)

Dysuria 52 (4.8) 0

Renal colic 14 (1.3) 2 (0.2)

Renal and urinary Haematuria 205 (18.8) 33 (3.0)disorders Pollakiuria 26 (2.4) 2 (0.2)

Hydronephrosis 25 (2.3) 13 (1.2)

Urinary retention 36 (3.3) 4 (0.4)

Urinary incontinence 22 (2.0) 0

Ureteric obstruction 8 (0.7) 6 (0.5)

Reproductive Pelvic pain 20 (1.8) 5 (0.5)system and breastdisorders

Fatigue 333 (30.5) 42 (3.8)

Asthenia 227 (20.8) 32 (2.9)

Pyrexia 90 (8.2) 5 (0.5)

General disorders Peripheral oedema 96 (8.8) 2 (0.2 )and administration Mucosal inflammation 23 (2.1) 1 (<0.1)site conditions Pain 36 (3.3) 7 (0.6)

Chest pain 11 (1.0) 2 (0.2)

Oedema 8 (0.7) 1 (<0.1)

Chills 12 (1.1) 0

Malaise 21 (1.9) 0

Weight decreased 81 (7.4) 0

Investigations Aspartate 13 (1.2) 1 (<0.1)aminotransferaseincreased

System Organ Adverse reaction All grades Grade>3

Class n (%) n (%)

Very Common Uncommoncommon

Transaminases 7 (0.6) 1 (<0.1)increaseda based on laboratory values

* see detailed section below

Neutropenia, and associated clinical events

The use of G-CSF has been shown to limit the incidence and severity of neutropenia (see sections 4.2and 4.4).

Incidence of grade ≥3 neutropenia based on laboratory data varied depending on use of G-CSF from44.7% to 76.7%, with the lowest incidence reported when G-CSF prophylaxis was used. Similarly, theincidence of grade ≥ 3 febrile neutropenia ranged from 3.2% to 8.6%.

Neutropenic complications (including febrile neutropenia, neutropenic infection/sepsis andneutropenic colitis) which in some cases resulted in a fatal outcome, were reported in 4.0% of thepatients when primary G-CSF prophylaxis was used, and in 12.8% of the patients otherwise.

Cardiac disorders and arrhythmias

In the pooled analysis, cardiac events were reported in 5.5% of the patients of which 1.1% hadgrade ≥3 cardiac arrhythmias. The incidence of tachycardia on cabazitaxel was 1.0%, of which lessthan 0.1% were grade ≥3. The incidence of atrial fibrillation was 1.3%. Cardiac failure events werereported for 2 patients (0.2%), one of which resulted in a fatal outcome. Fatal ventricular fibrillationwas reported in 1 patient (0.3%), and cardiac arrest in 3 patients (0.5%). None were considered relatedby the investigator.

Haematuria

In the pooled analysis, haematuria all grades frequency was 18.8% at 25 mg/m2 (see section 5.1).

Confounding causes when documented, such as disease progression, instrumentation, infection oranticoagulation/NSAID/acetylsalicylic acid therapy were identified in nearly half of the cases.

Other laboratory abnormalities

In pooled analysis, the incidence of grade ≥3 anaemia, increased AST, ALT, and bilirubin based onlaboratory abnormalities were 12.0%, 1.3%, 1.0%, and 0.5%, respectively.

Colitis (including enterocolitis and neutropenic enterocolitis), and gastritis have been observed.

Gastrointestinal hemorrhage, gastrointestinal perforation, and ileus (intestinal obstruction) have alsobeen reported (see section 4.4).

Cases of interstitial pneumonia/pneumonitis and interstitial lung disease, sometimes fatal have beenreported with an unknown frequency (cannot be estimated from the available data) (see section 4.4).

Cystitis due to radiation recall phenomenon, including haemorrhagic cystitis, were reporteduncommonly.

See section 4.2

Of the 1092 patients treated with cabazitaxel 25 mg/m2 in the prostate cancer studies, 755 patientswere 65 years or over including 238 patients older than 75 years. The following non hematologicadverse reactions were reported at rates ≥5% higher in patients 65 years of age or greater compared toyounger patients: fatigue (33.5% vs. 23.7%), asthenia (23.7 vs. 14.2%), constipation (20.4% vs.14.2%) and dyspnoea (10.3% vs. 5.6%) respectively. Neutropenia (90.9% vs. 81.2%) andthrombocytopenia (48.8% vs. 36.1%) were also 5% higher in patients 65 years of age or greatercompared to younger patients. Grade ≥3 neutropenia and febrile neutropenia were reported with thehighest difference rates between both groups of age (respectively 14% and 4% higher in patients ≥ 65years old compared to patients < 65 years old) (see sections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known antidote to cabazitaxel. The anticipated complications of overdose would consist ofexacerbation 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. Patientsshould receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriatesymptomatic measures should be taken.

Pharmacotherapeutic group: Antineoplastic agents, taxanes, ATC code: L01CD04

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 whilesimultaneously inhibiting their disassembly. This leads to the stabilisation of microtubules, whichresults in the inhibition of mitotic and interphase cellular functions.

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

The efficacy and safety of JEVTANA in combination with prednisone or prednisolone were evaluatedin a randomised, open-label, international, multi-center, phase III study (EFC6193 study), in patientswith metastatic castration resistant prostate cancer previsouly treated with a docetaxel containingregimen.

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

Secondary endpoints included progression free survival [PFS (defined as time from randomization totumour progression, prostatic specific antigen (PSA) progression, pain progression, or death due toany cause, whichever occurred first], tumour response rate based on response evaluation criteria insolid tumours (RECIST), PSA progression (defined as a ≥25% increase or >50% in PSAnon-responders or responders respectively), PSA response (declines in serum PSA levels of at least50%), pain progression [assessed using the present pain intensity (PPI) scale from the McGill-Melzackquestionnaire and an analgesic score (AS)] and pain response (defined as 2-point greater reductionfrom baseline median PPI with no concomitant increase in AS, or reduction of ≥50% in analgesic usefrom baseline mean AS with no concomitant increase in pain).

A total of 755 patients were randomised to receive either JEVTANA 25 mg/m2 intravenously every3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=378), orto receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles withprednisone or prednisolone 10 mg orally daily (n=377).

This study included patients over 18 years of age with metastatic castration resistant prostate cancereither measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearanceof new lesions, and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patientshad 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, orpatients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not includedin the study.

Demographics, including age, race, and ECOG performance status (0 to 2), were balanced between thetreatment arms. In the JEVTANA group, the mean age was 68 years, range (46-92) and the racialdistribution 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. Thenumber 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 monthsversus 12.7 respectively), with a 30% reduction in the risk of death compared to mitoxantrone (seetable 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 overallsurvival in this group of patients (HR (95%CI) 0.96 (0.49-1.86)).

Table 3 - Efficacy of JEVTANA in EFC6193 study in the treatment of patients with metastaticcastration resistant prostate cancer

JEVTANA + prednisone mitoxantrone + prednisonen=378 n=377

Overall survival

Number of patients with deaths (%) 234 (61.9%) 279 (74%)

Median survival (months) (95% CI) 15.1 (14.1-16.3) 12.7 (11.6-13.7)

Hazard Ratio (HR)1 (95% CI) 0.70 (0.59-0.83)p-value <0.00011HR estimated using Cox model; a hazard ratio of less than 1 favours JEVTANA

Figure 1: Kaplan Meier overall survival curves (EFC6193)

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 progressionof 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 PSAresponse was 39.2% in patients on JEVTANA arm (95%CI: 33.9-44.5) versus 17.8% of patients onmitoxantrone (95%CI: 13.7-22.0), p=0.0002.

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

In a non-inferiority, multicenter, multinational, randomised, open label phase III study (EFC11785study), 1200 patients with metastatic castration resistant prostate cancer, previously treated with adocetaxel-containing regimen, were randomized to receive either cabazitaxel 25 mg/m2 (n=602) or 20mg/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 incomparison with 25 mg/m2 (see table 4). A statistically significantly higher percentage (p<0.001) ofpatients 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/m2dose with respect to the 25 mg/m2 dose was observed (HR 1.195 ; 95%CI: 1.025 to 1.393). There wasno statistically difference with regards to the other secondary endpoints (PFS, tumour and painresponse, tumour and pain progression, and four subcategories of FACT-P).

Table 4 - Overall survival in EFC11785 study in cabazitaxel 25 mg/m2 arm versus cabazitaxel 20mg/m2 arm (Intent-to-treat analysis) - Efficacy primary endpoint

CBZ20+PRED CBZ25+PREDn=598 n=602

Overall Survival

Number of deaths, n (%) 497 (83.1 %) 501 (83.2%)

Median survival (95% CI) (months) 13.4 (12.19 to 14.88) 14.5 (13.47 to 15.28)

Hazard Ratioaversus CBZ25+PRED 1.024 -1-sided 98.89% UCI 1.184 -1-sided 95% LCI 0.922 -

CBZ20=Cabazitaxel 20 mg/m2, CBZ25=Cabazitaxel 25 mg/m2, PRED=Prednisone/Prednisolone

CI=confidence interval, LCI=lower bound of the confidence interval, UCI=upper bound of theconfidence intervala Hazard ratio is estimated using a Cox Proportional Hazards regression model. A hazard ratio < 1indicates a lower risk of cabazitaxel 20 mg/m2 with respect to 25 mg/m2.

The safety profile of cabazitaxel 25 mg/m2 observed in study EFC11785 was qualitatively andquantitatively similar to that observed in the study EFC6193. Study EFC11785 demonstrated a bettersafety profile for the cabazitaxel 20 mg/m2 dose.

Table 5 - Summary of safety data for cabazitaxel 25 mg/m2 arm versus cabazitaxel 20 mg/m2arm in EFC11785 study

CBZ20+PRED CBZ25+PREDn=580 n=595

Median number of cycles/ 6/ 18 weeks 7/ 21 weeksmedian duration of treatment

Number of patients with From 25 to 20 mg/m2: 128 (21.5%)dose reduction 2n (%) From 20 to 15 mg/m2: 58 (10.0%) From 20 to 15 mg/m : 19 (3.2%)

From 15 to 12 mg/m2: 9 (1.6%) From 15 to 12 mg/m : 1 (0.2%)

All grade adverse reactionsa (%)

Diarrhoea 30.7 39.8

Nausea 24.5 32.1

Fatigue 24.7 27.1

Haematuria 14.1 20.8

Asthenia 15.3 19.7

Decreased appetite 13.1 18.5

Vomiting 14.5 18.2

Constipation 17.6 18.0

Back pain 11.0 13.9

Clinical neutropenia 3.1 10.9

Urinary tract infection 6.9 10.8

Peripheral sensory 6.6 10.6neuropathy

Dysgeusia 7.1 10.6

Grade ≥ 3 adverse reactionsb (%)

Clinical neutropenia 2.4 9.6

Febrile neutropenia 2.1 9.2

Haematological abnormalitiesc (%)

Grade ≥ 3 neutropenia 41.8 73.3

Grade ≥ 3 anaemia 9.9 13.7

Grade ≥ 3 thrombocytopenia 2.6 4.2

CBZ20=Cabazitaxel 20 mg/m2, CBZ25=Cabazitaxel 25 mg/m2, PRED=Prednisone/Prednisolonea All grade adverse reactions with an incidence higher than 10%b Grade ≥ 3 adverse reactions with an incidence higher than 5%c Based on laboratory values

In a prospective , multinational, randomized , active-controlled and open-label phase IV study(LPS14201/CARD study) 255 patients with metastatic castration resistant prostate cancer (mCRPC),previously treated in any order with a docetaxel containing regimen and with an AR-targeted agent(abiraterone or enzalutamide, with disease progression within 12 months of treatment initiation), wererandomized to receive either JEVTANA 25 mg/m2 every 3 week plus prednisone/prednisolone 10 mgdaily (n=129) or AR-targeted agents (abiraterone 1000 mg once daily plus prednisone/prednisolone 5mg twice daily or enzalutamide 160 mg once daily) (n=126). Radiographic progression free-survival(rPFS) as defined by Prostate Cancer Working Group-2 (PCWG2) was the primary endpoint.

Secondary endpoints included overall survival, progression-free survival, PSA response and tumourresponse.

Demographics and disease characteristics were balanced between treatment arms. At baseline, theoverall median age was 70 years, 95% of patients had an ECOG PS of 0 to 1 and median Gleasonscore was 8. Sixty one percent (61%) of the patients had their prior treatment with an AR-targetedagent after prior docetaxel.

The study met its primary endpoint: rPFS was significantly longer with JEVTANA compared to AR-targeted agent (8.0 months versus 3.7 respectively), with a 46% reduction in the risk of radiographicprogression compared to AR-targeted agent (see table 6 and figure 2).

Table 6 - Efficacy of JEVTANA in CARD study in the treatment of patients with metastaticcastration resistant prostate cancer (Intent-to-treat analysis) - Radiographic progression free-survival(rPFS)

JEVTANA AR-targeted agent:

+ prednisone/prednisolone Abiraterone ++ G-CSF prednisone/prednisoloneor

Enzalutamiden=129 n=126

Number of events at the cut-off date (%) 95 (73.6%) 101 (80.2%)

Median rPFS (months) (95% CI) 8.0 (5.7 to 9.2) 3.7 (2.8 to 5.1)

Hazard Ratio (HR) (95% CI) 0.54 (0.40 to 0.73)p-value1 < 0.00011stratified log-rank test, significance threshold = 0.05

Figure 2 - Primary endpoint: Kaplan-Meier plot of radiographic PFS (ITT Population)

Tick marks indicate censored data.

Planned subgroup analyses for rPFS based on stratification factors at randomization yielded a hazardratio of 0.61 (95% CI: 0.39 to 0.96) in patients who received a prior AR-targeted agent beforedocetaxel and a hazard ratio of 0.48 (95% CI: 0.32 to 0.70) in patients who received a prior AR-targeted agent after docetaxel.

JEVTANA was statistically superior to the AR-targeted comparators for each of the alpha-protectedkey secondary endpoints including overall survival (13.6 months for JEVTANA arm versus 11.0months for AR-targeted agent arm, HR 0.64, 95%CI: 0.46 to 0.89; p=0.008), progression-free survival(4.4 months for JEVTANA arm versus 2.7 months for AR-targeted agent arm, HR 0.52; 95%CI: 0.40to 0.68), confirmed PSA response (36.3% for JEVTANA arm versus 14.3% for AR-targeted agentarm, p=0.0003) and best tumour response (36.5% for JEVTANA arm versus 11.5% for AR-targetedagent arm, p=0.004).

The safety profile of JEVTANA 25 mg/m2 observed in CARD study was overall consistentwith that observed in TROPIC and PROSELICA studies (see section 4.8). The incidence ofgrade ≥ 3 adverse events was 53.2% in JEVTANA arm versus 46.0% in the AR-targetedagent arm. The incidence of grade ≥ 3 serious adverse events were 31.7% in JEVTANA armversus 37.1% in the AR-targeted agent arm. The incidence of patients who permanentlydiscontinued study treatment due to adverse events was 19.8% in JEVTANA arm versus 8.1%in the AR-targeted agent arm. The incidence of patients having an adverse event leading todeath was 5.6% in JEVTANA arm versus 10.5% in the AR-targeted agent arm.

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 (seesection 4.2 for information on paediatric use).

JEVTANA was evaluated in an open label, multi-center Phase 1/2 study conducted in a total of 39paediatric patients (aged between 4 to18 years for the phase 1 part of the study and between 3 to 16years for the phase 2 part of the study). The phase 2 part did not demonstrate efficacy of cabazitaxel assingle agent in paediatric population with recurrent or refractory diffuse intrinsic pontine glioma(DIPG) and high grade glioma (HGG) treated at 30 mg/m².

A population pharmacokinetic analysis was carried out in 170 patients including patients withadvanced 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.

After 1-hour intravenous administration at 25 mg/m2 cabazitaxel in patients with metastatic prostatecancer (n=67), the Cmax was 226 ng/ml (Coefficient of Variation (CV): 107%) and was reached at theend of the 1-hour infusion (Tmax). 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 withadvanced solid tumours (n=126).

The volume of distribution (Vss) was 4870 l (2640 l/m² for a patient with a median BSA of 1.84 m²) atsteady state.

In vitro, the binding of cabazitaxel to human serum proteins was 89-92% and was not saturable up to50,000 ng/ml, which covers the maximum concentration observed in clinical studies. Cabazitaxel ismainly 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 from0.90 to 0.99 indicating that cabazitaxel was equally distributed between blood and plasma.

Cabazitaxel is extensively metabolised in the liver (>95%), mainly by the CYP3A isoenzyme (80% to90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites weredetected in plasma (including 3 active metabolites issued form O-demethylations), with the main oneaccounting for 5% of parent exposure. Around 20 metabolites of cabazitaxel are excreted into humanurine and faeces.

Based on in vitro studies, the potential risk of inhibition by cabazitaxel at clinically relevantconcentrations is possible towards medicinal products that are mainly substrate of CYP3A.

However a clinical study has shown that cabazitaxel (25 mg/m2 administered as a single 1-hourinfusion) did not modify the plasma levels of midazolam, a probe substrate of CYP3A. Therefore, attherapeutic doses, co-administration of CYP3A substrates with cabazitaxel to patients is not expectedto have any clinical impact.

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 onmedicinal products that are substrates of CYP1A, CYP2C9, and CYP3A. Cabazitaxel did not inhibit invitro 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.

In vitro cabazitaxel did not inhibit Multidrug-Resistant Proteins (MRP): MRP1 and MRP2 or Organic

Cation Transporter (OCT1). Cabazitaxel inhibited the transport of P-glycoprotein (PgP) (digoxin,vinblastin), Breast-Cancer-Resistant-Proteins (BCRP) (methotrexate) and Organic Anion Transporting

Polypeptide OATP1B3 (CCK8) at concentrations at least 15 fold what is observed in clinical settingwhile it inhibited the transport of OATP1B1 (estradiol-17β-glucuronide) at concentrations only 5 foldwhat is observed in clinical setting. Therefore the risk of interaction with substrates of MRP, OCT1,

PgP, BCRP and OATP1B3 is unlikely in vivo at the dose of 25 mg/m2. The risk of interaction with

OATP1B1 transporter is possible, notably during the infusion duration (1 hour) and up to 20 minutesafter the end of the infusion (see section 4.5).

After a 1-hour intravenous infusion [14C]-cabazitaxel at 25 mg/m2 in patients, approximately 80% ofthe administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the faeces asnumerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites accountfor 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 of1.84 m²) and a long terminal half-life of 95 hours.

In the population pharmacokinetic analysis in 70 patients of 65 years and older (57 from 65 to 75 and13 patients above 75), no age effect on the pharmacokinetics of cabazitaxel was observed.

Safety and effectiveness of JEVTANA have not been established in children and adolescents below18 years of age.

Cabazitaxel is eliminated primarily via liver metabolism.

A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (totalbilirubin >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 dose (MTD) ofcabazitaxel was 20 and 15 mg/m2, respectively.

In 3 patients with severe hepatic impairment (total bilirubin >3 ULN), a 39% decrease in clearancewas observed when compared to patients with mild hepatic impairment, indicating some effect ofsevere hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients withsevere hepatic impairment was not established.

Based on safety and tolerability data, cabazitaxel dose should be reduced in patients with mild hepaticimpairment (see sections 4.2, pct. 4.4). JEVTANA is contraindicated in patients with severe hepaticimpairment (see section 4.3).

Cabazitaxel is minimally excreted via the kidney (2.3% of the dose). A population pharmacokineticanalysis 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 impairmentdid not have meaningful effects on the pharmacokinetics of cabazitaxel. This was confirmed by adedicated comparative pharmacokinetic study in solid cancer patients with normal renal function(8 patients), moderate (8 patients) and severe (9 patients) renal impairment, who received severalcycles of cabazitaxel in single IV infusion up to 25 mg/m2.

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

Adverse reactions not observed in clinical studies, but seen in rats during repeat-dose toxicity studiesat exposure levels higher than clinical exposure levels and with possible relevance to clinical use wereeye disorders characterized by subcapsular lens fiber swelling/degeneration. These effects werepartially 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 notclastogenic in an in vitro test in human lymphocytes (no induction of structural chromosomalaberration but it increased number of polyploid cells) and induced an increase of micronuclei in the invivo test in rats. These genotoxicity findings (by an aneugenic mechanism) are inherent to thepharmacological activity of the compound (inhibition of tubulin depolymerization).

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

Cabazitaxel induced embryofoetal toxicity in female rats treated intravenously once daily fromgestational days 6 through 17 linked with maternal toxicity and consisted of foetal deaths anddecreased mean foetal weight associated with delay in skeletal ossification. Exposures in animals werelower than those seen in humans receiving clinically relevant doses of cabazitaxel. Cabazitaxel crossedthe placenta barrier in rats.

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

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

Polysorbate 80

Citric acid

Ethanol 96%

Water for injections

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

PVC infusion containers or polyurethane infusion sets should not be used for the preparation andadministration of the infusion solution.

Unopened vial3 years.

The concentrate and solvent vials must be used immediately. If not used immediately, in-use storagetimes 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 usedimmediately. If not used immediately, in-use storage times and conditions are the responsibility of theuser and would normally not be longer than 24 hour at 2°C - 8°C, unless dilution has taken place incontrolled 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 ambienttemperature (including the 1-hour infusion time) and for 48 hours at refrigerated conditions (includingthe 1-hour infusion time).

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

Do not store above 30°C.

Do not refrigerate.

For storage conditions after opening and dilution of the 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 greychlorobutyl rubber closure sealed by an aluminium cap covered with a light green plasticflip-off cap. Each vial contains 60 mg cabazitaxel per 1.5 ml nominal volume (fill volume:73.2 mg of cabazitaxel/1.83 ml). This fill volume has been established during the developmentof JEVTANA to compensate for liquid loss during preparation of the premix. This overfillensures that after dilution with the entire content of the accompanying solvent for JEVTANA,there is a minimal extractable premix volume of 6 ml containing 10 mg/ml JEVTANA whichcorresponds to the labelled amount of 60 mg per vial.

* Solvent: 4.5 ml of solvent in a 15 ml clear glass vial (type I) closed with a grey chlorobutylrubber closure sealed by a gold colour aluminium cap covered with a colourless plastic flip-offcap. Each vial contains 4.5 ml nominal volume (fill volume: 5.67 ml). This fill volume has beenestablished during the development and the overfill ensures, after the addition of the entirecontent of the solvent vial to the content of JEVTANA 60 mg concentrate vial, a concentrationof the premix solution of 10 mg/ml JEVTANA.

JEVTANA should only be prepared and administered by personnel trained in handling cytotoxicagents. Pregnant staff should not handle the medicinal product. As for any other antineoplastic agent,caution should be exercised when handling and preparing JEVTANA solutions, taking into accountthe use of containment devices, personal protective equipment (e.g. gloves), and preparationprocedures. If JEVTANA, at any step of its handling, should come into contact with the skin, washimmediately and thoroughly with soap and water. If it should come into contact with mucousmembranes, wash immediately and thoroughly with water.

Always dilute the concentrate for solution for infusion with the entire supplied solvent before addingto infusion solution.

Read this ENTIRE section carefully before mixing and diluting. JEVTANA requires TWO dilutionsprior to administration. Follow the preparation instructions provided below.

Note: Both the JEVTANA 60 mg/1.5 ml concentrate vial (fill volume: 73.2 mg of cabazitaxel/1.83 ml)and the solvent vial (fill volume: 5.67 ml) contain an overfill to compensate for liquid loss duringpreparation. This overfill ensures that after dilution with the ENTIRE contents of the accompanyingsolvent, there is solution containing 10 mg/ml cabazitaxel.

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

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

Step 1.1

Inspect the concentrate vial and the suppliedsolvent. The concentrate solution and thesolvent should be clear.

Concentrate vial(60 mg - 1.5 ml) Solvent vial

Step 1.2

Using a syringe fitted with a needle,aseptically withdraw the entire contents ofthe supplied solvent by partially inverting thevial.

Solvent vial

Step 1.3

Inject the entire contents into the correspondingconcentrate vial.

To limit foaming as much as possible wheninjecting the solvent, direct the needle onto theinside wall of the vial of concentrate solutionand inject slowly.

Once reconstituted, the resultant solution Concentrate- Solvent vialcontains 10 mg/ml of cabazitaxel. solvent mixture10 mg/ml

Step 1.4

Remove the syringe and needle and mixmanually and gently by repeated inversionsuntil obtaining a clear and homogeneoussolution. It could take approximately45 seconds.

Concentrate-solventmixture 10 mg/ml

Step 1.5

Let this solution stand for approximately5 minutes and check then that the solution ishomogeneous and clear.

It is normal for foam to persist after this timeperiod.

Concentrate-solventmixture 10 mg/ml

This resulting concentrate-solvent mixture contains 10 mg/ml of cabazitaxel (at least 6 ml deliverablevolume). The second dilution should be done immediately (within 1 hour) as detailed in Step 2.

More than one vial of the concentrate-solvent mixture may be necessary to administer the prescribeddose.

Step 2: Second (final) dilution for infusion

Step 2.1

Aseptically withdraw the required amount ofconcentrate-solvent mixture (10 mg/ml ofcabazitaxel), with a graduated syringe fittedwith a needle. As an example, a dose of 45 mg

JEVTANA would require 4.5 ml of theconcentrate-solvent mixture prepared following

Step 1.

Since foam may persist on the wall of the vial ofthis solution, following its preparation describedin Step 1, it is preferable to place the needle ofthe syringe in the middle when extracting. Concentrate-solventmixture 10 mg/ml

Step 2.2

Inject in a sterile PVC-free container of either5% glucose solution or sodium chloride9 mg/ml (0.9%) solution for infusion. Theconcentration of the infusion solution should bebetween 0.10 mg/ml and 0.26 mg/ml. Required amount of 5% glucose solutionconcentrate-solvent or sodium chloridemixture 9 mg/ml (0.9%)solution for infusion

Step 2.3

Remove the syringe and mix the content of theinfusion bag or bottle manually using a rockingmotion.

Step 2.4

As with all parenteral products, the resultinginfusion solution should be visually inspectedprior to use. As the infusion solution issupersaturated, it may crystallize over time. Inthis case, the solution must not be used andshould be discarded.

The infusion solution should be used immediately. However, in-use storage time can be longer underspecific conditions mentioned in section 6.3.

An in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) isrecommended during administration.

Do not use PVC infusion containers or polyurethane infusion sets for the preparation andadministration of JEVTANA.

JEVTANA must not be mixed with any other medicinal products than those mentioned.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/11/676/001

Date of first authorisation: 17 March 2011

Date of latest renewal: 14 December 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.