Cabazitaxel

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.

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.

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.

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

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.

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

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. In addition, patients should also refrain from taking St. John’s Wort.

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.

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.

Animal studies showed that cabazitaxel affected reproductive system in male rats and dogs without any functional effect on fertility. 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 6 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.

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.

Cardiac arrhythmias have been reported, most commonly tachycardia and atrial fibrillation.

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia, or pancytopenia may occur.

All patients should be pre-medicated prior to the initiation of the infusion of cabazitaxel.

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 cabazitaxel.

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. If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics.

Anaemia has been observed in patients receiving cabazitaxel. 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.

Interstitial pneumonia/pneumonitis and interstitial lung disease have been reported and may be associated with fatal outcome.

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.

Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with cabazitaxel. 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.

There are no data from the use of cabazitaxel in pregnant women. Studies in animals have shown reproductive toxicity at maternotoxic doses and that cabazitaxel crosses the placenta barrier. 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.

Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites in milk. 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. 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 6 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.

Cabazitaxel has 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.

Summary of safety profile

The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 371 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 cycles of cabazitaxel.

The most commonly (≥10%) occurring adverse reactions in all grades were anaemia (97.3%), leukopenia (95.7%), neutropenia (93.5%), thrombocytopenia (47.4%), and diarrhoea (46.6%). The most commonly (≥5%) occurring grade ≥3 adverse reactions in the cabazitaxel group were neutropenia (81.7%), leukopenia (68.2%), anaemia (10.5%), febrile neutropenia (7.5%), diarrhoea (6.2%).

Discontinuation of treatment due to adverse reactions occurred in 68 patients (18.3%) receiving cabazitaxel. The most common adverse reactions leading to cabazitaxel discontinuation was neutropenia.

Tabulated list of adverse reactions

Adverse reactions are listed in the following table 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).

Reported adverse reactions and haematological abnormalities with cabazitaxel in combination with prednisone or prednisolone in the TROPIC study (n=371):

^a based on laboratory values
^* see detailed section below

Description of selected adverse reactions

Neutropenia, and associated clinical events

Incidence of grade ≥3 neutropenia based on laboratory data was 81.7%. The incidence of grade ≥3 clinical neutropenia and febrile neutropenia adverse reactions were 21.3% and 7.5% respectively. Neutropenia was the most common adverse reaction leading to medicinal product discontinuation (2.4%).

Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases resulted in a fatal outcome. The use of G-CSF has been shown to limit the incidence and severity of neutropenia.

Cardiac disorders and arrhythmias

All Grade events among cardiac disorders were more common on cabazitaxel of which 6 patients (1.6%) had Grade ≥3 cardiac arrhythmias. The incidence of tachycardia on cabazitaxel was 1.6%, none of which were Grade ≥3. The incidence of atrial fibrillation was 1.1% in the cabazitaxel group. Cardiac failure events were more common on cabazitaxel, the event term being reported for 2 patients (0.5%). One patient in the cabazitaxel group died from cardiac failure. Fatal ventricular fibrillation was reported in 1 patient (0.3%), and cardiac arrest in 2 patients (0.5%). None were considered related by the investigator.

Haematuria

Haematuria all grades frequency was 20.8% at 25 mg/m² in EFC11785 study. Confounding causes such as disease progression, instrumentation, infection or anticoagulation/NSAID/aspirin therapy were identified in nearly two thirds of the cases.

Other laboratory abnormalities

The incidence of grade ≥3 anaemia, increased AST, ALT, and bilirubin based on laboratory abnormalities were 10.5%, 0.7%, 0.9%, and 0.6%, respectively.

Gastrointestinal disorders

Colitis, enterocolitis, gastritis, neutropenic enterocolitis have been observed. Gastrointestinal hemorrhage and perforation, ileus and intestinal obstruction have also been reported.

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).

Renal and urinary disorders

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

Special populations

Elderly population

Among the 371 patients treated with cabazitaxel in the prostate cancer study, 240 patients were 65 years or over including 70 patients older than 75 years. The following adverse reactions reported at rates 5% higher in patients 65 years of age or greater compared to younger patients were fatigue (40.4% versus 29.8%), clinical neutropenia (24.2% versus 17.6%), asthenia (23.8% versus 14.5%), pyrexia (14.6% versus 7.6%), dizziness (10.0% versus 4.6%), urinary tract infection (9.6% versus 3.1%) and dehydration (6.7% versus 1.5%), respectively. The incidence of the following grade ≥3 adverse reactions were higher in patients 65 years of age compared to younger patients; neutropenia based on laboratory abnormalities (86.3% versus 73.3%), clinical neutropenia (23.8% versus 16.8%) and febrile neutropenia (8.3% versus 6.1%).

Of the 595 patients treated with cabazitaxel 25 mg/m² in the prostate cancer EFC 11785 study, 420 patients were 65 years or over. The adverse reactions reported at rates of at least 5% higher in patients 65 years of age or greater compared to younger patients were diarrhoea (42.9% vs. 32.6%), fatigue (30.2% vs. 19.4%), asthenia (22.4% vs. 13.1%), constipation (20.2% vs. 12.6%), clinical neutropenia (12.9% vs. 6.3%), febrile neutropenia (11.2% vs. 4.6%) and dyspnoea (9.5% vs. 3.4%).