Cabazitaxel Accord · 4.6 Fertility, pregnancy and lactation · 1

HOS-099291 · has-adverse-reaction-information · PDF-Seite 7

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), totaling 1092 patients with metastatic castration resistant prostate cancer who were treated with 25 mg/m2 cabazitaxel 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 7 (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%) and 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 Adverse reaction All grades n (%) Grade>3 Class n (%) Very Common Uncommon common Infections and Neutropenic 48 (4.4) 42 infestations infection/sepsis* (3.8)

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HOS-099287 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to cabazitaxel, to other taxanes, to polysorbate 80 or to any of the excipients listed 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).

HOS-099286 · has-indication-information · PDF-Seite 2

Cabazitaxel Accord 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).

HOS-099289 · has-interaction-information · PDF-Seite 6

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. 6 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.

HOS-099290 · has-pregnancy-information · PDF-Seite 7

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 indicated for use in women. Breastfeeding Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites in milk (see section 5.3). 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 by an aneugenic mechanism and effect of several compounds of this class 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 to treatment.

HOS-099288 · has-warning-information · PDF-Seite 4

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 generalized 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 cabazitaxel (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 discon

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