CABAZITAXEL ACCORD 20mg / ml perfusive solution concentrate medication leaflet

Cabazitaxel Accord 20 mg/ml concentrate for solution for infusion

One ml of concentrate contains 20 mg cabazitaxel.

One vial of 3 ml of concentrate contains 60 mg cabazitaxel.

The finished product contains 395 mg/ml of ethanol anhydrous, thus each 3 ml vial contains 1,185 mgethanol anhydrous.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a clear colourless to pale yellow or brownish yellow solution.

Cabazitaxel Accord in combination with prednisone or prednisolone is indicated for the treatment ofadult patients with metastatic castration resistant prostate cancer previously treated with adocetaxel-containing regimen (see section 5.1).

The use of cabazitaxel 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 cabazitaxel with the following intravenous medicinal products to mitigate the risk andseverity 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 cabazitaxel is 25 mg/m2 administered as a 1 hour intravenous infusion every3 weeks in combination with oral prednisone or prednisolone 10 mg administered daily throughouttreatment.

Dose modifications should be made if patients experience the following adverse reactions (Grades referto 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 diarrhea despite Delay treatment until improvement or resolution,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 to15 mg/m2 or discontinuation of cabazitaxel may be considered. Data in patients below the 20 mg/m2dose are limited.

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% cabazitaxeldose reduction should be considered (see sections 4.4 and 4.5).

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 to patients with mildhepatic impairment should be undertaken with caution and close monitoring of safety.

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 Accord 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 patients withrenal impairment, not requiring hemodialysis. Patients presenting end stage renal disease (creatinineclearance (CLCR< 15 mL/min/1.73 m2), by their condition and the limited amount of data availableshould be treated with caution and monitored carefully during treatment (see sections 4.4 and 5.2).

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

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

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

Cabazitaxel Accord is for intravenous use.

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

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

Cabazitaxel 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 (see section4.2).

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

Bone marrow suppression

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia, or pancytopenia mayoccur (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 priorradiation ports, 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 despite appropriatetreatment (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 to re-hydratepatients. Diarrhoea can occur more frequently in patients that have received prior abdomino-pelvicradiation. Dehydration is more common in patients aged 65 or older. Appropriate measures should betaken 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). Ifpatients experience nausea or vomiting, they may be treated with commonly used anti-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 history ofpelvic 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 been observed.

Appropriate measures should be taken to identify the cause and intensively treat the patients if thisoccurs.

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 (see section4.8).

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

Patients with liver impairment

Treatment with Cabazitaxel Accord 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 the plasmaconcentrations of cabazitaxel (see sections 4.2 and 4.5). If co-administration with a strong CYP3Ainhibitor cannot be avoided, close monitoring for toxicity and a cabazitaxel dose reduction should beconsidered (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 1185 mg of alcohol (ethanol) in each vial, which is equivalent to 395 mg/ml.

The amount in each vial of this medicine is equivalent to 30 ml of beer or 12 ml of wine.

The amount of alcohol in this medicine is not likely to have an effect in adults and adolescents, and itseffects in children are not likely to be noticeable.

It may have some effects in younger children, for example feeling sleepy. The alcohol in this medicinemay alter the effects of other medicines. Talk to your doctor or pharmacist if you are taking othermedicines.

If you are pregnant or breast-feeding, talk to your doctor or pharmacist before taking this medicine.

If you are addicted to alcohol, talk to your doctor or pharmacist before taking this medicine.

A dose of 60 mg of this medicinal product administered to an adult weighing 70 kg would result in anexposure to 17mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about2,8 mg/100 ml. For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC islikely to be about 50 mg/100 ml.

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. Therefore concomitantadministration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir,nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided as anincrease of plasma concentrations of cabazitaxel may occur (see sections 4.2 and 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 plasma concentrationsof cabazitaxel may occur (see sections 4.2 and 4.4). In addition, patients should also refrain 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 foetal harmin 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 without anyfunctional effect on fertility (see section 5.3). Nevertheless, considering the pharmacological activity oftaxanes, their genotoxic potential by an aneugenic mechanism and effect of several compounds of thisclass on fertility in animal studies, effect on male fertility could not be excluded in human.

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

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

The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 3randomized, open label, controlled studies (TROPIC, PROSELICA and CARD), totaling 1092 patientswith metastatic castration resistant prostate cancer who were treated with 25 mg/m2 cabazitaxel onceevery 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 n (%) Grade>3

Class n (%)

Very Common Uncommoncommon

Infections and Neutropenic 48 (4.4) 42infestations infection/sepsis* (3.8)

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)

Influenza 22 (2.0) 0

Cystitis 22 (2.0) 2 (0.2)

Upper respiratory 23 (2.1) 0tract infection

Herpes zoster 14 (1.3) 0

Candidiasis 11 (1.0) 1(<0.1)

Blood and Neutropeniaa* 950 (87.9) 790lymphatic (73.1)system Anaemiaa 1073 130disorders (99.0) (12.0)

Leukopeniaa 1008 645(93.0) (59.5)

Thrombocytopeniaa 478 (44.1) 44 (4.1)

Febrile neutropenia 87 (8.0) 87 (8.0)

Immune system Hypersensitivity 7 (0.6) 0disorders

Metabolism and Decreased appetite 192 (17.6) 11 (1.0)nutrition Dehydration 27 (2.5) 11 (1.0)disorders Hyperglycaemia 11 (1.0) 7 (0.6)

Hypokalemia 8 (0.7) 2 (0.2)

System Organ Adverse reaction All grades n (%) Grade>3

Class n (%)

Very Common Uncommoncommon

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

Confusional state 12 (1.1) 2 (0.2)

Nervous system Dysgeusia 64 (5.9) 0disorders Taste disorder 56 (5.1) 0

Neuropathy peripheral 40 (3.7) 2 (0.2)

Peripheral sensory 89 (8.2) 6 (0.5)neuropathy

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

Cardiac Atrial fibrillation 14 (1.3) 5 (0.5)disorders* Tachycardia 11 (1.0) 1 (<0.1)

Vascular Hypotension 38 (3.5) 5 (0.5)disorders Deep vein thrombosis 12 (1.1) 9 (0.8)

Hypertension 29 (2.7) 12 (1.1)

Orthostatic hypotension 6 (0.5) 1 (<0.1)

Hot flush 23 (2.1) 1 (<0.1)

Flushing 9 (0.8) 0

Respiratory, Dyspnoea 97 (8.9) 9 (0.8)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)

System Organ Adverse reaction All grades n (%) Grade>3

Class n (%)

Very Common Uncommoncommon

Gastrointestinal Diarrhoea 460 (42.1) 51 (4.7)disorders Nausea 347 (31.8) 14 (1.3)

Vomiting 207 (19.0) 14 (1.3)

Constipation 202 (18.5) 8 (0.7)

Abdominal pain 105 (9.6) 15 (1.4)

Dyspepsia 53 (4.9) 0

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

Haemorrhoids 22 (2.0) 0

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

Rectal haemorrhage 14 (1.3) 4 (0.4)

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) 0

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) 0subcutaneoustissue disorders Dry skin 23 (2.1) 0

Erythema 8 (0.7) 0

Nail disorder 18 (1.6) 0

Musculoskeletal Back pain 166 (15.2) 24 (2.2)and connective Arthralgia 88 (8.1) 9 (0.8)tissue disorders Pain in extremity 76 (7.0) 9 (0.8)

Muscle spasms 51 (4.7) 0

Myalgia 40 (3.7) 2 (0.2)

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)

Renal and Acute renal failure 21 (1.9) 14 (1.3)urinary Renal failure 8 (0.7) 6 (0.5)disorders Dysuria 52 (4.8) 0

Renal colic 14 (1.3) 2 (0.2)

Haematuria 205 (18.8) 33 (3.0)

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 andbreast disorders

System Organ Adverse reaction All grades n (%) Grade>3

Class n (%)

Very Common Uncommoncommon

General Fatigue 333 (30.5) 42 (3.8)disorders and Asthenia 227 (20.8) 32 (2.9)administration Pyrexia 90 (8.2) 5 (0.5)site conditions Peripheral oedema 96 (8.8) 2 (0.2 )

Mucosal inflammation 23 (2.1) 1 (<0.1)

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

Investigations Weight decreased 81 (7.4) 0

Aspartate 13 (1.2) 1 (<0.1)aminotransferaseincreased

Transaminases increased 7 (0.6) 1 (<0.1)a 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 and neutropeniccolitis) which in some cases resulted in a fatal outcome, were reported in 4.0% of the patients whenprimary 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% had grade ≥3cardiac arrhythmias. The incidence of tachycardia on cabazitaxel was 1.0%, of which less than 0.1%were grade ≥3. The incidence of atrial fibrillation was 1.3%. Cardiac failure events were reported for2 patients (0.2%), one of which resulted in a fatal outcome. Fatal ventricular fibrillation was reported in1 patient (0.3%), and cardiac arrest in 3 patients (0.5%). None were considered related by theinvestigator.

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 patients were65 years or over including 238 patients older than 75 years. The following non hematologic adversereactions were reported at rates ≥5% higher in patients 65 years of age or greater compared to youngerpatients: fatigue (33.5% vs. 23.7%), asthenia (23.7 vs. 14.2%), constipation (20.4% vs. 14.2%) anddyspnoea (10.3% vs. 5.6%) respectively. Neutropenia (90.9% vs. 81.2%) and thrombocytopenia (48.8%vs. 36.1%) were also 5% higher in patients 65 years of age or greater compared to younger patients.

Grade ≥3 neutropenia and febrile neutropenia were reported with the highest difference rates betweenboth groups of age (respectively 14% and 4% higher in patients ≥ 65 years 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 system listedin 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 cabazitaxel 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 previously 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 to anycause, whichever occurred first], tumour response rate based on response evaluation criteria in solidtumours (RECIST), PSA progression (defined as a ≥25% increase or >50% in PSA non-responders orresponders respectively), PSA response (declines in serum PSA levels of at least 50%), painprogression [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 cabazitaxel 25 mg/m2 intravenously every3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=378), or toreceive 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 cabazitaxel 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 cabazitaxel group and 4 in the mitoxantrone group. Thenumber of patients who completed the study treatment (10 cycles) was respectively 29.4% and 13.5% inthe cabazitaxel group and in the comparator group.

Overall survival was significant longer with cabazitaxel compared to mitoxantrone (15.1 months versus12.7 respectively), with a 30% reduction in the risk of death compared to mitoxantrone (see table 3 andfigure 1).

A sub-group of 59 patients received prior cumulative dose of docetaxel <225 mg/m2 (29 patients incabazitaxel 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 cabazitaxel in EFC6193 study in the treatment of patients with metastaticcastration resistant prostate cancer

Cabazitaxel+ 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 cabazitaxel

Figure 1: Kaplan Meier overall survival curves (EFC6193)

There was an improvement in PFS in the cabazitaxel 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 thecabazitaxel 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 cabazitaxel arm. There was a median PSA progression of6.4 months (95%CI: 5.1-7.3) for patients in cabazitaxel 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 cabazitaxel 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.

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) or20 mg/m2 (n=598) dose. Overall survival (OS) was the primary efficacy end-point.

The study met its primary objective of demonstrating the non-inferiority of cabazitaxel 20 mg/m2 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/m2 dosewith respect to the 25 mg/m2 dose was observed (HR 1.195 ; 95%CI: 1.025 to 1.393). There was nostatistically difference with regards to the other secondary endpoints (PFS, tumour and pain response,tumour and pain progression, and four subcategories of FACT-P).

Table 4 - Overall survival in EFC11785 study in cabazitaxel 25 mg/m2 arm versus cabazitaxel20 mg/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/m2 arm in

EFC11785 study

CBZ20+PRED CBZ25+PREDn=580 n=595

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

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

From 15 to 12 mg/m2: 9 From 20 to 15 mg/m2: 19(1.6%) (3.2%)

From 15 to 12 mg/m2: 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

CBZ20+PRED CBZ25+PREDn=580 n=595

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 CABAZITAXEL 25 mg/m2 every 3 week plus prednisone/prednisolone 10mg daily (n=129) or AR-targeted agents (abiraterone 1000 mg once daily plus prednisone/prednisolone5 mg 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. Secondaryendpoints included overall survival, progression-free survival, PSA response and tumour response.

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 Gleason scorewas 8. Sixty one percent (61%) of the patients had their prior treatment with an AR-targeted agent afterprior docetaxel.

The study met its primary endpoint: rPFS was significantly longer with CABAZITAXEL compared to

AR-targeted agent (8.0 months versus 3.7 respectively), with a 46% reduction in the risk ofradiographic progression compared to AR-targeted agent (see table 6 and figure 2).

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

CABAZITAXEL 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 before docetaxeland a hazard ratio of 0.48 (95% CI: 0.32 to 0.70) in patients who received a prior AR-targeted agentafter docetaxel.

CABAZITAXEL was statistically superior to the AR-targeted comparators for each of the alpha-protected key secondary endpoints including overall survival (13.6 months for CABAZITAXEL armversus 11.0 months 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 CABAZITAXEL arm versus 2.7 months for AR-targeted agent arm, HR0.52; 95%CI: 0.40 to 0.68), confirmed PSA response (36.3% for CABAZITAXEL arm versus 14.3%for AR-targeted agent arm, p=0.0003) and best tumour response (36.5% for CABAZITAXEL armversus 11.5% for AR-targeted agent arm, p=0.004).

The safety profile of CABAZITAXEL 25 mg/m2 observed in CARD study was overall consistent withthat observed in TROPIC and PROSELICA studies (see section 4.8). The incidence of grade ≥ 3adverse events was 53.2% in CABAZITAXEL arm versus 46.0% in the AR-targeted agent arm. Theincidence of grade ≥ 3 serious adverse events were 31.7% in CABAZITAXEL arm versus 37.1% in the

AR-targeted agent arm. The incidence of patients who permanently discontinued study treatment due toadverse events was 19.8% in CABAZITAXEL arm versus 8.1% in the AR-targeted agent arm. Theincidence of patients having an adverse event leading to death was 5.6% in CABAZITAXEL armversus 10.5% in the AR-targeted agent arm.

The European Medicines Agency has waived the obligation to submit the results of studies withcabazitaxel in all subsets of the paediatric population in the indication of prostate cancer (see section 4.2for information on paediatric use).

Cabazitaxel 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 with advancedsolid tumours (n=69), metastatic breast cancer (n=34) and metastatic prostate cancer (n=67). Thesepatients 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, and55.8% for VLDL). The in vitro blood-to-plasma concentration ratios in human blood ranged from 0.90to 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 were detectedin plasma (including 3 active metabolites issued form O-demethylations), with the main one accountingfor 5% of parent exposure. Around 20 metabolites of cabazitaxel are excreted into human urine andfaeces.

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 aclinical study has shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did notmodify the plasma levels of midazolam, a probe substrate of CYP3A. Therefore, at therapeutic doses,co-administration of CYP3A substrates with cabazitaxel to patients is not expected to have any clinicalimpact.

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 inhibitin 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.

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 1/h (26.4 1/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 and 13patients above 75), no age effect on the pharmacokinetics of cabazitaxel was observed.

Safety and effectiveness of cabazitaxel have not been established in children and adolescents below 18years 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 clearance wasobserved when compared to patients with mild hepatic impairment, indicating some effect of severehepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severehepatic 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). Cabazitaxel Accord 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 (creatinineclearance in the range of 30 to 50 ml/min) and 59 patients with mild renal impairment (creatinineclearance in the range of 50 to 80 ml/min) showed that mild to moderate renal impairment did not havemeaningful effects on the pharmacokinetics of cabazitaxel. This was confirmed by a dedicatedcomparative pharmacokinetic study in solid cancer patients with normal renal function (8 patients),moderate (8 patients) and severe (9 patients) renal impairment, who received several cycles ofcabazitaxel in single intravenous 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 studies atexposure levels higher than clinical exposure levels and with possible relevance to clinical use were eyedisorders characterized by subcapsular lens fiber swelling/degeneration. These effects were partiallyreversible 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 chromosomal aberrationbut it increased number of polyploid cells) and induced an increase of micronuclei in the in vivo test inrats.These genotoxicity findings (by an aneugenic mechanism) are inherent to the pharmacologicalactivity of the compound (inhibition of tubulin depolymerization).

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 wereobserved in rats, and testicular degeneration (minimal epithelial single cell necrosis in epididymis), wasobserved in dogs. Exposures in animals were similar or lower than those seen in humans receivingclinically 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 and decreasedmean foetal weight associated with delay in skeletal ossification. Exposures in animals were lower thanthose seen in humans receiving clinically relevant doses of cabazitaxel. Cabazitaxel crossed the placentabarrier 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 cabazitaxel will not causesignificant risk to the aquatic environment (see section 6.6 for disposal of unused product).

6 PHARMACEUTICAL PARTICULARS

Polysorbate 80

Citric acid

Ethanol anhydrous

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.

Each vial is for single use and should be used immediately after opening. If not used immediately, in-use storage times and conditions are the responsibility of the user.

After final dilution in the infusion bag/bottle

Chemical and physical stability of the infusion solution has been demonstrated for 8 hours at ambienttemperature (15°C - 30°C) including the 1-hour infusion time and for 48 hours at refrigerated conditionsincluding the 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.

This medicinal product does not require any special temperature storage conditions. Store in the originalpackage in order to protect from light.

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

3 ml of concentrate in a 6 ml clear tubular glass vial (type I) closed with a 20 mm grey siliconizedrubber closure (type I) with teflon film on plug surface and sealed by an aluminium cap covered with aviolet plastic flip-off cap.

Each carton contains one single use vial.

Cabazitaxel 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 cabazitaxel solutions, taking into account theuse of containment devices, personal protective equipment (e.g. gloves), and preparation procedures. Ifcabazitaxel, at any step of its handling, should come into contact with the skin, wash immediately andthoroughly with soap and water. If it should come into contact with mucous membranes, washimmediately and thoroughly with water.

Preparation for the intravenous administration

DO NOT use together with other cabazitaxel medicinal products with a different concentrationcabazitaxel. Cabazitaxel Accord contains 20 mg/ml of cabazitaxel (at least 3 ml deliverable volume).

Each vial is of single use and should be used immediately. Discard any unused solution.

More than one vial of Cabazitaxel Accord may be necessary to administer the prescribed dose.

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

Preparation of the infusion solution

Step 1

Aseptically withdraw the required volume of

Cabazitaxel Accord (which contains 20 mg/ml ofcabazitaxel), with a graduated syringe fitted with aneedle. As an example, a dose of 45 mg cabazitaxelwould require 2.25 ml of the Cabazitaxel Accord.

Step 2

Inject in a sterile PVC-free container of either 5%glucose solution or sodium chloride 9 mg/ml (0.9%)solution for infusion. The concentration of theinfusion solution should be between 0.10 mg/ml and0.26 mg/ml.

Step 3

Remove the syringe and mix the content of theinfusion bag or bottle manually using a rockingmotion. The infusion solution is clear colourlesssolution.

Step 4

As with all parenteral products, the resultinginfusion solution should be visually inspected priorto use. As the infusion solution is supersaturated, itmay crystallize over time. In this case, the solutionmust not be used and should 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 and administrationof cabazitaxel.

Cabazitaxel 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.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n, Edifici Est 6ª planta,

Barcelona, 08039, Spain

EU/1/20/1448/001

Date of first authorisation: 28th August 2020

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