4.1. Therapeutic indications

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

4.2. Posology and method of administration

The use of cabazitaxel should be confined to units specialised in the administration of cytotoxics and it should only be administered under the supervision of a physician experienced in the use of anticancer chemotherapy. Facilities and equipment for the treatment of serious hypersensitivity reactions like hypotension and bronchospasm must be available (see section 4.4).

Premedication

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

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

• corticosteroid (dexamethasone 8 mg or equivalent), and

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

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

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

Posology

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

Dose adjustments

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

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

Adverse reactions

Dose modification

Prolonged grade ≥3 neutropenia (longer than 1 week) despite appropriate treatment including G-CSF

Delay treatment until neutrophil count is >1,500 cells/mm3, then reduce cabazitaxel dose 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 to 20 mg/m2.

Grade ≥3 diarrhoea or persisting diarrhoea despite appropriate treatment, including fluid and electrolytes replacement

Delay treatment until improvement or resolution, then reduce cabazitaxel dose from 25 mg/m2 to 20 mg/m2

Grade >2 peripheral neuropathy

Delay treatment until improvement, then reduce cabazitaxel 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 15 mg/m2 or discontinuation of Cabazitaxel may be considered. Data in patients below the 20 mg/m2 dose are limited.

Special populations

Patients with hepatic impairment

Cabazitaxel is extensively metabolised by the liver. Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 x Upper Limit of Normal (ULN) or AST >1.5 x ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic 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 maximum tolerated dose (MTD) was 15 mg/m2. If the treatment is envisaged in patients with moderate hepatic impairment the dose of cabazitaxel should not exceed 15 mg/m2. However, limited efficacy data are available at this dose.

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

Patients with renal impairment

Cabazitaxel is minimally excreted through the kidney. No dose adjustment is necessary in patients with 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 data available should be treated with caution and monitored carefully during treatment (see sections 4.4 and 5.2).

Elderly

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

Concomitant medicinal products use

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

Paediatric population

There is no relevant use of Cabzitaxel in the paediatric population. The safety and the efficacy of Cabzitaxel in children and adolescents below 18 years of age have not been established (see section 5.1).

Method of administration

For instructions on preparation and administration of the product, see section 6.6. PVC infusion containers and polyurethane infusion sets should not be used. Cabazitaxel must not be mixed with any other medicinal products than those mentioned in section 6.6.

4.3. Contraindications

• Hypersensitivity to cabazitaxel, to other taxanes, to polysorbate 80 or any excipients listed in section 6.1.

• Neutrophil counts less than 1,500/mm3.

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

4.4. Special warnings and precautions for use

Hypersensitivity reactions

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

Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can occur and may include generalised rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of cabazitaxel and appropriate therapy. Patients with a hypersensitivity reaction must stop treatment with CABZITAXEL (see section 4.3).

Bone marrow suppression

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia, or pancytopenia may 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 manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection). Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age >65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. The use of G-CSF has been shown to limit the incidence and severity of neutropenia.

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

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

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

Gastrointestinal disorders

Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated 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 with commonly used anti-diarrhoeal medicinal products. Appropriate measures should be taken to re-hydrate patients. Diarrhoea can occur more frequently in patients that have received prior abdomino-pelvic radiation. Dehydration is more common in patients aged 65 or older. Appropriate measures should be taken to rehydrate patients and to monitor and correct serum electrolyte levels, particularly potassium. Treatment delay or dose reduction may be necessary for grade ≥3 diarrhoea (see section 4.2). If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics.

Risk of serious gastrointestinal reactions

Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with cabazitaxel (see section 4.8). Caution is advised with treatment of patients 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 of pelvic radiotherapy or gastrointestinal disease, such as ulceration and GI bleeding.

Peripheral neuropathy

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

Anaemia

Anaemia has been observed in patients receiving cabazitaxel (see section 4.8). Haemoglobin and haematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs or symptoms of anaemia or blood loss. Caution is recommended in patients with haemoglobin <10 g/dl and 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 this occurs.

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

Respiratory disorders

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

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

Risk of cardiac arrhythmias

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

Elderly

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

Patients with liver impairment

Treatment with Cabazitaxel is contraindicated in patients with severe hepatic impairment (total bilirubin > 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).

Interactions

Co-administration with strong CYP3A inhibitors should be avoided since they may increase the plasma 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 reduction should be considered (see sections 4.2 and 4.5).

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

Excipients

This medicinal product contains ethanol (alcohol) in each dosage unit which is equivalent to 1,185mg per vial.

Harmful for those suffering from alcoholism.

Contraception measure

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

4.5. Interaction with other medicinal products and other forms of interaction

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

CYP3A inhibitors

Repeated administration of ketoconazole (400 mg once daily), a strong CYP3A inhibitor, resulted in a 20% decrease in cabazitaxel clearance corresponding to a 25% increase in AUC. Therefore concomitant 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 4.2 and 4.4).

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

CYP3A inducers

Repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, resulted in an increase 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 concentrations of 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 minutes after the end of the infusion. A time interval of 12 hours is recommended before the infusion and at least 3 hours after the end of infusion before administering the OATP1B1 substrates.

Vaccinations

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

4.6. Fertility, pregnancy and lactation

Contraception measure

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

Pregnancy

There are no data from the use of cabazitaxel in pregnant women. Studies in animals have shown reproductive toxicity at maternotoxic doses (see section 5.3) and that cabazitaxel crosses the placenta barrier (see section 5.3). As with other cytotoxic medicinal products, cabazitaxel may cause foetal harm in exposed pregnant women. Cabazitaxel is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites in milk (see section 5.3). A risk to the breast-feeding child cannot be excluded. Cabazitaxel should not be used during breast-feeding.

Fertility

Animal studies showed that cabazitaxel affected reproductive system in male rats and dogs without any functional effect on fertility (see section 5.3). Nevertheless, considering the pharmacological activity of taxanes, their genotoxic potential and effect of several compounds of this class on fertility in animal studies, effect on male fertility could not be excluded in human.

Due to potential effects on male gametes and to potential exposure via seminal liquid, men treated with cabazitaxel should use effective contraception throughout treatment and are recommended to continue this for up to 4 months after the last dose of cabazitaxel. Due to potential exposure via seminal liquid, men treated with cabazitaxel should prevent contact with the ejaculate by another person throughout treatment. Men being treated with cabazitaxel are advised to seek advice on conservation of sperm prior to treatment.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 3 randomized, open label, controlled studies (TROPIC, PROSELICA and CARD), totalling 1092 patients with metastatic castration resistant prostate cancer who were treated with 25 mg/m2 cabazitaxel once every three weeks in a randomised open label, controlled phase III study. Patients received a median duration of 6 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%), and diarrhoea (42.1%), fatigue (25.0%) and asthenia (15.4%). The most common grade (≥3%) adverse reactions occurring in at least 5% of patients were neutropenia (73.1%), leukopenia (59.5%), anaemia (12.0%), febrile neutropenia (8.0%), diarrhoea (4.7%).

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

Tabulated list of adverse reactions

Adverse reactions are listed in table 2 according to MedDRA system organ class and frequency categories. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Intensity of the adverse reactions is graded according to CTCAE 4.0 (grade ≥3 = 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 combination with prednisone or prednisolone from pooled analysis (n=1092)

System Organ Class

Adverse reaction

All grades

n (%)

Grade≥3

n (%)

Very common

Common

Uncommon

Infections and infestations

Neutropenic infection/sepsis*

48 (4.4)

42 (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 tract infection

23 (2.1)

0

Herpes zoster

14 (1.3)

0

Candidiasis

11 (1.0)

1 (<0.1)

Blood and lymphatic system disorders

Neutropeniaa*

950 (87.9)

790 (73.1)

Anaemiaa

1073 (99.0)

130 (12.0)

Leukopeniaa

1008 (93.0)

645 (59.5)

Thrombocytopeniaa

478 (44.1)

44 (4.1)

Febrile neutropenia

87 (8.0)

87 (8.0)

Immune system disorders

Hypersensitivity

7 (0.6)

0

Metabolism and nutrition disorders

Decreased appetite

192 (17.6)

11 (1.0)

Dehydration

27 (2.5)

11 (1.0)

Hyperglycaemia

11 (1.0)

7 (0.6)

Hypokalemia

8 (0.7)

2 (0.2)

Psychiatric disorders

Insomnia

45 (4.1)

0

Anxiety

13 (1.2)

0

Confusional state

12 (1.1)

2 (0.2)

Nervous system disorders

Dysgeusia

64 (5.9)

0

Taste disorder

56 (5.1)

0

Neuropathy peripheral

40 (3.7)

2 (0.2)

Peripheral sensory neuropathy

89 (8.2)

6 (0.5)

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 disorders

Tinnitus

7 (0.6)

0

Vertigo

15 (1.4)

1 (<0.1)

Cardiac disorders*

Atrial fibrillation

14 (1.3)

5 (0.5)

Tachycardia

11 (1.0)

1 (<0.1)

Vascular disorders

Hypotension

38 (3.5)

5 (0.5)

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, thoracic and mediastinal disorders

Dyspnoea

97 (8.9)

9 (0.8)

Cough

79 (7.2)

0

Oropharyngeal pain

26 (2.4)

1 (< 0.1)

Pneumonia

26 (2.4)

16 (1.5)

Pulmonary embolism

30 (2.7)

23 (2.1)

Gastrointestinal disorders

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)

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 disease

26 (2.4)

1 (< 0.1)

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 perforation

3 (0.3)

1 (<0.1)

Gastrointestinal haemorrhage

2 (0.2)

1 (<0.1)

Skin and subcutaneous tissue disorders

Alopecia

80 (7.3)

0

Dry skin

23 (2.1)

0

Erythema

8 (0.7)

0

Nail disorder

18 (1.6)

0

Musculoskeletal and connective tissue disorders

Back pain

166 (15.2)

24 (2.2)

Arthralgia

88 (8.1)

9 (0.8)

Pain in extremity

76 (7.0)

9 (0.8)

Muscle spasms

51 (4.7)

0

Myalgia

40 (3.7)

2 (0.2)

Musculoskeletal chest pain

34 (3.1)

3 (0.3)

Muscular weakness

31 (2.8)

1 (0.2)

Flank pain

17 (1.6)

5 (0.5)

Renal and urinary disorders

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)

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 system and breast disorders

Pelvic pain

20 (1.8)

5 (0.5)

General disorders and administration site conditions

Fatigue

333 (30.5)

42 (3.8)

Asthenia

227 (20.8)

32 (2.9)

Pyrexia

90 (8.2)

5 (0.5)

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 aminotransferase increased

13 (1.2)

1 (<0.1)

Transaminases increased

7 (0.6)

1 (<0.1)

a based on laboratory values

* see detailed section below

Description of selected adverse reactions

Neutropenia, and associated clinical events

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

Incidence of grade ≥ 3 neutropenia based on laboratory data varied depending on use of G-CSF from 44.7% to 76.7%, with the lowest in incidence reported when G-CSF prophylaxis was used. Similarly, the incidence of grade ≥ 3 febrile neutropenia ranged from 3.2% to 8.6%.

Neutropenic complications (including febrile neutropenia, neutropenic infection/sepsis and neutropenic colitis) which in some cases resulted in a fatal outcome, were reported in 4.0% of the patients 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% had grade ≥3 cardiac 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 for 2 patients (0.2%), one of which resulted in a fatal outcome. Fatal ventricular fibrillation was reported in 1 patient (0.3%), and cardiac arrest in 3 patients (0.5%). None were considered related by 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 or anticoagulation/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 on laboratory abnormalities were 12.0%, 1.3%, 1.0%, and 0.5%, respectively.

Gastrointestinal disorders

Colitis (including enterocolitis and neutropenic enterocolitis) and gastritis have been observed. Gastrointestinal haemorrhage, gastrointestinal perforation and ileus (intestinal obstruction) have also been reported (see section 4.4).

Respiratory disorders

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

Renal and urinary disorders

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

Paediatric population

See section 4.2.

Other special populations

Elderly population

Of the 1092 patients treated with cabazitaxel 25 mg/m2 in the prostate cancer studies, 755 patients were 65 years or over including 238 patients older than 75 years.

The following non hematologic adverse reactions were reported at rates ≥5% higher in patients 65 years of age or greater compared to younger 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%) 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 between both 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known antidote to cabazitaxel. The anticipated complications of overdose would consist of exacerbation of adverse reactions as bone marrow suppression and gastrointestinal disorders. In case of overdose, the patient should be kept in a specialised unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken.