Taxelen (Concentrate) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

ATC Code

L01CD02 (Docetaxel)

Active Substance

Docetaxel (Rec.INN registered by WHO)

Dosage Forms

	Taxelen	Concentrate for solution for infusion 20 mg/ml: 1 ml, 2 ml, 4 ml, 5 ml, 5.5 ml, 6 ml, 7 ml, 7.5 ml, 8 ml or 9 ml vial. 1 pc.
		Concentrate for solution for infusion 40 mg/ml: 0.5 ml, 1 ml, 2 ml, 3 ml or 4 ml vial. 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion from light yellow to brownish-yellow, clear, oily.

Excipients : ethanol 96% – up to 1 ml, polysorbate 80.

1 ml – vials of colorless neutral glass (1) – cardboard packs.
2 ml – vials of colorless neutral glass (1) – cardboard packs.
4 ml – vials of colorless neutral glass (1) – cardboard packs.
5 ml – vials of colorless neutral glass (1) – cardboard packs.
5.5 ml – vials of colorless neutral glass (1) – cardboard packs.
6 ml – vials of colorless neutral glass (1) – cardboard packs.
7 ml – vials of colorless neutral glass (1) – cardboard packs.
7.5 ml – vials of colorless neutral glass (1) – cardboard packs.
8 ml – vials of colorless neutral glass (1) – cardboard packs.
9 ml – vials of colorless neutral glass (1) – cardboard packs.

Concentrate for solution for infusion from light yellow to brownish-yellow, clear, oily.

Excipients : ethanol 96% – up to 1 ml, polysorbate 80.

0.5 ml – vials of colorless neutral glass (1) – cardboard packs.
1 ml – vials of colorless neutral glass (1) – cardboard packs.
3 ml – vials of colorless neutral glass (1) – cardboard packs.
4 ml – vials of colorless neutral glass (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic agent, a semisynthetic analogue of paclitaxel. The mechanism of action is associated with the accumulation of tubulin in the microtubules of the mitotic spindle, which leads to disruption of their assembly and disassembly processes. Disrupts cell division in the G₂ and M phases of the cell cycle.

Docetaxel persists in cells for a long time, where its concentration reaches high values. Furthermore, Docetaxel exhibits activity against some, though not all, cells that produce excessive amounts of P-glycoprotein (Pgp), encoded by the multidrug resistance gene.

Pharmacokinetics

After a single IV administration at a dose of 100 mg/m², the mean C_max of docetaxel in plasma is 3.7 µg/ml, AUC – 4.6 µg*h/ml. The mean values for total clearance and V_d at steady state were 21 L/h/m² and 113 L, respectively. The total clearance values of docetaxel varied by approximately 50% among different patients.

Docetaxel is more than 95% bound to plasma proteins.

Docetaxel, after oxidation of the tert-butyl ether group by the cytochrome P450 isoenzyme system, is eliminated over 7 days through the kidneys, in urine (6% of the administered dose) and through the gastrointestinal tract, in feces (75% of the administered dose). About 80% of the docetaxel dose is excreted in feces within 48 hours as metabolites (the main inactive metabolite and three less significant inactive metabolites) and in very insignificant amounts – unchanged.

Indications

As a first-line treatment for breast cancer, as well as for therapy-resistant disease with anthracycline-based drugs; non-small cell lung cancer (including when other antineoplastic agents are ineffective); malignant tumors of the head and neck; ovarian cancer; prostate cancer; stomach cancer (adenocarcinoma).

ICD codes

Dosage Regimen

Administer intravenously as an infusion over one hour. Calculate the dose individually based on body surface area.

Premedicate all patients with oral corticosteroids for three days starting one day before docetaxel administration to reduce the risk and severity of hypersensitivity reactions and fluid retention.

For breast cancer, the recommended dose is 60-100 mg/m² administered every three weeks.

For non-small cell lung cancer, the recommended dose is 75 mg/m² administered every three weeks.

For prostate cancer, administer 75 mg/m² every three weeks in combination with prednisone.

For gastric adenocarcinoma, the recommended dose is 75 mg/m² every three weeks in combination with cisplatin and fluorouracil.

For head and neck cancer, administer 75 mg/m² every three weeks in combination with cisplatin and fluorouracil.

Adjust the dose based on tolerability and the presence of toxicities such as febrile neutropenia, severe neutropenia, severe cutaneous reactions, or severe peripheral neuropathy.

Withhold therapy if the neutrophil count is below 1500 cells/mm³. Do not administer until recovery to >1500 cells/mm³.

Reduce the dose by 25% for patients who experienced febrile neutropenia, neutrophil count <500/mm³ for more than one week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy.

Perform liver function tests prior to each treatment cycle. Do not administer if bilirubin is above the upper limit of normal or if ALT/AST are >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN.

Dilute the entire contents of the vial in a 250 mL infusion bag of 0.9% Sodium Chloride or 5% Dextrose solution to achieve a final concentration not exceeding 0.9 mg/mL. Mix by manual rotation.

Administer the prepared infusion solution immediately through a polyethylene-lined infusion set. Complete the infusion within four hours.

Adverse Reactions

From the hematopoietic system very common – reversible and non-cumulative (not increasing with repeated administrations) neutropenia; common – bleeding, combined with thrombocytopenia <50,000/µl and anemia (hemoglobin <11 g/dL), including severe anemia (hemoglobin <8 g/dL); uncommon – severe thrombocytopenia.

Infections and parasitic diseases severe infections, combined with a decrease in the number of neutrophils in peripheral blood <500/µl; severe infections including sepsis and pneumonia, including fatal outcomes.

From the immune system very common – allergic reactions (usually occur within a few minutes after the start of IV infusion and are mild or moderate) – flushing, rash with and without itching; chest tightness, back pain, shortness of breath, drug fever or chills; common – severe allergic reactions, characterized by decreased blood pressure and/or bronchospasm or generalized rash/erythema.

From the skin and subcutaneous tissues: very common – reversible skin reactions (usually mild or moderate) – localized rashes, mainly on the hands and feet, as well as on the face and chest, often accompanied by itching; hypo- and hyperpigmentation of nails, pain and onycholysis (separation of the nail plate from the nail bed); alopecia; common – severe skin reactions, such as rash followed by desquamation, including severe palmar-plantar erythrodysesthesia syndrome; uncommon – severe alopecia.

From the digestive system very common – nausea, vomiting, diarrhea, anorexia, stomatitis; common – severe nausea, severe vomiting, severe diarrhea, constipation, severe stomatitis, esophagitis; abdominal pain, including severe; gastrointestinal bleeding; uncommon – severe gastrointestinal bleeding, severe constipation, severe esophagitis.

From the liver and biliary tract: common – increased activity of AST, ALT, ALP and serum bilirubin concentration, more than 2.5 times the upper limit of normal (ULN).

From the nervous system very common – mild or moderate neurosensory reactions (paresthesia, dysesthesia, pain, including burning sensation) and neuromotor reactions, mainly manifested by muscle weakness; taste disturbance; common – severe neurosensory and neuromotor reactions (grade 3-4); rare – severe taste disturbance.

From the cardiovascular system common – cardiac arrhythmias, increased or decreased blood pressure, bleeding; uncommon – heart failure.

From the respiratory system: very common – dyspnea; common – severe dyspnea.

From the musculoskeletal system: very common – myalgia; common – arthralgia.

From fluid and electrolyte balance very common – peripheral edema; common – pleural and pericardial effusion, ascites.

General reactions: very common – asthenia, including severe asthenia, weight gain; generalized and localized pain syndrome, including non-cardiac chest pain.

Local reactions: very common – hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, bleeding from the punctured vein or vein swelling.

Contraindications

Hypersensitivity to docetaxel in history; neutropenia less than 1500/µl; pregnancy, breastfeeding period; severe liver dysfunction; children and adolescents under 18 years of age.

With caution when used concomitantly with strong inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); when used concomitantly with drugs that induce or inhibit CYP3A isoenzymes, or are metabolized by CYP3A isoenzymes.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use reliable methods of contraception during docetaxel therapy.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use in Renal Impairment

Should be used with caution in patients with impaired renal function.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Treatment with docetaxel should be carried out only under the supervision of a physician experienced in anticancer chemotherapy in a specialized hospital setting.

Docetaxel is not used when bilirubin levels are above the ULN in combination with hepatic transaminase activity exceeding 1.5 times the ULN and ALP exceeding 2.5 times the ULN.

Before starting docetaxel therapy, patients are prescribed oral corticosteroids. The likelihood of developing allergic reactions and edema significantly increases in patients who have not previously received such therapy.

During treatment, systematic monitoring of the peripheral blood picture is necessary to identify the degree of myelosuppression.

Clinical blood tests should be monitored in patients receiving docetaxel therapy. The maximum decrease in neutrophils occurs by day 7, but in patients who have previously undergone intensive chemotherapy, this interval may be shorter. If severe neutropenia (<500/µl for 7 days) develops during a course of docetaxel, it is recommended to reduce its dose in subsequent cycles or take adequate symptomatic measures. Treatment with docetaxel can be continued after the neutrophil count recovers to > 1500/µl.

Docetaxel should be used with caution in patients with neutropenia, especially at risk of gastrointestinal complications. Enterocolitis can develop throughout the entire treatment. Enterocolitis can lead to death even on the first day of its development.

To detect the development of hypersensitivity reactions, patients should be carefully observed, especially during the first and second infusions. Hypersensitivity reactions can develop in the very first minutes of docetaxel infusion, so when administering it, it is necessary to have medications and equipment for the treatment of arterial hypotension and bronchospasm.

In patients receiving docetaxel monotherapy at a dose of 100 mg/m² and having elevated hepatic transaminase activity (ALT and/or AST), more than 1.5 times the ULN, in combination with increased ALP activity, more than 2.5 times the ULN, there is an extremely high risk of developing severe adverse effects such as sepsis, gastrointestinal bleeding, febrile neutropenia, infections, thrombocytopenia, severe toxic skin lesions up to fatal outcome, as well as stomatitis and asthenia. Liver function tests should be performed before starting treatment and before each subsequent cycle of docetaxel therapy.

Careful monitoring is necessary for patients with significant fluid retention: with pleural effusion, pericardial effusion, or ascites. If edema occurs, salt and fluid intake should be restricted and diuretics should be used.

In patients aged 65 years and older treated with docetaxel every 3 weeks for prostate cancer, the frequency of nail changes, anemia, infections, anorexia, and weight loss was >10% greater than in younger patients, and in patients aged 75 years and older, the frequency of fever, diarrhea, anorexia, and peripheral edema was >10% greater than in younger patients. No differences in treatment efficacy were found when comparing elderly and younger patients.

Men and women of reproductive age should use reliable methods of contraception during docetaxel treatment. Men receiving docetaxel treatment are advised to avoid conceiving a child during docetaxel treatment and for at least 6 months after the end of chemotherapy.

Effect on ability to drive vehicles and operate machinery

During treatment, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

It has been shown that the biotransformation of docetaxel may be altered with the concomitant use of substances that induce or inhibit cytochrome CYP3A isoenzymes, or are metabolized (competitive inhibition) by cytochrome CYP3A isoenzymes, such as cyclosporine, terfenadine, erythromycin, and troleandomycin. In this regard, caution is necessary when co-administering such drugs, considering the possibility of significant interaction.

When docetaxel is used concomitantly with strong inhibitors of the CYP3A4 isoenzyme, the frequency of docetaxel adverse effects may increase due to a decrease in its metabolism.

The pharmacokinetics of docetaxel in the presence of prednisolone were studied in patients with metastatic prostate cancer. Although Docetaxel is metabolized by the CYP3A4 isoenzyme and prednisolone is an inducer of the CYP3A4 isoenzyme, no statistically significant effect of prednisolone on the pharmacokinetics of docetaxel was observed.

There is information on the interaction of docetaxel and carboplatin. When using a combination of carboplatin and docetaxel, the clearance of carboplatin increases by 50% compared with carboplatin monotherapy.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°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.