Oncology

Therapeutic indications

JEVTANA 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..

POSOLOGY AND METHOD OF ADMINISTRATION

The use of JEVTANA should be confined to units specialized in the administration of cytotoxic 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.

Dosage

The recommended premedication regimen should be performed at least 30 minutes prior to each administration of JEVTANA 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).

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 JEVTANA 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]):

Refer to full Summary of Product Characteristics

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

Special populations

Patients with hepatic impairment
Cabazitaxel is extensively metabolized by the liver. Patients with mild hepatic impairment (total bilirubin >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 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).

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.

Elderly
No specific dose adjustment for the use of Cabazitaxel in elderly patients is recommended.

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.

Paediatric population
There is no relevant use of JEVTANA in the paediatric population.
The safety and the efficacy of JEVTANA in children and adolescents below 18 years of age have not been established

Method of administration

JEVTANA is for intravenous use.
For instructions on preparation and administration of the medicinal product.
PVC infusion containers and polyurethane infusion sets should not be used.
JEVTANA must not be mixed with any other medicinal products than those mentioned in section 6.6 of full Summary of Product Characteristics.

CONTRAINDICATIONS

• 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.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Hypersensitivity reactions

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 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 JEVTANA.

Bone marrow suppression

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

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

Gastrointestinal disorders

Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhea, 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, diarrhea and dehydration
If patients experience diarrhea following administration of Cabazitaxel they may be treated with commonly used anti-diarrhea medicinal products. Appropriate measures should be taken to re-hydrate patients. Diarrhea 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 diarrhea. 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. 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.

Anemia

Anemia has been observed in patients receiving Cabazitaxel. Hemoglobin and hematocrit 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 hemoglobin < 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 diarrhea, 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.
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.

Elderly

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

Patients with liver impairment

Treatment with JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin > 3 x ULN).
Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 x ULN or AST >1.5 x ULN), hepatic impairment.

Interactions

Co-administration with strong CYP3A inhibitors should be avoided since they may increase the plasma concentrations of Cabazitaxel. If co-administration with a strong CYP3A inhibitor cannot be avoided, close monitoring for toxicity and a Cabazitaxel dose reduction should be considered.
Co-administration with strong CYP3A inducers should be avoided since they may decrease plasma concentrations of Cabazitaxel.

Excipients

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

INTERACTIONS

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

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.

Concomitant administration of 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, rifapentine, 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.

PREGNANCY AND LACTATION

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 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.

UNDESIRABLE EFFECTS

Summary of safety profile

The safety of JEVTANA 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 in the tabulated list shown in the full Summary of Product Characteristics. The most common all grades adverse reactions were anaemia (99.0%), leukopenia (93.0%), neutropenia (87.9%), thrombocytopenia (41.1%), diarrhea (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%) and diarrhea (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. See full Summary of Product Characteristics for table showing reported adverse reactions and hematological abnormalities with Cabazitaxel in combination with prednisone or prednisolone from pooled analysis (n=1092)

Neutropenia, and associated clinical events
The use of G-CSF has been shown to limit the incidence and severity of neutropenia. 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 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. 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, 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.

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 national reporting system.

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 specialized 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.

PHARMACODYNAMIC PROPERTIES

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

Date of SmPC approval: 2020;
Date of abbreviated prescribing information: August 2022
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.