Taxotere^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Aventis Pharma S.A. (France)

Manufactured By

Aventis Pharma (Dagenham) (United Kingdom)

ATC Code

L01CD02 (Docetaxel)

Active Substance

Docetaxel (Rec.INN registered by WHO)

Dosage Forms

	Taxotere®	Concentrate for solution for infusion 20 mg/0.5 ml: vial 1 pc. in a set with solvent
		Concentrate for solution for infusion 20 mg/1 ml: vial 1 pc.
		Concentrate for solution for infusion 80 mg/4 ml: vial 1 pc.
		Concentrate for solution for infusion 160 mg/8 ml: vial 1 pc.
		Concentrate for solution for infusion 80 mg/2 ml: vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, oily solution from yellow to brownish-yellow; supplied solvent is clear, colorless.

Excipients: polysorbate 80 – up to 0.5 ml.

Solvent (13% ethanol solution in water for injection) ethanol 95% (V/V) – 191.1 mg, water for injection – up to 1.5 ml.

0.61 ml – vials of colorless glass (1) in a set with solvent (vial 1.98 ml 1 pc.) – contour cell packaging (1) – cardboard packs.

Concentrate for solution for infusion as a clear, oily solution from yellow to brownish-yellow; supplied solvent is clear, colorless.

Excipients: polysorbate 80 – up to 2.0 ml.

Solvent (13% ethanol solution in water for injection) ethanol 95% (V/V) – 764.4 mg, water for injection – up to 6.0 ml.

2.36 ml – vials of colorless glass (1) in a set with solvent (vial 7.33 ml 1 pc.) – contour cell packaging (1) – cardboard packs.

Concentrate for solution for infusion as a clear solution from light yellow to brownish-yellow.

Excipients: polysorbate 80 – 4.32 g, anhydrous ethanol – 3.16 g.

8 ml – vials of colorless glass (1) – contour cell packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic drug of plant origin (from the taxoid group). It accumulates tubulin in microtubules, prevents their disintegration, which disrupts the process of tumor cell division. Docetaxel persists in cells for a long time, where its concentration reaches high levels. Furthermore, Docetaxel shows activity against some, though not all, cells that overproduce P-glycoprotein (P-gP), encoded by the multidrug resistance gene.

In vivo, Docetaxel has a broad spectrum of activity against mouse tumors and human tumor cell lines.

The efficacy of docetaxel has been proven in breast cancer, non-small cell lung cancer, ovarian cancer, hormone-refractory prostate cancer, gastric cancer, and head and neck cancer.

Pharmacokinetics

Distribution

The pharmacokinetics of docetaxel is dose-dependent and corresponds to a three-phase pharmacokinetic model with T_1/2 in the α-, β-, and γ-phases of 4 min, 36 min, and 11.1 h, respectively.

After a one-hour infusion of docetaxel at a dose of 100 mg/m², the mean C_max of docetaxel in plasma was 3.7 µg/ml with a corresponding AUC value of 4.6 µg×h/ml. The mean V_d at steady state is 113 L.

Binding of docetaxel to plasma proteins is more than 95%.

Metabolism and excretion

The mean total clearance at steady state is 21 L/h/m². Total clearance values of docetaxel varied by approximately 50% among different patients.

Docetaxel, after oxidation of the tert-butyl ether group by cytochrome P450 isoenzymes, is eliminated over 7 days by 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 administered 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.

Pharmacokinetics in special clinical cases

The pharmacokinetics of docetaxel does not depend on the patient’s age and gender.

In mild hepatic impairment (ALT and AST activity not more than 1.5 times the upper limit of normal (ULN) combined with alkaline phosphatase activity not more than 2.5 times ULN), the total clearance of docetaxel decreases by an average of 27%.

In mild or moderate fluid retention, the clearance of docetaxel does not change; there is no information on its clearance in severe fluid retention.

When used in combination, Docetaxel does not affect the clearance of doxorubicin or the plasma concentration of doxorubicinol (a metabolite of doxorubicin).

Pharmacokinetic parameters of docetaxel, doxorubicin, and cyclophosphamide did not change when used simultaneously.

Capecitabine does not affect the pharmacokinetics of docetaxel (C_max, AUC), and Docetaxel, in turn, does not affect the pharmacokinetics of capecitabine and the most important metabolite of capecitabine (5'-DFUR).

The clearance of docetaxel during combination therapy with cisplatin does not change compared to its clearance during monotherapy. The pharmacokinetic profile of cisplatin administered shortly after the docetaxel infusion did not differ from that of cisplatin alone.

Prednisone does not affect the pharmacokinetics of docetaxel administered after standard premedication with dexamethasone.

Combination therapy with docetaxel, cisplatin, and fluorouracil does not change their pharmacokinetic parameters.

In children, the pharmacokinetic parameters during docetaxel monotherapy and docetaxel therapy in combination with cisplatin and fluorouracil were similar to those in adults.

Indications

Operable breast cancer (Taxotere^® in combination with doxorubicin and cyclophosphamide, adjuvant chemotherapy)

• Operable breast cancer with regional lymph node involvement;
• Operable breast cancer without regional lymph node involvement in patients for whom chemotherapy is indicated according to established international selection criteria for primary chemotherapy of early-stage breast cancer (in the presence of one or more high-risk factors for recurrence: tumor size greater than 2 cm, negative estrogen and progesterone receptor status, high histological/nuclear tumor grade /grade 2-3/, age less than 35 years).

Metastatic and/or locally advanced breast cancer

• Locally advanced or metastatic breast cancer (Taxotere^® in combination with doxorubicin, 1st-line therapy);
• Metastatic breast cancer with tumor HER2 overexpression (Taxotere^® in combination with trastuzumab, 1st-line therapy);
• Locally advanced or metastatic breast cancer after failure of prior chemotherapy that included anthracyclines or alkylating agents (Taxotere^® as monotherapy) or after failure of prior chemotherapy that included anthracyclines (Taxotere^® in combination with capecitabine).

Non-small cell lung cancer:

• Locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy (Taxotere^® as monotherapy);
• Unresectable locally advanced or metastatic non-small cell lung cancer (Taxotere^® in combination with cisplatin, 1st-line therapy).

Ovarian cancer

• Metastatic ovarian cancer after failure of prior 1st-line therapy (Taxotere^® as monotherapy, 2nd-line therapy).

Prostate cancer

• Metastatic hormone-refractory (androgen-independent) prostate cancer (Taxotere^® in combination with prednisone or prednisolone).

Gastric cancer

• Metastatic gastric cancer, including cancer of the gastroesophageal junction area (Taxotere^® in combination with cisplatin and fluorouracil, 1st-line therapy).

Head and neck cancer

• Locally advanced squamous cell carcinoma of the head and neck (Taxotere^® in combination with cisplatin and fluorouracil, induction therapy).

ICD codes

Dosage Regimen

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

To prevent hypersensitivity reactions, as well as to reduce fluid retention, all patients (except patients with prostate cancer) should receive premedication with corticosteroids, for example, dexamethasone at a dose of 16 mg/day (8 mg twice a day) orally for 3 days, starting one day before the administration of Taxotere^®.

In patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, premedication with dexamethasone is administered at a dose of 8 mg 12, 3, and 1 hour before the start of Taxotere^® administration.

To reduce the risk of hematological complications, prophylactic administration of G-CSF is recommended.

Taxotere^® is administered intravenously by drip over 1 hour once every 3 weeks.

Breast cancer

For adjuvant therapy of operable breast cancer with regional lymph node involvement and operable breast cancer without regional lymph node involvement, the recommended dose of Taxotere^® is 75 mg/m² 1 hour after administration of doxorubicin (50 mg/m²) and cyclophosphamide (500 mg/m²) every 3 weeks (TAC regimen). A total of 6 cycles.

For locally advanced or metastatic breast cancer as 1st-line therapy, Docetaxel 75 mg/m² is administered in combination with doxorubicin 50 mg/m²; as 2nd-line therapy, the recommended dose of docetaxel for monotherapy is 100 mg/m².

For combination of Taxotere^® plus trastuzumab, the recommended dose of Taxotere^® is 100 mg/m² every 3 weeks with weekly administration of trastuzumab. The initial docetaxel infusion is administered the day after the first dose of trastuzumab. Subsequent doses of docetaxel are administered immediately after the end of the trastuzumab infusion (if the previous dose of trastuzumab was well tolerated). Doses and methods of administration of trastuzumab are indicated in the prescribing information for trastuzumab.

For combination with capecitabine, the recommended dose of docetaxel is 75 mg/m² every 3 weeks, and capecitabine is 1250 mg/m² orally twice a day (within 30 minutes after a meal) for 2 weeks followed by a one-week rest period. For calculation of the capecitabine dose according to body surface area, see the prescribing information for capecitabine.

Non-small cell lung cancer

In patients who have not previously received chemotherapy, the following treatment regimen is recommended: Docetaxel 75 mg/m², immediately followed by administration of cisplatin at a dose of 75 mg/m² over 30-60 minutes.

For treatment after failure of platinum-based chemotherapy, monotherapy with docetaxel at a dose of 75 mg/m² is recommended.

Metastatic ovarian cancer

For 2nd-line therapy of ovarian cancer, Taxotere^® is recommended as monotherapy at a dose of 100 mg/m² every 3 weeks.

Prostate cancer

The recommended dose of Taxotere^® is 75 mg/m² once every 3 weeks. Prednisone or prednisolone is prescribed long-term at 5 mg orally twice a day.

Gastric cancer

The recommended dose of Taxotere^® is 75 mg/m² as a one-hour infusion followed by an infusion of cisplatin at a dose of 75 mg/m² over 1-3 hours (both drugs only on the first day of each chemotherapy cycle). After completion of cisplatin administration, a 24-hour infusion of fluorouracil is administered at a dose of 750 mg/m²/day for 5 days. Treatment is repeated every 3 weeks. Premedication with antiemetics and appropriate hydration for cisplatin administration should be performed. To reduce the risk of hematological toxicity, prophylactic administration of G-CSF is indicated.

Head and neck cancer

Premedication with antiemetics should be performed, as well as appropriate hydration (before and after cisplatin administration). Prophylaxis of neutropenic infections should be carried out. All patients receiving treatment regimens containing Taxotere^® were prophylactically prescribed antibiotics.

Induction chemotherapy followed by radiotherapy. For induction therapy for locally advanced inoperable squamous cell carcinoma of the head and neck, the recommended dose of Taxotere^® is 75 mg/m² as a one-hour intravenous infusion followed by administration of cisplatin at a dose of 75 mg/m² over 1 hour (both drugs are administered only on the first day of each chemotherapy cycle). After this, a continuous infusion of fluorouracil is administered at a dose of 750 mg/m²/day for 5 days. This regimen is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should receive radiotherapy.

Induction chemotherapy followed by chemoradiotherapy. For induction therapy for locally advanced squamous cell carcinoma of the head and neck (technically unresectable, with low probability of surgical cure, or when organ preservation is decided), the recommended dose of Taxotere^® is 75 mg/m² as a one-hour intravenous infusion followed by a 0.5-3-hour infusion of cisplatin at a dose of 100 mg/m² (both drugs are administered only on the first day of each chemotherapy cycle) and followed by a continuous infusion of fluorouracil at a dose of 1000 mg/m²/day from day 1 to day 4. This treatment regimen is repeated every 3 weeks, for a total of 3 cycles. After chemotherapy, patients should receive chemoradiotherapy. For information on dose adjustments of cisplatin and fluorouracil, refer to the prescribing information for these drugs.

Dose Adjustment

General principles

Taxotere^® should be administered when the neutrophil count in peripheral blood is ≥1500/µL. In case of development of febrile neutropenia, neutrophil count <500/µL lasting more than one week, severe or cumulative (increasing with repeated administrations) skin reactions, or severe peripheral neuropathy during docetaxel therapy, its dose in subsequent administrations should be reduced from 100 mg/m² to 75 mg/m² and/or from 75 mg/m² to 60 mg/m². If such reactions persist even at a docetaxel dose of 60 mg/m², treatment with the drug should be discontinued.

Adjuvant therapy for breast cancer

For breast cancer patients receiving adjuvant therapy with Taxotere^® in combination with doxorubicin and cyclophosphamide (TAC regimen), administration of G-CSF is recommended for primary prophylaxis. For patients who have experienced febrile neutropenia or neutropenic infection, the dose of Taxotere^® should be reduced to 60 mg/m² in all subsequent cycles. In patients who developed grade 3 or 4 stomatitis, the docetaxel dose should be reduced to 60 mg/m².

Taxotere^® in combination with cisplatin

In patients who initially received Docetaxel at a dose of 75 mg/m² in combination with cisplatin and whose platelet count in the previous cycle decreased to 25,000/µL, or in patients who developed febrile neutropenia, or in patients with severe non-hematological toxicity, the dose of docetaxel in subsequent cycles should be reduced to 65 mg/m².

For dose adjustment of cisplatin, refer to the prescribing information for cisplatin.

Taxotere^® in combination with capecitabine

For dose adjustment of capecitabine when combined with Taxotere^®, refer to the prescribing information for capecitabine.

Upon first occurrence of grade 2 toxicity that persists by the start of the next Taxotere^®/capecitabine cycle, the next treatment cycle may be delayed until toxicity decreases to grade 0-1, with 100% of the initial dose administered during the next treatment cycle.

In patients with recurrent grade 2 toxicity or first occurrence of grade 3 toxicity at any time during the cycle, treatment is delayed until toxicity decreases to grade 0-1, then treatment with Taxotere^® is resumed at a dose of 55 mg/m².

Upon any subsequent occurrence of toxicity or occurrence of any grade 4 toxicity, the administration of Taxotere^® should be discontinued.

Taxotere^® in combination with trastuzumab

For dose adjustment of trastuzumab, the prescribing information for trastuzumab should be used.

Taxotere^® in combination with cisplatin and fluorouracil

Patients receiving Taxotere^® in combination with cisplatin and fluorouracil should receive antiemetics and adequate hydration according to existing generally accepted recommendations. To reduce the risk of complicated neutropenia, G-CSF should be used.

If, despite G-CSF administration, febrile neutropenia, prolonged neutropenia, or neutropenic infection occurs, the dose of Taxotere^® should be reduced from 75 mg/m² to 60 mg/m². Upon subsequent episodes of complicated neutropenia, it is recommended to reduce the dose of Taxotere^® from 60 mg/m² to 45 mg/m². If grade 4 thrombocytopenia develops, the dose of Taxotere^® is recommended to be reduced from 75 mg/m² to 60 mg/m². Subsequent cycles with docetaxel are possible when neutrophil count is >1500/µl and platelet count is >100,000/µl. If these toxic manifestations persist, treatment should be discontinued.

Recommended dose adjustments for toxicity in patients receiving Taxotere^® in combination with cisplatin and fluorouracil (FU)

For recommendations on dose adjustments for cisplatin and fluorouracil, the respective prescribing information should be used.

In non-small cell lung cancer of the head and neck in patients who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), prophylactic use of G-CSF is recommended in all subsequent cycles (e.g., from day 1 to day 15).

Special patient groups

Children. The safety and efficacy of Taxotere^® in children have not been sufficiently studied. There is limited experience with the use of Taxotere^® in children. The efficacy and safety of Taxotere^® for nasopharyngeal cancer in children and adolescents from 1 month to 18 years have not yet been established. Taxotere^® has not been used in children for the following indications: breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, and head and neck cancer, except for poorly differentiated nasopharyngeal carcinoma (type I and II).

Elderly patients. Based on population pharmacokinetic analysis data, there are no specific instructions for the use of Taxotere^® in elderly patients. In patients aged 60 years and older when Taxotere^® is combined with capecitabine, a 25% reduction in the dose of capecitabine is recommended (according to the prescribing information for capecitabine).

Patients with hepatic impairment. Based on pharmacokinetic data for Taxotere^® monotherapy at a dose of 100 mg/m², in patients with ALT and/or AST activity >1.5 times the upper limit of normal (ULN) or alkaline phosphatase activity >2.5 times ULN, the recommended dose of Taxotere^® is 75 mg/m². In patients with elevated blood bilirubin (>1 times ULN) and/or increased ALT and AST activity (>3.5 times ULN) in combination with increased alkaline phosphatase activity (> 6 times ULN), a dose reduction cannot be recommended, and Docetaxel should not be used without strict indications.

The combination of Taxotere^® with cisplatin and fluorouracil for the treatment of gastric cancer has not been used in patients with increased ALT and/or AST activity (>1.5 times ULN) in combination with increased alkaline phosphatase activity (>2.5 times ULN) and elevated blood bilirubin (>1 times ULN); in such patients, a dose reduction cannot be recommended and Docetaxel should not be used without strict indications.

Currently, there are no data regarding the use of Taxotere^® in combination with other drugs in patients with impaired liver function.

Patients with renal impairment. There are no data on the use of docetaxel in patients with severe renal impairment.

Preparation of the infusion solution

Do not use Taxotere^®, concentrate for solution for infusion (20 mg/1 ml, 80 mg/4 ml and 160 mg/8 ml), containing concentrate and solvent in one vial, together with the forms of Taxotere^® in 2 vials (concentrate and solvent).

Taxotere^®, concentrate for solution for infusion (20 mg/1 ml, 80 mg/4 ml and 160 mg/8 ml), containing concentrate and solvent in one vial, does not require preliminary dilution with a solvent and is ready for addition to the infusion solution.

Each vial is for single use only and must be used immediately.

If the vials are stored in the refrigerator, the required number of packs of Taxotere^® with concentrate for solution for infusion should be kept at room temperature (not above 25°C (77°F)) for 5 minutes before use for preparing the infusion solution.

The required volume of Taxotere^® 20 mg/1 ml concentrate for solution for infusion, according to the required dose, is aseptically withdrawn from the vials using a single graduated syringe connected to a 21G needle and introduced into an infusion bag or vial containing 250 ml of 5% dextrose solution or 0.9% sodium chloride solution (administration is performed by a single introduction of the entire required dose into the infusion container). If the required dose of docetaxel exceeds 190 mg, larger volume infusion containers should be used so that the concentration of docetaxel does not exceed 0.74 mg/ml.

The contents of the infusion bag or vial should be mixed by slowly inverting them. Infusion of the prepared solution must be completed no later than 6 hours after preparation (including 1 hour of administration) when stored at room temperature and under normal lighting conditions. After preparation of the infusion solution under aseptic conditions, its physical and chemical stability has been demonstrated for 48 hours when stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) in a non-PVC container.

The concentrate for solution for infusion Taxotere^® 20 mg/1 ml, 80 mg/4 ml and 160 mg/8 ml, and the infusion solution, like any other parenteral drugs, must be inspected before administration: if sediment is present, they must not be administered and should be disposed of.

Drug residues and all materials used for its dilution and administration should be disposed of in accordance with standard regulations.

Adverse Reactions

Definition of the frequency of adverse reactions (according to WHO classification): very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%), frequency not known (when available data do not allow estimation of the frequency of adverse reactions).

Monotherapy with Taxotere^® (75 mg/m² and 100 mg/m²)

Hematologic system very common – reversible and non-cumulative (not increasing with repeated administrations) neutropenia, observed in 96.6% of patients not receiving G-CSF (neutrophil count decreases to nadir on average after 7 days, in patients with intensive prior chemotherapy this period may be shorter; the average duration of severe neutropenia, <500 cells/µl, is also 7 days), febrile neutropenia, infections; common - severe infections due to decrease in peripheral blood neutrophils <500/µl, severe infections including sepsis and pneumonia (including fatal cases), thrombocytopenia <100,000/µl, bleeding due to thrombocytopenia <50,000/µl, anemia (hemoglobin <11 g/dl), including severe anemia (hemoglobin <8 g/dl); uncommon - severe thrombocytopenia.

Allergic reactions very common – skin flushing; rash with or without itching; chest tightness; back pain; dyspnea; drug fever or chills (usually occur within a few minutes after the start of Taxotere^® infusion and are mild or moderate in severity); common – severe allergic reactions characterized by decreased blood pressure and/or bronchospasm, generalized rash/erythema (resolved after stopping the infusion and administering appropriate therapy).

Skin and subcutaneous tissue disorders very common – localized rash, mainly on the hands and feet, as well as on the face and chest, often accompanied by itching (these reactions are usually mild or moderate, usually occurred within one week after docetaxel infusion), nail hypo- and hyperpigmentation, nail pain, onycholysis (nail loss from the free edge of the nail), alopecia; common – severe skin reactions such as rash followed by desquamation, including severe hand-foot syndrome, which may require interruption or discontinuation of docetaxel treatment; uncommon – severe alopecia. In some cases, the occurrence of these reactions was additionally influenced by a combination of several factors, such as concomitant infections, concomitant therapy, and the underlying disease.

Digestive system very common – nausea, vomiting, diarrhea, anorexia, stomatitis; common – severe nausea, severe vomiting, severe diarrhea, constipation, severe stomatitis, esophagitis, epigastric pain (including severe), gastrointestinal bleeding, increased serum activity of AST, ALT, alkaline phosphatase and blood bilirubin levels, more than 2.5 times ULN; uncommon – severe gastrointestinal bleeding, severe constipation, severe esophagitis.

Nervous system very common – mild or moderate neurosensory reactions, including paresthesia, dysesthesia, pain, including burning sensation, and neuromotor reactions, mainly manifested as muscle weakness, taste disturbance; common – severe neurosensory and neuromotor reactions (grade 3-4); uncommon – severe taste disturbance. If these neurological symptoms occur, the dosing regimen should be adjusted. If neuropathy symptoms persist, treatment should be discontinued. The average time to spontaneous resolution of neurotoxic reactions was 81 days from their onset (from 0 to 741 days).

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

Respiratory system very common – dyspnea; common – severe dyspnea.

Musculoskeletal system very common – myalgia; common – arthralgia.

General disorders very common – asthenia (including severe asthenia), generalized and localized pain syndrome, (including non-cardiac chest pain), fluid retention (reports of peripheral edema and weight gain and less frequently pleural and pericardial effusion, ascites). Peripheral edema usually started in the lower limbs and could progress to generalized with a weight gain of 3 kg or more. Fluid retention is cumulative (increases with repeated administrations of the drug). Fluid retention was not accompanied by acute episodes of oliguria or decreased blood pressure. Common – pronounced generalized and localized pain syndrome (including non-cardiac chest pain).

Severe forms of fluid retention. In patients treated with docetaxel monotherapy at a dose of 100 mg/m², the median cumulative dose until treatment discontinuation due to fluid retention was more than 1000 mg/m², and the median time to resolution of fluid retention was 16.4 weeks (from 0 to 42 weeks). In patients who received premedication, there was a delay in the onset of moderate or severe fluid retention (mean cumulative doses of docetaxel at which fluid retention was observed were 818.9 mg/m² with premedication, and 489.7 mg/m² without premedication), however, in some cases, fluid retention developed as early as during the first courses of therapy.

Local reactions common – reactions at the injection site were usually mild and manifested as hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage from the punctured vein, or vein swelling.

Taxotere^® in combination with other drugs

Taxotere^® in combination with doxorubicin

When using Taxotere^® in combination with doxorubicin compared with Taxotere^® monotherapy, the following adverse reactions were observed more frequently: neutropenia, including severe neutropenia; febrile neutropenia; thrombocytopenia, including severe thrombocytopenia; anemia; infections, including severe infections; nausea; vomiting; diarrhea, including severe diarrhea; constipation; stomatitis, including severe stomatitis; heart failure; alopecia. But allergic reactions; skin reactions, including severe; nail disorders, including severe; fluid retention, including severe; anorexia, neurosensory and neuromotor reactions, including severe forms; arterial hypotension; arrhythmias; increased liver transaminases, alkaline phosphatase, blood bilirubin levels; myalgia; asthenia were observed less frequently.

Taxotere^® in combination with doxorubicin and cyclophosphamide (TAC regimen)

When using this chemotherapy regimen compared with Taxotere^® monotherapy, the following adverse reactions occurred less frequently: neutropenia, severe anemia, febrile neutropenia, infections, allergic reactions, peripheral edema, neurosensory and neuromotor reactions, nail disorders, diarrhea, arrhythmia. But the following reactions occurred more frequently: non-severe anemia, thrombocytopenia, nausea, vomiting, stomatitis, taste disturbances, constipation, asthenia, arthralgia, alopecia. Additionally observed were: colitis, enterocolitis, large intestine perforation without fatal outcomes (in 2 out of 4 patients treatment discontinuation was required), acute myeloid leukemia, acute leukemia.

Prophylactic use of G-CSF reduced the incidence of neutropenia (by 60%) and grade 3-4 neutropenic infections.

Taxotere^® in combination with capecitabine

When using Taxotere^® in combination with capecitabine, adverse reactions from the digestive system occur more frequently (stomatitis, diarrhea, vomiting, constipation, abdominal pain, taste disturbances); arthralgia; severe thrombocytopenia and anemia; hyperbilirubinemia; palmar-plantar erythrodysesthesia syndrome (skin redness of the extremities – palms and soles – followed by swelling and desquamation); but less frequent development of severe neutropenia; alopecia; nail disorders, including onycholysis; asthenia; myalgia; decreased appetite and anorexia. Additionally observed were dyspepsia, dry mouth, sore throat, oral candidiasis, dermatitis, erythematous rash, nail discoloration, pyrexia, limb pain, pain, back pain, lethargy (drowsiness, sluggishness, stupor), dyspnea, cough, epistaxis, paresthesia, dizziness, headache, peripheral neuropathy, dehydration, lacrimation, weight loss.

Compared with younger patients, patients aged 60 years and older receiving the combination of Taxotere^® with capecitabine more frequently experience grade 3-4 toxicity.

Taxotere^® in combination with trastuzumab

In patients receiving the combination of Taxotere^® with trastuzumab (compared with Taxotere^® monotherapy) nausea, diarrhea, constipation, abdominal pain, taste disturbances, febrile neutropenia, arthralgia, anorexia, grade 4 toxicities, cases of heart failure were observed more frequently, especially in patients previously treated with anthracyclines as adjuvant therapy, but grade 3-4 neutropenia, asthenia, weakness, alopecia, nail disorders, skin rash, vomiting, stomatitis and myalgia were observed less frequently. Additionally observed were: lacrimation, conjunctivitis, mucosal inflammation, nasopharyngitis, pharyngeal and laryngeal pain, epistaxis, rhinorrhea, influenza-like illness, cough, pyrexia, chills, pain, chest pain, limb pain, back pain, bone pain, lethargy (drowsiness, sluggishness, stupor), insomnia, dyspnea, erythema, dyspepsia, paresthesia, headache, hypesthesia.

Compared with docetaxel monotherapy, an increase in the frequency of severe adverse reactions was observed.

Combination of Taxotere^® with cisplatin

When using this chemotherapy regimen compared with Taxotere^® monotherapy, thrombocytopenia, including grade 3-4 thrombocytopenia; anemia, including grade 3-4 anemia; nausea, including grade 3-4 nausea; grade 3-4 diarrhea; anorexia, including grade 3-4 diarrhea; injection site reactions occurred more frequently. However, neutropenia, including grade 3-4 neutropenia; infections; febrile neutropenia; allergic reactions; skin reactions; nail disorders; fluid retention; including grade 3-4 fluid retention; stomatitis, neurosensory neuropathy and to a lesser extent neuromotor neuropathy; alopecia; asthenia and myalgia were observed less frequently. Additionally observed: fever in the absence of infection, including grade 3-4; pain.

Combination of Taxotere^® with prednisolone or prednisone

When using Taxotere^® in combination with prednisolone or prednisone compared with Taxotere^® monotherapy, the frequency of the following adverse reactions was significantly reduced: anemia, including grade 3-4; infections; neutropenia, including grade 3-4; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory and neuromotor reactions; alopecia; rash; desquamation; nausea; diarrhea; stomatitis; vomiting; anorexia; myalgia; arthralgia; fluid retention. But taste disturbances and heart failure were observed more frequently. Additionally observed: epistaxis, cough, dyspnea, weakness, lacrimation.

Combination of the drug Taxotere^® with cisplatin and fluorouracil

When using this combination compared to Taxotere^® monotherapy, the following were observed more frequently: anemia, including grades 3-4; thrombocytopenia, including grades 3-4; febrile neutropenia; neutropenic infections (even with the use of G-CSF); nausea; vomiting; anorexia; stomatitis; diarrhea; esophagitis/dysphagia/pain on swallowing; but the following were observed less frequently: infections; allergic reactions; fluid retention; neurosensory and neuromotor reactions; myalgia; alopecia; rash; itching; nail disorders; skin desquamation; arrhythmias.

Additionally observed were: fever in the absence of infection; lethargy (drowsiness, sluggishness, stupor); hearing changes; dizziness; lachrymation; dry skin; heartburn; myocardial ischemia; accentuated venous pattern; cancer pain; conjunctivitis; weight loss).

Prophylactic administration of G-CSF reduces the incidence of febrile neutropenia and/or neutropenic infectious complications.

Data obtained from post-marketing use

Benign, malignant and unspecified neoplasms (including cysts and polyps) very rarely – acute myeloid leukemia and myelodysplastic syndrome associated with docetaxel, when used in combination with other chemotherapeutic agents and/or radiation therapy.

Hematopoietic system reports of bone marrow suppression and other hematological adverse reactions, development of DIC syndrome often in combination with sepsis or multiorgan failure.

Allergic reactions: rarely – anaphylactic shock, sometimes with fatal outcome. In patients who received premedication, these cases resulted in death very rarely.

Nervous system: rarely – seizures, transient loss of consciousness, sometimes developing during the drug infusion.

Organ of vision: rarely – lacrimation in combination with conjunctivitis (or without it), transient visual disturbances (flashes of light in the eyes, scotomas) (usually occurring during the drug infusion and combined with the development of hypersensitivity reactions, which usually disappeared after stopping the infusion) ; very rarely – lacrimal duct obstruction, leading to its rupture.

Organ of hearing: rarely – ototoxic effect of the drug, hearing impairment and/or hearing loss.

Cardiovascular system rarely – thromboembolism and myocardial infarction.

Respiratory system:acute respiratory distress syndrome, interstitial pneumonia, pulmonary fibrosis. With simultaneous radiation therapy – rare cases of radiation pneumonitis.

Digestive system rarely – dehydration as a consequence of gastrointestinal reactions, gastric or intestinal perforation, colitis, including ischemic; neutropenic enterocolitis; in rare cases – ileus (intestinal obstruction), intestinal obstruction, hepatitis (sometimes with fatal outcome, predominantly in patients with concomitant liver diseases).

Skin and subcutaneous tissues very rarely – cutaneous lupus erythematosus, bullous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (in some cases, the development of these conditions was facilitated by concomitant infections, other simultaneously taken medications and concomitant diseases); development of scleroderma-like changes was reported, usually preceded by lymphangiectatic edema.

General reactions: rarely – radiation recall phenomenon in a previously irradiated area, pulmonary edema.

Contraindications

• Baseline neutrophil count in peripheral blood <1500/µl;
• Severe liver function impairment;
• Pregnancy;
• Period of lactation (breastfeeding);
• Childhood and adolescence under 18 years;
• Hypersensitivity to docetaxel or polysorbate 80.

When using the drug Taxotere^® in combination with other drugs, contraindications to their use should also be considered.

Use with caution simultaneously with drugs that induce or inhibit cytochrome CYP3A isoenzymes, or metabolized with the participation of cytochrome CYP3A isoenzymes, such as cyclosporine, terfenadine, antifungal agents from the imidazole group (ketoconazole, itraconazole), erythromycin and troleandomycin, protease inhibitors (ritonavir).

Use in Pregnancy and Lactation

Taxotere^® is contraindicated for use during pregnancy and the period of lactation (breastfeeding).

Women and men of childbearing potential should avoid conception by using reliable methods of contraception during the use of the drug and for at least 3 months after its discontinuation.

Women in case of pregnancy during treatment should urgently inform their attending physician.

Since preclinical studies have shown that Docetaxel has genotoxic effects and may impair male fertility (ability to conceive), men receiving docetaxel treatment are recommended to refrain from conceiving a child during docetaxel treatment and for at least 6 months after the end of chemotherapy. Patients can be advised to perform sperm cryopreservation before treatment.

Use in Hepatic Impairment

Use of the drug is contraindicated in severe liver function impairment. For patients with liver function impairment with ALT or AST levels exceeding the upper limit of normal (ULN) by more than 1.5 times, or alkaline phosphatase level exceeding ULN by more than 2.5 times, the recommended dose is 75 mg/m².

Pediatric Use

The safety and efficacy of Taxotere^® use in children have not been sufficiently studied. There is limited experience with the use of Taxotere^® in children.

Geriatric Use

Compared to patients younger than 60 years, patients aged 60 years and older receiving combination chemotherapy Taxotere^® + capecitabine showed an increased frequency of treatment-related adverse reactions of grades 3 and 4, treatment-related serious adverse reactions and early treatment discontinuation due to adverse reactions.

There are limited data on the use of the combination of docetaxel with doxorubicin and cyclophosphamide in patients over 70 years of age.

In patients aged 65 years and older receiving treatment with Taxotere^® every 3 weeks for prostate cancer, the frequency of nail changes was ≥10% higher than in younger patients, and in patients 75 years and older, the frequency of fever, diarrhea, anorexia and peripheral edema was ≥10% higher than in younger patients.

When using the combination of docetaxel with cisplatin and fluorouracil, the following adverse reactions (all grades of severity) occurred in patients over 65 years of age ≥10% more often than in younger patients: lethargy (drowsiness, sluggishness, stupor), stomatitis, neutropenic infection. Therefore, patients over 65 years of age receiving this combination require careful monitoring.

Special Precautions

Neutropenia

Clinical blood tests should be carefully monitored in patients receiving therapy with Taxotere^®. If severe neutropenia (< 500/µl for 7 days) develops during a course of therapy with Taxotere^®, it is recommended to reduce the dose of the drug in subsequent cycles or conduct adequate symptomatic therapy. Treatment with Taxotere^® can be continued after the neutrophil count recovers to 1500/µl.

In case of G-CSF administration to patients receiving Taxotere^® in combination with cisplatin and fluorouracil, febrile neutropenia and/or neutropenic infections develop less frequently. Therefore, when using this combination, prophylactic administration of G-CSF is necessary to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection). The condition and laboratory parameters of patients receiving this chemotherapy regimen should be carefully monitored. If patients receive primary G-CSF prophylaxis (from the first cycle) when prescribing Taxotere^® in combination with doxorubicin and cyclophosphamide (TAC chemotherapy regimen), febrile neutropenia and/or neutropenic infection develop less frequently. Therefore, in adjuvant chemotherapy for breast cancer according to the TAC regimen, to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection), the issue of prophylactic G-CSF administration from the first cycle should be considered. Patients receiving TAC should be carefully monitored.

Hypersensitivity reactions

To detect hypersensitivity reactions, patients should be carefully observed, especially during the first and second infusions. The development of hypersensitivity reactions is possible in the very first minutes of Taxotere^® infusions, so when administering it, it is necessary to have medications and equipment for the treatment of arterial hypotension and bronchospasm. Mild manifestations of hypersensitivity (facial redness or localized skin reactions) do not require interruption of drug administration. Despite premedication, patients experienced severe hypersensitivity reactions, such as a marked decrease in blood pressure, bronchospasm or generalized rash/erythema and very rarely fatal anaphylactic reactions. The appearance of hypersensitivity reactions requires immediate cessation of Taxotere^® administration and appropriate therapy. Re-administration of Taxotere^® in patients who have experienced severe hypersensitivity reactions is prohibited.

Patients with hepatic insufficiency

In patients receiving docetaxel monotherapy at a dose of 100 mg/m² and having elevated serum transaminase activity (ALT and/or AST), more than 1.5 times ULN, in combination with an increase in serum alkaline phosphatase level more than 2.5 times above 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. In this regard, in such patients with elevated liver function parameters, the recommended dose of Taxotere^® is 75 mg/m².

Liver function tests should be performed before starting treatment and before each subsequent cycle of therapy with Taxotere^®. In patients with elevated bilirubin levels and/or elevated ALT and AST activity (>3.5 ULN) in combination with an increase in alkaline phosphatase level >6 ULN, the use of Taxotere^® is not recommended. Currently, there are no data regarding the use of the drug Taxotere^® in combination with other drugs in patients with liver function impairment.

Fluid retention

Careful monitoring of patients with severe fluid retention is necessary: with pleural effusion, pericardial effusion or ascites. If edema appears – restrict salt and fluid intake and prescribe diuretics.

Leukemia

When using the combination of Taxotere^® with doxorubicin and cyclophosphamide for operable breast cancer, the risk of developing delayed myelodysplasia and/or myeloid leukemia requires regular hematological control.

Heart failure

In patients receiving Taxotere^® in combination with trastuzumab for metastatic breast cancer with tumor HER2 overexpression, especially after anthracycline-containing chemotherapy (doxorubicin or epirubicin), heart failure may develop, it can be moderate or severe and lead to death. When a patient is indicated for treatment with Taxotere^® in combination with trastuzumab, she should undergo a baseline cardiac examination. Cardiac function should be monitored every 3 months to detect developing heart failure. The prescribing information for trastuzumab should be consulted.

Elderly patients

Compared to patients younger than 60 years, patients aged 60 years and older receiving combination chemotherapy Taxotere^® + capecitabine showed an increased frequency of treatment-related adverse reactions of grades 3 and 4, treatment-related serious adverse reactions and early treatment discontinuation due to adverse reactions.

There are limited data on the use of the combination of docetaxel with doxorubicin and cyclophosphamide in patients over 70 years of age.

In patients aged 65 years and older receiving treatment with Taxotere^® every 3 weeks for prostate cancer, the frequency of nail changes was ≥10% higher than in younger patients, and in patients 75 years and older, the frequency of fever, diarrhea, anorexia and peripheral edema was ≥10% higher than in younger patients.

When using the combination of docetaxel with cisplatin and fluorouracil, the following adverse reactions (all grades of severity) occurred in patients over 65 years of age ≥10% more often than in younger patients: lethargy (drowsiness, sluggishness, stupor), stomatitis, neutropenic infection. Therefore, patients over 65 years of age receiving this combination require careful monitoring.

Neurotoxicity

Development of severe sensory neuropathy requires a reduction in the dose of Taxotere^®.

Ethanol content

The drug Taxotere^® contains ethanol at a concentration of 50% by volume (i.e., up to 0.385 g (0.5 ml) of anhydrous ethanol in a 20 mg/1 ml vial, up to 1.58 g (2 ml) of anhydrous ethanol in an 80 mg/4 ml vial and up to 3.16 g (4 ml) of anhydrous ethanol in a 160 mg/8 ml vial). This should be taken into account when using the drug in patients with alcoholism and patients at risk (patients with liver diseases and epilepsy).

Precautions for handling the drug Taxotere^®

As with other potentially toxic substances, caution should be exercised when using the drug Taxotere^® and preparing solutions. The use of gloves is recommended. If the concentrate of the drug Taxotere^® or the infusion solution of the drug Taxotere^® comes into contact with the skin, it should be immediately washed thoroughly with soap and water. If the concentrate or infusion solution of the drug Taxotere^® comes into contact with mucous membranes, they should be immediately rinsed thoroughly with water.

Effect on ability to drive vehicles and mechanisms

Special studies have not been conducted. However, the development of adverse reactions from the nervous system, organ of vision, gastrointestinal tract, as well as the presence of ethanol in the drug may lead to a decrease in the speed of psychomotor reactions and attention. In this regard, patients are not recommended to drive a car and engage in other potentially hazardous activities during treatment with Taxotere^®.

Overdose

There are a small number of reports of overdose.

Symptoms : suppression of bone marrow function, peripheral neurotoxicity and mucositis (inflammation of mucous membranes).

Treatment: currently, there is no known antidote for docetaxel. In case of overdose, hospitalization in a specialized department and careful monitoring of vital organs is required. G-CSF should be prescribed as soon as possible. If necessary – symptomatic therapy.

Drug Interactions

In vitro studies have shown that biotransformation of the drug may change with simultaneous use of substances that induce or inhibit cytochrome CYP3A isoenzymes, or metabolized (competitive inhibition) with the participation of cytochrome CYP3A, such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, caution should be exercised when prescribing such drugs simultaneously, taking into account the possibility of a pronounced interaction.

When using docetaxel simultaneously with inhibitors of the CYP3A4 isoenzyme, such as antifungal drugs from the imidazole group (ketoconazole, itraconazole) and protease inhibitors (ritonavir), caution is necessary.

Studies conducted in patients simultaneously receiving Docetaxel and ketoconazole showed that the clearance of docetaxel decreased by 50%, apparently due to the fact that the main pathway of docetaxel metabolism is its metabolism with the participation of the CYP3A4 isoenzyme. In this case, even with the use of docetaxel in lower doses, its tolerability may worsen.

The pharmacokinetics of docetaxel in the presence of prednisolone was studied in patients with metastatic prostate cancer. Although Docetaxel is metabolized with the participation of 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.

Docetaxel is characterized by a high degree of binding to plasma proteins (>95%). In vitro, drugs that are strongly bound to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and sodium valproate, do not disrupt the binding of docetaxel to plasma proteins. Dexamethasone also does not affect the degree of binding of docetaxel to plasma proteins. Docetaxel does not affect the binding of digoxin to plasma proteins.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not change when used together.

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

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature from 2°C (35.6°F) to 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

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.