Novotax^® (Concentrate) Instructions for Use

ATC Code

L01CD02 (Docetaxel)

Active Substance

Docetaxel (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; plant alkaloids and other natural substances; taxanes

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 disrupts the processes of their assembly and disassembly. It 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 an excess amount of P-glycoprotein (Pgp), encoded by the multidrug resistance gene.

Pharmacokinetics

After a single intravenous administration at a dose of 100 mg/m², the mean C_max of docetaxel in plasma is 3.7 µg/ml, and the AUC is 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 anthracycline therapy failure; non-small cell lung cancer (including cases resistant to other antineoplastic agents); malignant tumors of the head and neck; ovarian cancer; prostate cancer; stomach cancer (adenocarcinoma).

ICD codes

Dosage Regimen

Administer intravenously as a one-hour infusion. Determine the dose, regimen, and number of cycles individually based on the specific malignancy, disease stage, and patient’s hematological status.

Premedicate all patients with oral corticosteroids (e.g., dexamethasone 16 mg daily for 3 days) starting one day prior to docetaxel administration to reduce the incidence and severity of fluid retention and hypersensitivity reactions.

For breast cancer (first-line or after anthracycline failure), the recommended dose is 75 mg/m² every 3 weeks. For non-small cell lung cancer and prostate cancer, the standard dose is 75 mg/m² every 3 weeks. For gastric adenocarcinoma and head and neck cancer, the recommended dose is 75 mg/m² every 3 weeks, typically in combination with other chemotherapeutic agents.

Adjust the dose based on hematological toxicity. Withhold therapy if the neutrophil count is below 1500 cells/mm³. For patients experiencing febrile neutropenia, neutropenic infection, or prolonged neutropenia (less than 500 cells/mm³ for more than 7 days) in a prior cycle, reduce the subsequent dose to 60 mg/m².

Perform liver function tests (bilirubin, AST, ALT, ALP) prior to the first cycle and before each subsequent cycle. Do not administer docetaxel if serum bilirubin exceeds the upper limit of normal (ULN) or if AST/ALT levels are greater than 1.5 times the ULN concurrent with alkaline phosphatase levels greater than 2.5 times the ULN.

For patients with mild to moderate hepatic impairment (elevated transaminases only), consider a dose reduction. Docetaxel is contraindicated in patients with severe hepatic impairment.

Monitor patients closely during the infusion for severe hypersensitivity reactions, which may include hypotension, bronchospasm, or generalized rash. Have resuscitation equipment and medications readily available.

Assess for the development of peripheral edema, pleural effusion, or ascites. Manage fluid retention with salt restriction and diuretics as clinically indicated.

Dilute the concentrate in a 250 mL infusion bag of 0.9% Sodium Chloride or 5% Dextrose solution to a final concentration between 0.3 to 0.9 mg/mL. Inspect the prepared solution for particulate matter or discoloration prior to administration; discard if present.

Adverse Reactions

From the hematopoietic system: very common – reversible and non-cumulative (not increasing with repeated administrations) neutropenia; common – bleeding associated 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 associated 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 intravenous infusion and are mild or moderate) – skin flushing, rash with or 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 – increase in AST, ALT, ALP activity 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 as muscle weakness; taste disturbance; common – severe neurosensory and neuromotor reactions (grades 3-4); rare – severe taste disturbance.

From the cardiovascular system: common – cardiac arrhythmias, increase or decrease in 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, hemorrhage from the punctured vein or vein swelling.

Contraindications

History of hypersensitivity to docetaxel; 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 renal impairment.

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 should not be used if 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 should be 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 peripheral blood counts 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. Continuation of docetaxel treatment is possible after the neutrophil count recovers to > 1500/µL.

Docetaxel should be used with caution in patients with neutropenia, especially those at risk of gastrointestinal complications. The development of enterocolitis is possible throughout the entire treatment period. 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 medications and equipment for treating arterial hypotension and bronchospasm must be available during its administration.

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 an increase in 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.

Close 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 receiving docetaxel treatment 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 childbearing potential must use reliable methods of contraception during docetaxel treatment. Men receiving docetaxel treatment are advised to avoid fathering 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 the treatment period, 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. Therefore, 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 reduced 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 between docetaxel and carboplatin. When using a combination of carboplatin and docetaxel, the clearance of carboplatin increases by 50% compared to carboplatin monotherapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.