Kabazitaxel-Kelun-Kazpharm (Concentrate) Instructions for Use

Marketing Authorization Holder

Kelun-Kazpharm, LLP (Kazakhstan)

ATC Code

L01CD04 (Cabazitaxel)

Active Substance

Cabazitaxel (Rec.INN registered by WHO)

Dosage Form

Cabazitaxel-Kelun-Kazpharm

Concentrate for solution for infusion 40 mg/ml: 1.5 ml vial in a set with solvent (vial) 4.5 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear, oily liquid from colorless to light yellow. The solvent is a clear, colorless liquid.

Each 1.5 ml vial of concentrate contains 60 mg of cabazitaxel. Each ml of solution after initial dilution with the entire solvent contains 10 mg of cabazitaxel.

Excipients: polysorbate 80, anhydrous citric acid.

Each vial of solvent contains: ethanol 96%, water for injections.

1.5 ml – glass vial (1) (in a set with solvent (vials) 4.5 ml) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkaloid

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antitumor drug, alkaloid. The mechanism of action is associated with the destruction of the cellular microtubule network. Cabazitaxel binds to tubulin and promotes the assembly of tubulin into microtubules and simultaneously inhibits their disassembly. This leads to the stabilization of microtubules, which ultimately inhibits the mitotic and interphase activity of the cell.

A wide spectrum of antitumor activity of cabazitaxel against advanced stages of human tumors xenotransplanted into mice has been shown. Cabazitaxel is active against docetaxel-sensitive tumors. Furthermore, the activity of cabazitaxel against tumor models insensitive to chemotherapy, including docetaxel, has been demonstrated.

Pharmacokinetics

After a 1-hour intravenous infusion of cabazitaxel at a dose of 25 mg/m² in patients with metastatic prostate cancer, the C_max of cabazitaxel in plasma was reached by the end of the infusion, with a mean C_max value of 226 ng/ml. The mean AUC value was 991 ng×h/ml. In patients with locally advanced solid tumors, no major deviations from dose proportionality of cabazitaxel plasma concentrations were observed in the dose range of 10-30 mg/m².

The V_ss was 4870 L. In vitro binding of cabazitaxel to human serum proteins is 89-92% and is non-saturable up to a concentration of 50,000 ng/ml, which exceeds the C_max observed during clinical use of the drug. Cabazitaxel mainly binds to serum albumin (82%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). In vitro, the blood-to-plasma concentration ratios in human blood range from 0.9 to 0.99, indicating similar distribution of cabazitaxel in blood and plasma.

Animal studies have shown that cabazitaxel and its metabolites are excreted in breast milk. Cabazitaxel crosses the placental barrier.

Cabazitaxel is extensively metabolized in the liver (≥95%), mainly by the CYP3A4 isoenzyme (80-90%). Cabazitaxel is the main compound circulating in plasma. Besides it, 7 metabolites (including 3 active metabolites formed by O-demethylation) have been identified in plasma. The plasma concentration of the main one is 5% of the plasma concentration of unchanged cabazitaxel. About 20 metabolites of cabazitaxel are excreted by the kidneys (in urine) and the intestine (in feces).

The potential risk of inhibition by cabazitaxel at clinically significant concentrations of hepatic metabolism is possible for drugs that are mainly substrates of the CYP3A isoenzyme. Potent inducers or inhibitors of the CYP3A isoenzyme may alter the plasma concentration of cabazitaxel, as cabazitaxel is mainly metabolized by the CYP3A isoenzyme.

After a 1-hour intravenous infusion of [¹⁴C]-cabazitaxel (radioisotope-labeled cabazitaxel) at a dose of 25 mg/m² to cancer patients, approximately 80% of the administered dose is excreted within 2 weeks. Cabazitaxel is mainly eliminated from the body through the intestine (in feces) as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and its metabolites is less than 4% of the administered dose (2.3% of the administered dose is excreted unchanged in urine). Cabazitaxel has a high plasma clearance of 48.5 L/h (26.44 L/h/m² in patients with a median body surface area of 1.84 m²) and a long T_1/2 of 95 hours.

Since cabazitaxel is eliminated from the body mainly through metabolism, increased systemic exposure to cabazitaxel can be expected in patients with hepatic impairment.

Indications

Hormone-resistant metastatic prostate cancer in patients previously treated with docetaxel-containing chemotherapy (in combination with prednisolone or prednisone).

ICD codes

Dosage Regimen

To reduce the risk and severity of hypersensitivity reactions, premedication with the following intravenous drugs is administered before cabazitaxel infusion: antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or a similar drug in equivalent doses); corticosteroids (dexamethasone 8 mg or equivalent doses of another corticosteroid); histamine H₂-receptor blockers (ranitidine or a similar drug in equivalent doses). Prophylactic use of antiemetics orally or, if necessary, intravenously is recommended.

The recommended dose of cabazitaxel is 25 mg/m² intravenously as a 1-hour infusion every 3 weeks in combination with prednisolone (or prednisone) 10 mg daily throughout the treatment period with cabazitaxel.

Dose adjustment is performed according to a specific scheme due to the development of adverse reactions.

Adverse Reactions

Infections and parasitic diseases Common – septic shock (all cases ≥ grade 3), sepsis (all cases ≥ grade 3), cellulitis, urinary tract infections of all grades, influenza, cystitis, upper respiratory tract infections, herpes zoster, candidiasis; Uncommon – cellulitis ≥ grade 3, cystitis ≥ grade 3.

From the hematopoietic system Very common – neutropenia of all grades, including neutropenia with clinical manifestations ≥ grade 3, anemia of all grades, leukopenia of all grades, thrombocytopenia; Common – febrile neutropenia, thrombocytopenia ≥ grade 3. Neutropenic infections, neutropenic sepsis, and septic shock in some cases led to a fatal outcome.

From the immune system Common – hypersensitivity reactions, including severe reactions such as generalized rash/erythema, decreased blood pressure, and bronchospasm.

From metabolism Very common – anorexia; Common – dehydration of all grades, hyperglycemia, hypokalemia, weight loss; Uncommon – anorexia ≥ grade 3, hyperglycemia ≥ grade 3, hypokalemia ≥ grade 3.

From the nervous system Very common – dysgeusia (taste disturbance); Common – peripheral neuropathy: peripheral sensory neuropathy (paresthesia, dysesthesia, hypesthesia) and peripheral motor neuropathy; dizziness, headache, lethargy, sciatica, anxiety, confusion; Uncommon – peripheral neuropathy ≥ grade 3, peripheral sensory neuropathy ≥ grade 3, lethargy ≥ grade 3, sciatica ≥ grade 3.

From the organ of vision Common – conjunctivitis, increased lacrimation.

From the organ of hearing and balance Common – tinnitus, vertigo (sensation of deviation or spinning of one’s own body or surrounding objects).

From the cardiovascular system Common – atrial fibrillation, tachycardia, decreased blood pressure, deep vein thrombosis of all grades, increased blood pressure, orthostatic hypotension, flushing, hyperemia; Uncommon – atrial fibrillation ≥ grade 3, decreased blood pressure ≥ grade 3, increased blood pressure ≥ grade 3, orthostatic hypotension ≥ grade 3. Cases of heart failure were observed with cabazitaxel use – in 2 patients (0.5%). One patient in the cabazitaxel group died from heart failure. Fatal ventricular fibrillation in 1 patient (0.3%) and cardiac arrest in 2 patients (0.5%) were observed. However, none of these cases were considered by the investigators to be related to cabazitaxel.

From the respiratory system Very common – dyspnea, cough; Common – dyspnea ≥ grade 3, pain in the oral cavity and pharynx, pneumonia of all grades.

From the digestive system Very common – diarrhea, nausea, vomiting, constipation, abdominal pain; Common – increased AST activity, diarrhea ≥ grade 3, nausea ≥ grade 3, vomiting ≥ grade 3, constipation ≥ grade 3, abdominal pain ≥ grade 3, dyspepsia, epigastric pain, hemorrhoids, gastroesophageal reflux disease, rectal bleeding, dry mouth, abdominal distension; Uncommon – increased serum bilirubin, increased ALT activity, rectal bleeding ≥ grade 3, dry mouth ≥ grade 3, abdominal distension ≥ grade 3.

From the skin and subcutaneous tissues Very common – alopecia; Common – dry skin, erythema.

From the musculoskeletal system Very common – back pain, arthralgia; Common – back pain ≥ grade 3, arthralgia ≥ grade 3, limb pain of all grades, muscle spasms, myalgia, musculoskeletal chest pain, flank pain; Uncommon – myalgia ≥ grade 3, musculoskeletal chest pain ≥ grade 3, flank pain ≥ grade 3.

From the urinary system Very common – hematuria; Common – acute renal failure of all grades, renal failure of all grades, dysuria, renal colic, hematuria ≥ grade 3, pollakiuria, hydronephrosis, urinary retention, urinary incontinence, ureteral obstruction of all grades; Uncommon – renal colic ≥ grade 3, pollakiuria ≥ grade 3, hydronephrosis ≥ grade 3, urinary retention ≥ grade 3.

From the genital organs Common – pelvic pain; Uncommon – pelvic pain ≥ grade 3.

General disorders Very common – weakness, asthenia, pyrexia; Common – weakness ≥ grade 3; asthenia ≥ grade 3, pyrexia ≥ grade 3, peripheral edema, mucosal inflammation, pain of all grades, chest pain, edema, chills, malaise; Uncommon – peripheral edema ≥ grade 3, mucosal inflammation ≥ grade 3, chest pain ≥ grade 3, edema ≥ grade 3.

Contraindications

Neutrophil count in peripheral blood less than 1500/µl; hepatic impairment (bilirubin ≥1×ULN, AST and/or ALT ≥1.5×ULN); concurrent vaccination with yellow fever vaccine; pregnancy, lactation; children and adolescents under 18 years of age; hypersensitivity to cabazitaxel; hypersensitivity to other taxanes.

Use in Pregnancy and Lactation

Cabazitaxel is contraindicated during pregnancy and lactation (breastfeeding).

Special Precautions

Cabazitaxel should be used with caution in patients with moderate renal impairment (CrCl 30-50 ml/min) (limited clinical data on the use of the drug), in patients with severe renal impairment (CrCl less than 30 ml/min) and end-stage renal disease (no clinical data on the use of the drug) (careful medical supervision during treatment is required); in patients with peripheral blood hemoglobin level <10 g/dl; in patients with conditions or diseases that predispose to the development of neutropenia and/or increased complications during prolonged neutropenia (age over 65 years, poor performance status, low body weight, previous episodes of febrile neutropenia, prior intensive radiation therapy, other serious comorbidities) (careful medical supervision during treatment is required, prophylactic administration of G-CSF is possible).

Patients should be carefully monitored for the development of hypersensitivity reactions, especially during the first few minutes after the start of the cabazitaxel infusion. During the infusion, appropriate equipment and medications for emergency care in case of decreased blood pressure or bronchospasm should be available. Severe reactions such as generalized rash/erythema, decreased blood pressure, and bronchospasm may develop. If severe hypersensitivity reactions occur, immediate discontinuation of the cabazitaxel infusion and necessary treatment are required. Patients with a history of severe hypersensitivity reaction should not be re-administered Cabazitaxel.

In accordance with the recommendations of the American Society of Clinical Oncology and/or current approved guidelines, to reduce the risk of or treat neutropenic complications (febrile neutropenia, prolonged neutropenia, or neutropenic infection), patients receiving Cabazitaxel may be prophylactically prescribed G-CSF.

During the first cycle (cycle 1) of treatment and before each new treatment cycle, weekly monitoring of blood cell counts (complete blood count) is required to reduce the dose in the next cycle if necessary. If febrile neutropenia or prolonged neutropenia develops despite appropriate treatment, treatment with cabazitaxel may be continued only after the neutrophil count in peripheral blood increases to ≥1500/µl.

If patients develop diarrhea after cabazitaxel administration, treatment with conventional antidiarrheal drugs should be carried out. Appropriate measures should be taken to restore fluid loss, monitor and correct blood electrolyte composition, especially potassium ion concentration. Diarrhea may occur more frequently in patients who have previously received abdominopelvic radiation therapy. Dehydration occurs more frequently in patients aged 65 years and older. If grade 3 diarrhea develops, a delay in the next treatment cycle or dose reduction may be required. For nausea and vomiting, antiemetics can be used.

Cases of peripheral neuropathy, peripheral sensory neuropathy (paresthesia, dysesthesia) and peripheral motor neuropathy have been observed in patients receiving Cabazitaxel. Patients receiving Cabazitaxel should be advised to inform their treating physician about any developed neuropathy symptoms, such as pain, burning sensation, tingling, numbness, before continuing treatment. The physician should assess the presence or worsening of neuropathy symptoms before each treatment cycle. Administration of cabazitaxel should be delayed until symptoms decrease. For persistent peripheral neuropathy ≥ grade 2, the dose of cabazitaxel should be reduced from 25 mg/m² body surface area to 20 mg/m² body surface area.

Renal function impairment has been reported in combination with sepsis, severe dehydration due to diarrhea and vomiting, and obstructive uropathy. Renal failure developed, including fatal cases. Appropriate measures should be taken to identify the cause and intensive therapy should be carried out for developing renal failure. Renal function should be monitored.

Adequate hydration should be maintained during treatment with cabazitaxel.

The patient should be advised to immediately report any changes in daily urine output. Creatinine levels should be determined before treatment, at each complete blood count test, and if the patient reports a change in urine output. If renal failure ≥ grade 3 develops, treatment with cabazitaxel should be discontinued.

Elderly patients (≥ 65 years) may be more predisposed to some adverse reactions, including neutropenia and febrile neutropenia.

It is recommended to use Cabazitaxel with caution in patients with a peripheral blood hemoglobin level <10 g/dl. Appropriate therapeutic measures aimed at increasing the peripheral blood hemoglobin concentration should be carried out.

Due to possible adverse effects on male gametes and possible excretion of the drug in semen, patients receiving Cabazitaxel and their sexual partners should use effective methods of contraception during treatment and for 6 months after the last dose of cabazitaxel. Due to the possible excretion of cabazitaxel in semen, men receiving Cabazitaxel should prevent contact of ejaculate with another person’s tissues during treatment. Patients planned for treatment with cabazitaxel are recommended to perform sperm cryopreservation before starting treatment.

The use of live vaccines or attenuated live vaccines in patients with immunosuppression resulting from treatment with chemotherapeutic drugs may lead to the development of serious or fatal infections. Vaccination with live attenuated vaccines should be avoided in patients receiving treatment with cabazitaxel. Killed or inactivated vaccines can be used; however, the body’s response to such vaccines may be less pronounced.

Effect on the ability to drive vehicles and mechanisms

During treatment, patients should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and rapid psychomotor reactions.

Drug Interactions

No specific studies on the interaction of cabazitaxel with other drugs have been conducted.

In vitro studies have shown that Cabazitaxel is predominantly metabolized with the participation of the CYP3A isoenzyme (80-90%) and inhibits the CYP3A isoenzyme.

When cabazitaxel is used concomitantly with potent inhibitors of the CYP3A isoenzyme (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), an increase in the plasma concentration of cabazitaxel is expected. Therefore, the concomitant use of cabazitaxel and potent inhibitors of the CYP3A isoenzyme should be avoided. Caution should be exercised when cabazitaxel is used concomitantly with moderate inhibitors of the CYP3A isoenzyme.

When cabazitaxel is used concomitantly with potent inducers of the CYP3A isoenzyme (such as phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital), a decrease in the plasma concentration of cabazitaxel is expected. Therefore, the concomitant use of cabazitaxel and potent inducers of the CYP3A isoenzyme should be avoided. In addition, patients receiving Cabazitaxel should refrain from taking St. John’s wort preparations.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.