Cabazitaxel

Cabazitaxel is a taxane antineoplastic agent that acts on the microtubule network of the cell. It binds to tubulin and promotes the assembly of tubulin into microtubules while preventing their disassembly. The stabilised microtubules cannot reorganise, which blocks the mitotic and interphase functions of the cell and stops tumour proliferation.

Mechanism of Action

• Microtubule stabilisation: cabazitaxel binds to the beta-tubulin subunit and favours microtubule assembly over disassembly. Microtubules form the mitotic spindle that separates chromosomes during cell division, so stabilising them prevents normal division.
• Antitumour activity in models: it showed a broad spectrum of activity against advanced human tumours grown in mice. It is active in docetaxel-sensitive tumours and also in tumour models that are insensitive to chemotherapy, including docetaxel.
• P-glycoprotein: cabazitaxel has a low affinity for P-glycoprotein, so it is less exposed to efflux by this pump.
• Active metabolites: three of the plasma metabolites, formed by O-demethylation, are active; the main metabolite accounts for about 5% of the exposure to the parent drug.

Pharmacokinetics

• Absorption: given intravenously. In 67 patients with metastatic prostate cancer given 25 mg/m² over 1 hour, mean Cmax was 226 ng/mL (CV 107%), reached at the end of the infusion, and mean AUC was 991 ng × h/mL (CV 34%). Exposure was dose-proportional from 10 to 30 mg/m² in patients with advanced solid tumours.
• Distribution: the steady-state volume of distribution is about 4,870 L (2,640 L/m² for a patient with a median body surface area of 1.84 m²). In vitro, 89–92% of cabazitaxel is bound to serum proteins, without saturation up to 50,000 ng/mL; it binds mainly to albumin (82.0%) and lipoproteins (87.9% HDL, 69.8% LDL, 55.8% VLDL). It is distributed equally between blood and plasma (ratio 0.90–0.99).
• Metabolism: more than 95% is metabolised in the liver, 80–90% of it through CYP3A and a smaller part through CYP2C8. Cabazitaxel is the main compound in plasma; seven metabolites were found in plasma, and about 20 metabolites are excreted in urine and faeces. A study with a CYP3A probe substrate showed that cabazitaxel (25 mg/m² as a single 1-hour infusion) did not change its plasma levels, so no clinical effect on CYP3A substrates is expected at therapeutic doses.
• Elimination: plasma concentrations follow a three-compartment model with half-lives of about 4 minutes, 2 hours and 95 hours. Plasma clearance is about 48.5 L/h. About 80% of a radiolabelled dose was eliminated within two weeks, mostly in the faeces as metabolites (76% of the dose); renal excretion is small (3.7%, of which 2.3% as unchanged drug).
• Special populations: cabazitaxel is extensively cleared by the liver, so hepatic impairment lowers the tolerated dose (see Administration and Dosage). Renal impairment has little effect because renal excretion is minimal.

• Metastatic castration-resistant prostate cancer: in combination with prednisone or prednisolone, for adults with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen.

• Hypersensitivity to cabazitaxel, to other taxanes, to polysorbate 80 or to any of the excipients.
• Neutrophil count below 1,500/mm³.
• Severe hepatic impairment (total bilirubin above 3 times the upper limit of normal).
• Concomitant vaccination with the yellow fever vaccine.

The safety data come from three randomised, open-label studies (TROPIC, PROSELICA and CARD) in 1,092 patients with metastatic castration-resistant prostate cancer treated with 25 mg/m² every 3 weeks together with prednisone or prednisolone, for a median of 6 to 7 cycles. The most common reactions of any grade were anaemia (99.0%), leukopenia (93.0%), neutropenia (87.9%), diarrhoea (42.1%), thrombocytopenia (over 40%), fatigue (25.0%) and asthenia (15.4%); the blood-count figures are based on laboratory values. The most common reactions of grade 3 or higher were neutropenia (73.1%), leukopenia (59.5%), anaemia (12.0%), febrile neutropenia (8.0%) and diarrhoea (4.7%). Adverse reactions led to discontinuation in 18.3% (TROPIC), 19.5% (PROSELICA) and 19.8% (CARD) of patients; the most common causes (above 1.0%) were haematuria, fatigue and neutropenia.

Very common (≥1/10): neutropenia, anaemia, leukopenia, thrombocytopenia, decreased appetite, diarrhoea, nausea, vomiting, constipation, back pain, haematuria, fatigue, asthenia.

Common (≥1/100 to <1/10): neutropenic infection or sepsis, sepsis, urinary tract infection, influenza, cystitis, upper respiratory tract infection, herpes zoster, candidiasis, febrile neutropenia, dehydration, hyperglycaemia, insomnia, anxiety, confusional state, dysgeusia, peripheral neuropathy, peripheral sensory neuropathy, paraesthesia, hypoaesthesia, dizziness, headache, lethargy, conjunctivitis, increased lacrimation, vertigo, atrial fibrillation, tachycardia, hypotension, deep vein thrombosis, hypertension, hot flush, dyspnoea, cough, oropharyngeal pain, pneumonia, pulmonary embolism, abdominal pain, dyspepsia, upper abdominal pain, haemorrhoids, gastro-oesophageal reflux, rectal haemorrhage, dry mouth, abdominal distension, stomatitis, alopecia, dry skin, nail disorder, arthralgia, pain in extremity, muscle spasms, myalgia, musculoskeletal chest pain, muscular weakness, flank pain, acute renal failure, dysuria, renal colic, pollakiuria, hydronephrosis, urinary retention, urinary incontinence, pelvic pain, pyrexia, peripheral oedema, mucosal inflammation, pain, chest pain, chills, malaise, weight decreased, increased aspartate aminotransferase.

Uncommon (≥1/1,000 to <1/100): septic shock, cellulitis, hypersensitivity, hypokalaemia, polyneuropathy, sciatica, tinnitus, orthostatic hypotension, flushing, ileus, gastritis, colitis, gastrointestinal perforation, gastrointestinal haemorrhage, erythema, renal failure, ureteric obstruction, oedema, increased transaminases. Cystitis due to radiation recall, including haemorrhagic cystitis, has also been reported as uncommon.

Not known: interstitial pneumonia or pneumonitis and interstitial lung disease, sometimes fatal.

Important serious reactions:

• Neutropenia and its complications: grade 3 or higher neutropenia ranged from 44.7% to 76.7% depending on G-CSF use, lowest with G-CSF prophylaxis; grade 3 or higher febrile neutropenia ranged from 3.2% to 8.6%. Neutropenic complications (febrile neutropenia, neutropenic infection or sepsis, neutropenic colitis), in some cases fatal, occurred in 4.0% of patients with primary G-CSF prophylaxis and 12.8% without it.
• Cardiac events and arrhythmias: cardiac events occurred in 5.5% of patients, 1.1% being grade 3 or higher arrhythmias; atrial fibrillation occurred in 1.3% and tachycardia in 1.0%.
• Haematuria: 18.8% of patients at 25 mg/m²; confounding factors such as disease progression, instrumentation, infection or anticoagulant, NSAID or aspirin use were found in nearly half of the cases.
• Laboratory abnormalities of grade 3 or higher: anaemia 12.0%, increased AST 1.3%, ALT 1.0% and bilirubin 0.5%.
• Gastrointestinal reactions: colitis (including enterocolitis and neutropenic enterocolitis) and gastritis, and also gastrointestinal haemorrhage, perforation and ileus (intestinal obstruction).
• Older patients: of the 1,092 patients, 755 were aged 65 or over (238 over 75). Fatigue, asthenia, constipation, dyspnoea, neutropenia and thrombocytopenia were at least 5 percentage points more frequent in them, and grade 3 or higher neutropenia and febrile neutropenia showed the largest differences (14% and 4% more than in younger patients).

Cabazitaxel is metabolised mainly by CYP3A (80–90%).

• Strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): ketoconazole lowered cabazitaxel clearance by 20%, raising AUC by 25%. Avoid the combination; if it cannot be avoided, monitor closely for toxicity and consider a 25% dose reduction.
• Strong CYP3A inducers (phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital): rifampicin raised cabazitaxel clearance by 21%, lowering AUC by 17%. Avoid the combination. Patients should also refrain from taking St John’s wort.
• Moderate CYP3A inhibitors: aprepitant had no effect on cabazitaxel clearance.
• OATP1B1 substrates (for example statins, valsartan, repaglinide): in vitro, cabazitaxel inhibits the transporter OATP1B1, so interaction is possible during the 1-hour infusion and for 20 minutes after it. Leave an interval of 12 hours before the infusion and at least 3 hours after its end before giving such substrates.
• Medicines that prolong the QT interval: polysorbate 80 may prolong the QT interval and cause torsades de pointes, so this must be considered with such medicines and in patients with congenital long-QT syndrome.
• Vaccines: live or live-attenuated vaccines can cause serious or fatal infections in patients made immunocompromised by chemotherapy. The yellow fever vaccine is contraindicated.
• NSAIDs, antiplatelet medicines and anticoagulants: these raise the risk of serious gastrointestinal complications (see Special Instructions).
• Grapefruit: grapefruit inhibits CYP3A4 and may raise cabazitaxel concentrations; avoid it.

Cabazitaxel must be given only in units specialised in cytotoxic administration and under the supervision of a physician experienced in anticancer chemotherapy. Facilities and equipment for treating serious hypersensitivity reactions, such as hypotension and bronchospasm, must be available. Adequate hydration must be ensured throughout treatment to prevent complications such as renal failure.

Premedication

At least 30 minutes before each infusion, the following are given intravenously to reduce the risk and severity of hypersensitivity:

• an antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg, or equivalent);
• a corticosteroid (dexamethasone 8 mg or equivalent);
• an H2 antagonist.

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

Recommended Dose

• 25 mg/m² as a 1-hour intravenous infusion every 3 weeks, together with oral prednisone or prednisolone 10 mg daily throughout treatment.
• Both the concentrate vial and the solvent vial contain an overfill. The whole content of the solvent vial is used for the initial dilution, which gives a solution of 10 mg/mL; preparation steps are in SmPC section 6.6.
• Polyvinyl chloride (PVC) infusion containers and polyurethane infusion sets must not be used. Cabazitaxel must not be mixed with any other medicinal products than those named in section 6.6.

Dose Adjustments

• Prolonged grade 3 or higher neutropenia (longer than 1 week) despite appropriate treatment including G-CSF: delay treatment until neutrophils are above 1,500/mm³, then reduce from 25 to 20 mg/m².
• Febrile neutropenia or neutropenic infection: delay treatment until improvement or resolution and neutrophils are above 1,500/mm³, then reduce to 20 mg/m².
• Grade 3 or higher diarrhoea, or diarrhoea persisting despite appropriate treatment including fluid and electrolyte replacement: delay until improvement or resolution, then reduce to 20 mg/m².
• Peripheral neuropathy above grade 2: delay until improvement, then reduce to 20 mg/m².
• If these reactions continue at 20 mg/m², a further reduction to 15 mg/m² or discontinuation may be considered; data below 20 mg/m² are limited.
• Strong CYP3A inhibitors: avoid strong inhibitors and inducers of CYP3A. If a strong inhibitor is required, a 25% dose reduction should be considered.

Special Populations

• Hepatic impairment: for mild impairment (total bilirubin above 1 and up to 1.5 × ULN, or AST above 1.5 × ULN), reduce to 20 mg/m² and monitor safety closely. For moderate impairment (total bilirubin above 1.5 and up to 3.0 × ULN), the maximum tolerated dose was 15 mg/m², so the dose should not exceed 15 mg/m²; efficacy data at this dose are limited. Cabazitaxel must not be given in severe impairment (total bilirubin above 3 × ULN).
• Renal impairment: cabazitaxel is minimally excreted by the kidney. No adjustment is needed when haemodialysis is not required. Patients with end-stage renal disease (creatinine clearance below 15 mL/min/1.73 m²) should be treated with caution and monitored carefully.
• Elderly: no specific dose adjustment is recommended, but neutropenia and febrile neutropenia are more likely (see Special Instructions).
• Children and adolescents: there is no relevant use in the paediatric population; safety and efficacy below 18 years have not been established.

Hypersensitivity Reactions

All patients are premedicated. They must be observed closely, especially during the first and second infusions, because reactions may begin within minutes. Severe reactions can include generalised rash or erythema, hypotension and bronchospasm. They require immediate discontinuation and appropriate treatment, and a patient who has had a hypersensitivity reaction must not continue cabazitaxel.

Neutropenia and Bone Marrow Suppression

Bone marrow suppression can appear as neutropenia, anaemia, thrombocytopenia or pancytopenia. Neutropenia is the most common adverse reaction. Complete blood counts are essential every week during cycle 1 and before each later cycle so that the dose can be adjusted. Patients may receive prophylactic G-CSF, in line with published oncology guidelines and/or institutional guidelines, to reduce neutropenic complications. Primary prophylaxis should be considered in patients with high-risk features (age above 65 years, poor performance status, earlier febrile neutropenia, extensive prior radiation ports, poor nutritional status or other serious comorbidity). Patients are re-treated only when neutrophils have recovered to 1,500/mm³ or more.

Anaemia

Haemoglobin and haematocrit are checked before treatment and whenever signs or symptoms of anaemia or blood loss appear. Caution is advised when haemoglobin is below 10 g/dL.

Gastrointestinal Reactions

Abdominal pain and tenderness, fever, persistent constipation or diarrhoea, with or without neutropenia, may be early signs of serious gastrointestinal toxicity and need prompt evaluation and treatment. Gastrointestinal haemorrhage and perforation, ileus and colitis, including fatal cases, have been reported. Caution is advised in patients most at risk: those with neutropenia, the elderly, those taking NSAIDs, antiplatelet medicines or anticoagulants, and those with a history of pelvic radiotherapy or gastrointestinal disease such as ulceration or bleeding.

Diarrhoea can be treated with usual antidiarrhoeal medicines, with rehydration and correction of electrolytes, especially potassium. It is more frequent after prior abdomino-pelvic radiation, and dehydration is more common at age 65 or over. Nausea and vomiting can be treated with usual antiemetics.

Peripheral Neuropathy

Peripheral neuropathy, sensory and motor, has been observed. Patients should tell their doctor about pain, burning, tingling, numbness or weakness before the next treatment. The doctor assesses for neuropathy before each treatment, delays treatment until symptoms improve, and reduces the dose to 20 mg/m² for persistent neuropathy above grade 2.

Renal Failure

Renal disorders, including fatal renal failure, have been reported with sepsis, severe dehydration from diarrhoea or vomiting, and obstructive uropathy. Hydration must be adequate throughout treatment, and patients should report any marked change in daily urine volume at once. Serum creatinine is measured at baseline, with each blood count and whenever urine output changes. Treatment is discontinued if renal function falls to grade 3 renal failure or worse.

Respiratory Disorders

Interstitial pneumonia, pneumonitis and interstitial lung disease have been reported and can be fatal. With new or worsening pulmonary symptoms, patients are closely monitored and promptly investigated, and treatment is interrupted until a diagnosis is available. The benefit of resuming must be weighed carefully.

Cardiac Arrhythmias

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

Hepatic Impairment and Elderly Patients

Cabazitaxel is contraindicated in severe hepatic impairment and the dose is reduced in mild or moderate impairment. Patients aged 65 or over may be more likely to have neutropenia and febrile neutropenia.

Excipients

• Ethanol: each solvent vial contains 573 mg of alcohol, equivalent to less than 11 mL of beer or 5 mL of wine in the dose given. It is not expected to have noticeable effects, but special precautions apply in high-risk groups such as patients with liver disease, epilepsy or a history of alcoholism.
• Polysorbate 80: each 60 mg vial of concentrate contains 1.56 g. Polysorbates may cause allergic reactions and can have cardiovascular effects (hypotension, cardiac depression); lowering the infusion rate can be considered to reduce these. They may also prolong the QT interval (see Drug Interactions).

Contraception, Pregnancy, Breastfeeding and Fertility

• Contraception: because of the genotoxic risk, men should use effective contraception during treatment and for 4 months after it ends.
• Pregnancy: cabazitaxel is not indicated for use in women. There are no data in pregnant women; animal studies showed reproductive toxicity at doses toxic to the mother, and cabazitaxel crosses the placenta. Like other cytotoxic medicines, it may cause foetal harm.
• Breastfeeding: animal data show that cabazitaxel and its metabolites pass into milk.
• Fertility: animal studies showed effects on the male reproductive system without a functional effect on fertility, but an effect on male fertility in humans cannot be excluded. Men are advised to seek advice on sperm conservation before treatment.

Effect on Driving

Cabazitaxel has a moderate influence on the ability to drive and use machines because it may cause fatigue and dizziness. Patients should not drive or use machines if they have these reactions.

Jevtana is not a cold-chain product: do not store it above 30 °C and do not refrigerate it. One pack contains one vial of concentrate and one vial of solvent. For storage after opening and after dilution, see Shelf Life.

3 years for the unopened vial. The concentrate and solvent vials must be used immediately once opened. After initial dilution of the concentrate with the solvent, chemical and physical in-use stability has been shown for 1 hour at ambient temperature (15–30 °C). From a microbiological point of view the mixture should be used immediately; otherwise in-use times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), on restricted medical prescription (Annex II B): cabazitaxel must be given in a unit specialised in cytotoxic administration, under the supervision of a physician experienced in anticancer chemotherapy. It is infused in hospital, so it is supplied to the hospital or clinic that administers it. It does not need refrigeration.