Docetaxel
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOCETAXEL (DOCETAXEL)
Composition:
Active substance: docetaxel;
1 ml of the preparation contains 40 mg of docetaxel;
Excipients: citric acid anhydrous, polysorbate.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: viscous, clear liquid ranging from colorless to light yellow.
Pharmacotherapeutic group.
Antineoplastic agents. Plant alkaloids and other natural agents. Taxanes. Docetaxel. ATC code L01C D02.
Pharmacological Properties
Pharmacodynamics
Docetaxel is an antineoplastic agent whose mechanism of action is based on promoting the accumulation of tubulin in cellular microtubules and preventing their disassembly, leading to a significant reduction in the level of free tubulin. Binding of docetaxel to microtubules does not alter the number of protofilaments.
In vitro studies have demonstrated that docetaxel disrupts the microtubular network, which plays a crucial role in essential cellular functions both during mitosis and interphase.
Clonogenic analysis in vitro showed cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against cells freshly isolated from human tumors. Docetaxel achieves significant concentrations in interstitial fluid and provides high cell survival duration. Furthermore, docetaxel exhibits activity against some (although not all) cell lines expressing P-glycoprotein encoded by the multidrug resistance gene. In vivo studies revealed that the effect of docetaxel is independent of the administration schedule and demonstrates a broad spectrum of antitumor activity against both experimental murine tumors and implanted human tumors.
Pharmacokinetics
The pharmacokinetics of docetaxel were studied in phase I trials in cancer patients receiving doses of 20–115 mg/m². The pharmacokinetic profile of docetaxel is dose-independent and fits a three-compartment pharmacokinetic model, with half-lives for the α-, β-, and γ-phases of 4 minutes, 36 minutes, and 11.1 hours, respectively. The prolonged half-life in the final phase is partly due to relatively slow efflux from the peripheral compartment. After administration of a 100 mg/m² dose infused over 1 hour, the mean peak plasma concentration of the drug was 3.7 µg/mL, with a corresponding AUC of 4.6 µg/mL/hour. Mean values for total clearance and volume of distribution at steady state were 21 L/m²/hour and 113 L, respectively. Inter-individual variability in total docetaxel clearance reached approximately 50%. Docetaxel is more than 95% bound to plasma proteins.
A study using radiolabeled 14C-docetaxel was conducted in three cancer patients. Following oxidative metabolism of the tert-butyl ester group by cytochrome P450, docetaxel was excreted both in urine and feces over 7 days; urinary excretion accounted for 6% and fecal excretion for 75% of the administered radioactivity. Approximately 80% of the isotope present in feces was excreted within the first 48 hours as one major inactive metabolite, three minor metabolites, and a very small amount of unchanged drug.
Population pharmacokinetic analysis of docetaxel was performed in 577 patients. Pharmacokinetic parameters estimated using this model were very similar to those obtained in phase I studies. Neither age nor gender of patients influenced the pharmacokinetics of the drug. In a small number of patients (n = 23) with mild to moderate hepatic impairment based on biochemical blood tests (ALT and AST levels ≥1.5 times above the upper limit of normal (ULN) together with alkaline phosphatase levels ≥2.5 times above ULN), total drug clearance was reduced by an average of 27%. Docetaxel clearance was unchanged in patients with mild or moderate fluid retention; data on docetaxel clearance in patients with severe fluid retention are not available.
When used in combination with other drugs, docetaxel did not affect the clearance of doxorubicin or plasma levels of doxorubicin (and its metabolites). The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were not altered when administered concurrently.
A phase I clinical study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect of capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC), nor any effect of docetaxel on the pharmacokinetics of the corresponding capecitabine metabolite, 5’-DFUR (5'-deoxy-5-fluorouridine).
The clearance of docetaxel administered in combination with cisplatin was similar to that observed during docetaxel monotherapy. The pharmacokinetic profile of cisplatin administered immediately after docetaxel infusion was similar to that observed during cisplatin monotherapy.
Combined administration of docetaxel, cisplatin, and 5-fluorouracil in 12 patients with solid tumors did not alter the pharmacokinetics of any of these medicinal products.
The effect of prednisone on the pharmacokinetics of docetaxel after standard premedication with dexamethasone was studied in 42 patients. No effect of prednisone on the pharmacokinetics of docetaxel was observed.
Clinical characteristics.
Indications.
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for adjuvant therapy in patients with:
- operable breast cancer with lymph node involvement;
- operable breast cancer without lymph node involvement.
Adjuvant therapy should be administered to patients with operable breast cancer without lymph node involvement if they meet internationally accepted criteria for chemotherapy in the primary treatment of early-stage breast cancer.
Docetaxel in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.
Docetaxel as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after prior cytotoxic therapy that included an anthracycline or an alkylating agent.
Docetaxel in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with HER-2 overexpression in tumor cells who have not previously received chemotherapy for metastatic disease.
Docetaxel in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after prior therapy that included an anthracycline.
Non-small cell lung cancer
Docetaxel is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.
Docetaxel in combination with cisplatin is indicated for the treatment of patients with inoperable locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
Prostate cancer
Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docetaxel in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic adenocarcinoma of the stomach, including adenocarcinoma of the gastroesophageal junction, who have not previously received chemotherapy for metastatic disease.
Head and neck cancer
Docetaxel in combination with cisplatin and 5-fluorouracil is indicated for induction therapy in patients with locally advanced squamous cell carcinoma of the head and neck.
Contraindications.
- Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
- Baseline neutrophil count <1500 cells/mm³.
- Severe hepatic impairment (see sections "Special precautions for use" and "Method of administration and dosage").
- Also consider contraindications associated with other medicinal products used in combination with docetaxel.
Special safety precautions.
Docetaxel should be administered only in departments specialized in the use of potentially toxic anticancer agents and under the supervision of a qualified physician experienced in chemotherapy for cancer treatment.
Handling this potentially toxic substance requires healthcare personnel to follow all precautionary measures to ensure protection of the worker and the surrounding environment.
Preparation of injectable solutions of potentially toxic substances should be performed by an experienced specialist familiar with the use of these medicinal products, under conditions ensuring environmental protection, especially for personnel handling these drugs. A specially designated area must be available for preparatory procedures. Smoking, eating, or drinking are prohibited in this designated area.
Personnel must be provided with appropriate protective equipment, such as sterile disposable gloves, waste containers, and disposal bags.
Special caution is required when handling patient excreta and vomitus.
Pregnant individuals should be advised to avoid handling potentially toxic substances.
Any damaged packaging must be handled according to these precautionary measures and considered contaminated waste.
In case of contact of docetaxel concentrate, reconstituted solution, or infusion solution with skin or mucous membranes, the affected area should be immediately and thoroughly rinsed with soap and water/water.
Disposal
Any unused portions of the medicinal product and all materials used for reconstitution and administration of docetaxel must be destroyed in accordance with standard procedures for disposal of potentially toxic waste, as per applicable regulations for toxic waste disposal.
Preparation of infusion solution.
Preparation of intermediate solution
To obtain the required patient dose, several vials of Docetaxel concentrate for infusion solution may be needed.
- Following aseptic techniques, select the required number of Docetaxel vials and solvent – 13% alcohol (if vials have been stored in the refrigerator, allow them to reach room temperature).
- Using a calibrated syringe with a needle and following aseptic techniques, withdraw the entire solvent from the solvent vial (approximately 1.8 ml for the 0.5 ml Docetaxel concentrate vial and approximately 7.1 ml for the 2 ml Docetaxel concentrate vial), which is supplied in the same package as the Docetaxel concentrate.
- Inject the solvent into the appropriate vial containing Docetaxel concentrate.
- After removing the syringe with needle from the vial, invert the vial and mix the resulting solution of solvent and concentrate for 45 seconds. DO NOT SHAKE! The resulting intermediate solution contains 10 mg/ml of docetaxel.
- Leave the vial with the prepared solution at room temperature for 5 minutes, then check for homogeneity and clarity of the solution (the presence of foam even after 5 minutes is normal due to the presence of polysorbate 80 in the formulation).
- From a microbiological standpoint, reconstitution/dilution of the medicinal product should be performed under controlled and aseptic conditions, and the intermediate solution containing 10 mg/ml docetaxel should be used immediately. However, it has been demonstrated that the intermediate solution, when prepared according to recommendations, remains physically and chemically stable for up to 8 hours when stored at 2°C to 8°C or at room temperature.
Preparation of infusion solution
When preparing the infusion solution, remember that 1 ml of the prepared intermediate solution contains 10 mg of docetaxel. Using a calibrated syringe with a needle, the required amount of intermediate solution should be injected in a single injection (at once) into a 250 ml infusion bag or bottle containing 5% glucose solution or 0.9% sodium chloride solution for injection to obtain an infusion solution with a concentration of 0.3 to 0.74 mg/ml. If the required dose exceeds 190 mg of docetaxel, a larger volume of infusion fluid should be used so that the docetaxel concentration does not exceed 0.74 mg/ml.
Gently mix the contents of the infusion bag or bottle by swirling.
The infusion solution should be used within the next 4 hours by 1-hour infusion under aseptic conditions, under normal room lighting and at room temperature.
The intermediate solution or infusion solution, like other parenteral preparations, should be visually inspected before administration. If precipitate is observed, the solution must be discarded.
Docetaxel infusion solution is a supersaturated solution and may crystallize over time. If crystals appear, the solution must not be used and should be discarded.
Interaction with other medicinal products and other types of interactions.
In vitro studies have demonstrated that docetaxel metabolism may be altered when co-administered with drugs that induce, inhibit, or are metabolized by cytochrome P450-3A (and thus may cause competitive inhibition), such as cyclosporine, terfenadine, ketoconazole, erythromycin, and troleandomycin. Therefore, these drugs should be used concomitantly with caution, considering the risk of clinically significant interactions.
Docetaxel is highly bound to plasma proteins (>95%). Although potential interactions of this drug with other drugs have not formally been studied in vivo, in vitro data indicate that drugs with high plasma protein binding (such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) do not impair docetaxel binding to plasma proteins. In addition, dexamethasone does not impair docetaxel binding to plasma proteins. Docetaxel does not affect protein binding of digoxin.
The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide are not altered when these drugs are administered concomitantly. Limited data from a single uncontrolled study suggest a possible interaction between docetaxel and carboplatin. When these drugs are used in combination, carboplatin clearance was nearly 50% higher than levels observed during carboplatin monotherapy in previous studies.
The pharmacokinetics of docetaxel when co-administered with prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolized by the CYP3A4 enzyme, and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Docetaxel should be administered with caution to patients taking drugs that potentially inhibit CYP3A4 (including protease inhibitors such as ritonavir; antifungal azoles such as ketoconazole or itraconazole). Drug interaction studies in patients receiving ketoconazole and docetaxel showed that ketoconazole reduced docetaxel clearance by half, possibly because CYP3A4 plays a key role in the main (sole) metabolic pathway of docetaxel. This may lead to worsened tolerability of docetaxel, even at lower doses.
The alcohol contained in docetaxel may alter the clinical effects of other medicinal products.
Special precautions for use.
In patients with breast cancer or non-small cell lung cancer, in the absence of contraindications, premedication with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days, starting 1 day before administration of docetaxel, may reduce the frequency and severity of hypersensitivity reactions. In patients with prostate cancer, premedication is performed with oral dexamethasone 8 mg administered 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.
Hematological changes during treatment with the drug
The most common adverse reaction during docetaxel therapy is neutropenia. The lowest neutrophil levels were observed on average on day 7 of treatment, although the time to reach the nadir of neutropenia may be shorter in patients who have previously received multiple courses of anticancer therapy. All patients receiving docetaxel require careful monitoring of peripheral blood counts. Docetaxel may be administered again in a new chemotherapy cycle only after neutrophil counts have recovered to ≥1500 cells/μL following completion of the previous cycle.
If severe neutropenia (<500 cells/μL for 7 days or longer) develops during docetaxel treatment, dose reduction of the drug in the next chemotherapy cycle or appropriate symptomatic treatment is recommended.
In patients receiving combination therapy with docetaxel, cisplatin, and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infections occurred less frequently when G-CSF was administered. Patients receiving TCF therapy should receive prophylactic G-CSF to reduce the risk of complicated neutropenias (febrile neutropenia, prolonged neutropenia, or neutropenic infections). Patients receiving TCF therapy must be under close monitoring.
In patients receiving docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred less frequently when primary prophylaxis with G-CSF was used. For patients receiving adjuvant TAC therapy for breast cancer, primary prophylaxis with G-CSF should be considered to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, or neutropenic infection). Patients receiving TAC therapy must be under close monitoring (see sections "Dosage and administration" and "Adverse reactions").
Hypersensitivity reactions
Patients must be carefully monitored for possible hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may develop within minutes after the start of docetaxel infusion; therefore, all necessary measures for treatment of arterial hypotension and bronchospasm must be readily available. A mild hypersensitivity reaction with minor symptoms such as flushing or localized skin reactions does not require interruption of therapy. However, severe reactions such as marked arterial hypotension, bronchospasm, or generalized rash/erythema, and very rarely anaphylaxis with fatal outcome, require immediate discontinuation of docetaxel infusion and initiation of appropriate therapy. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction.
Skin reactions
Cases of localized erythema of the skin of the extremities (on palms and soles), accompanied by edema and subsequent epidermal desquamation, have been observed. Cases of severe symptoms, such as widespread skin rash with subsequent epidermal desquamation, requiring interruption or complete discontinuation of docetaxel therapy, have also been reported.
Fluid retention
Patients with significant fluid retention, such as pleural effusion, pericardial effusion, or ascites, must be carefully monitored.
Respiratory disorders. Cases of acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis, and respiratory failure, which may be fatal, have been reported. Cases of radiation pneumonitis have been observed in patients who received concomitant radiotherapy.
In the event of new pulmonary symptoms or worsening of existing symptoms, close monitoring, urgent evaluation, and appropriate treatment are required. Docetaxel therapy should be discontinued until diagnosis is established. Early supportive therapy may help improve the patient's condition. The benefit of resuming docetaxel therapy should be carefully evaluated.
Patients with impaired liver function
Patients who, during monotherapy with docetaxel 100 mg/m², have elevated levels of transaminases (ALT and/or AST) more than 1.5 times above ULN and alkaline phosphatase more than 2.5 times above ULN, are at higher risk of developing severe adverse reactions, including fatal outcomes due to drug toxicity (e.g., due to sepsis or fatal gastrointestinal bleeding), febrile neutropenia, infections, thrombocytopenia, stomatitis, and asthenia. Therefore, the recommended dose of docetaxel for patients with elevated liver enzymes is 75 mg/m²; liver enzyme levels must be assessed before initiation of treatment and before each new chemotherapy cycle.
For patients with elevated serum bilirubin (>ULN) and/or ALT and AST more than 3.5 times above ULN, accompanied by alkaline phosphatase levels more than 6 times above ULN, dose reduction is not recommended, but docetaxel should not be administered at all unless absolutely necessary.
In the pivotal clinical trial of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated levels of ALT and/or AST >1.5 times ULN, alkaline phosphatase >2.5 times ULN, and bilirubin >ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended for such patients, and the drug should not be administered to this patient group unless absolutely necessary. There are no data on the use of docetaxel in combination therapy for other indications in patients with impaired liver function.
Patients with impaired renal function
There are no data on treatment with docetaxel in patients with severe renal impairment.
Nervous system
The occurrence of severe peripheral neurotoxic effects requires dose reduction of the drug.
Cardiotoxic effects
In patients receiving docetaxel in combination with trastuzumab, especially if anthracyclines (doxorubicin or epirubicin) were used in prior chemotherapy, cases of heart failure have been observed. This heart failure may be moderate or severe and is associated with a high risk of fatal outcome. If docetaxel must be used in combination with trastuzumab, cardiovascular status should be evaluated before initiation of therapy. During treatment with these drugs, cardiac function must be monitored regularly (e.g., every 3 months) to detect patients who may develop cardiac dysfunction. More detailed information is provided in the "General characteristics" section of trastuzumab.
Disorders of the visual organs. Cases of crystalline macular edema (CME) have been observed in patients receiving docetaxel. Patients with visual disturbances require urgent and complete ophthalmological examination. If CME is diagnosed, docetaxel must be discontinued and appropriate treatment initiated (see section "Adverse reactions").
Other warnings
During treatment and for at least six months after completion of therapy, effective contraceptive methods should be used.
Concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Additional warnings for the use of docetaxel in adjuvant therapy of breast cancer
Complicated neutropenia
In patients who develop complicated neutropenia (prolonged neutropenia, febrile neutropenia, or infections), the use of G-CSF and dose reduction of docetaxel should be considered.
Gastrointestinal tract reactions
Symptoms such as abdominal pain, tenderness, and abdominal pain on palpation, fever, and diarrhea (with or without neutropenia) may indicate severe gastrointestinal toxicity and require immediate evaluation and treatment.
Congestive heart failure
Patients must be carefully monitored during treatment and follow-up for signs of congestive heart failure. It has been demonstrated that patients receiving TAC therapy for breast cancer with regional lymph node involvement have an increased risk of developing congestive heart failure during the first year of treatment (see sections "Pharmacological properties" and "Adverse reactions").
Leukemia
The risk of delayed manifestation of myelodysplasia or development of acute myeloid leukemia in patients treated with the TAC regimen necessitates monitoring of key hematological parameters during follow-up.
Patients with metastases in ≥4 lymph nodes
During interim analysis, the benefit-risk ratio of TAC for patients with metastases in ≥4 lymph nodes has not been fully established.
Older patients
Safety data analysis in patients aged 60 years and older receiving the combination of docetaxel + capecitabine showed increased incidence of treatment-related adverse events of grade 3-4 severity, serious treatment-related adverse events, and early discontinuation of the drug due to adverse events compared to patients under 60 years of age.
There are limited data on the use of docetaxel in combination with doxorubicin and cyclophosphamide in patients aged 70 years and older.
In one study of prostate cancer among 333 patients receiving docetaxel every three weeks, 209 patients were aged 65 years or older and 68 patients were aged 75 years or older. When treating with docetaxel every three weeks, patients over 65 years of age had a >10% higher incidence of treatment-related nail changes compared to younger patients. The incidence of treatment-related fever, diarrhea, anorexia, and peripheral edema was ≥10% higher in patients over 75 years of age compared to patients under 65 years of age.
In a study of gastric adenocarcinoma among 300 patients (221 patients in the phase III part and 79 patients in the phase II part) receiving docetaxel in combination with cisplatin and 5-fluorouracil, 74 patients were aged 65 years or older and 4 patients were aged 75 years or older. The incidence of severe adverse events was higher in elderly patients compared to younger patients. The incidence of adverse events (all grades) such as fatigue, stomatitis, and neutropenic infections was over 10% higher in patients over 65 years of age compared to younger patients.
Careful monitoring is required for elderly patients receiving TCF therapy.
Warnings regarding excipients
After reconstitution, this medicinal product contains ethanol. This may be harmful for patients suffering from alcoholism, and when treating children, pregnant or breastfeeding women, and patients belonging to high-risk groups, such as those with liver disease or epilepsy.
The potential impact of the drug on the central nervous system should be considered.
The amount of alcohol contained in this medicinal product may influence the effects of other medicinal products.
The amount of alcohol contained in this medicinal product may affect the ability to drive or operate machinery.
Preparation of the drug for intravenous administration
Detailed information on the preparation of the infusion solution is provided in the section "Special precautions for handling."
One vial is intended for single use and should be used immediately after opening. If the drug is not used immediately, storage duration and conditions must be monitored by the person handling it.
Use during pregnancy or breastfeeding.
Pregnancy
There are no data on the use of docetaxel in pregnant women. In animal studies, docetaxel showed embryotoxic and fetotoxic effects; in addition, in rats, the drug caused reduced fertility. Like other cytotoxic medicinal products, docetaxel may be harmful to the fetus if administered during pregnancy. Therefore, docetaxel should not be administered during pregnancy except in cases of absolute necessity. Women of reproductive age receiving docetaxel should be advised to avoid pregnancy and to inform their physician immediately if pregnancy occurs.
Effective contraceptive methods should be used throughout the entire treatment period.
Period of breastfeeding
Docetaxel is a lipophilic substance, but it is unknown whether it passes into breast milk. Therefore, considering the risk of adverse effects in infants who are breastfed, breastfeeding should be discontinued during docetaxel treatment.
Fertility
In preclinical studies, docetaxel showed genotoxic effects and could affect fertility in male experimental animals. Therefore, men receiving docetaxel are advised to use appropriate contraceptive methods during treatment and for 6 months after its completion. They should seek consultation regarding sperm cryopreservation before starting treatment.
Ability to affect reaction speed when driving or operating machinery.
Studies on the effect of docetaxel on the ability to drive or operate machinery have not been conducted.
The ethanol contained in the prepared docetaxel solution may impair patients' ability to drive or operate machinery.
Method of Administration and Dosage
The use of docetaxel should be restricted to departments specializing in cytotoxic chemotherapy. Docetaxel must be prescribed exclusively by a physician experienced in the use of anticancer chemotherapy.
Recommended Doses
For the treatment of breast cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer, premedication with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days may be used if not contraindicated; the first dose should be administered one day prior to the first docetaxel infusion (see section "Special Instructions"). To reduce the risk of hematological toxicity associated with docetaxel, prophylactic administration of granulocyte colony-stimulating factor (G-CSF) may be considered.
For the treatment of prostate cancer, the recommended premedication regimen includes oral dexamethasone, taking into account the concomitant use of prednisone or prednisolone. It should include administration of 8 mg of dexamethasone 12 hours, 3 hours, and 1 hour before the start of the first docetaxel infusion (see section "Special Instructions").
Docetaxel is administered by intravenous infusion over 1 hour every 3 weeks.
Breast Cancer
For adjuvant therapy of operable breast cancer, with or without lymph node involvement, the recommended dose of docetaxel is 75 mg/m², administered over 1 hour after doxorubicin (50 mg/m²) and cyclophosphamide (500 mg/m²) every 3 weeks for a total of 6 cycles (see also subsection "Dose Modifications During Treatment").
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of docetaxel as monotherapy is 100 mg/m². As first-line therapy, docetaxel 75 mg/m² is used in combination with doxorubicin (50 mg/m²).
In combination with trastuzumab (administered weekly), docetaxel is given at the recommended dose of 100 mg/m² every 3 weeks. In the pivotal clinical trial with docetaxel, the first infusion of the drug was administered the day after the first dose of trastuzumab. Subsequently, doses of docetaxel were given immediately after completion of trastuzumab infusion, provided the patient tolerated the most recent trastuzumab infusion well. Dosing and administration instructions for trastuzumab are described in the "Summary of Product Characteristics" for trastuzumab.
In combination with capecitabine, docetaxel is administered at the recommended dose of 75 mg/m² every 3 weeks; capecitabine is administered at a dose of 1250 mg/m² twice daily (no later than 30 minutes after meals) for 2 weeks followed by a 1-week break. Details on dose calculation of capecitabine according to body surface area are provided in the "Summary of Product Characteristics" for capecitabine.
Non-Small Cell Lung Cancer
For the treatment of patients with non-small cell lung cancer who have not previously received chemotherapy, docetaxel is recommended at a dose of 75 mg/m², followed immediately by cisplatin 75 mg/m² administered over 30–60 minutes. For patients in whom prior platinum-based chemotherapy has failed, monotherapy with docetaxel at a dose of 75 mg/m² is recommended.
Prostate Cancer
The recommended dose of docetaxel is 75 mg/m². Prednisone or prednisolone 5 mg orally twice daily should be administered continuously (see section "Pharmacodynamic Properties").
Gastric Adenocarcinoma
The recommended dose of docetaxel is 75 mg/m² administered by intravenous infusion over 1 hour, immediately followed by cisplatin 75 mg/m² infused over 1–3 hours (both drugs administered only on day 1 of the cycle); immediately after completion of cisplatin infusion, continuous infusion of 5-fluorouracil (750 mg/m²/day) is initiated and continued for 5 days. This cycle is repeated every 3 weeks. Patients should receive premedication with antiemetics and adequate hydration (sufficient fluid intake) during cisplatin administration. To reduce the risk of hematological toxicity of chemotherapy, prophylactic use of G-CSF is recommended (see also subsection "Dose Modifications During Treatment").
Head and Neck Cancer
Patients should receive premedication with antiemetic agents and appropriate hydration (before and after cisplatin administration). To reduce the risk of hematological toxicity of chemotherapy, prophylactic use of G-CSF may be considered. All patients enrolled in clinical trials TAX 323 and TAX 324 who were assigned to docetaxel-containing treatment groups received antibiotics for prophylaxis.
- Induction chemotherapy followed by radiotherapy (based on data from study TAX 323).
For induction chemotherapy of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m² administered by intravenous infusion over 1 hour, immediately followed on day 1 of the cycle by cisplatin 75 mg/m² infused over 1–3 hours; immediately after completion of cisplatin infusion, continuous infusion of 5-fluorouracil (750 mg/m²/day) is initiated and continued for 5 days. This regimen is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should receive radiotherapy.
- Induction chemotherapy followed by chemoradiotherapy (based on data from study TAX 324).
For induction chemotherapy of locally advanced SCCHN (technically unresectable, with low likelihood of surgical intervention or requiring an organ-preserving approach), the recommended dose of docetaxel is 75 mg/m² administered by intravenous infusion over 1 hour, immediately followed on day 1 of the cycle by cisplatin 100 mg/m² infused over 0.5–3 hours; immediately after completion of cisplatin infusion, continuous infusion of 5-fluorouracil (1000 mg/m²/day) is initiated and continued for 4 days. This regimen is repeated every 3 weeks for 5 cycles. After chemotherapy, patients should receive chemoradiotherapy.
Details on dose adjustments for cisplatin and 5-fluorouracil are provided in their respective "Summary of Product Characteristics."
Dose Modifications During Treatment
General Principles
Docetaxel should be administered only if the neutrophil count is ≥1500 cells/mm³. If febrile neutropenia develops during docetaxel therapy, or if the neutrophil count remains <500 cells/mm³ for more than one week, or if severe acute or cumulative skin reactions occur, or if severe peripheral neuropathy develops, the docetaxel dose should be reduced from 100 to 75 mg/m² and/or from 75 to 60 mg/m². If such reactions persist at the 60 mg/m² dose level, the drug should be discontinued.
Adjuvant Therapy of Breast Cancer
For patients receiving adjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide (TAC regimen), primary prophylaxis with G-CSF should be considered. Patients who develop febrile neutropenia and/or neutropenic infection should have the docetaxel dose reduced to 60 mg/m² in all subsequent treatment cycles (see sections "Special Instructions" and "Side Effects"). Patients who develop grade 3 or 4 stomatitis should have the docetaxel dose reduced to 60 mg/m².
In Combination with Cisplatin
For patients who, during the previous cycle with docetaxel 75 mg/m² in combination with cisplatin, had a nadir leukocyte count <25,000 cells/mm³, for patients who developed febrile neutropenia during docetaxel therapy, and for patients who experienced serious non-hematological toxicities, the docetaxel dose should be reduced to 65 mg/m² in subsequent cycles. Details on cisplatin dose adjustments are provided in the "Summary of Product Characteristics" for cisplatin.
In Combination with Capecitabine
- Details on capecitabine dose adjustments are provided in the "Summary of Product Characteristics" for capecitabine.
- For patients who develop grade 2 toxicity that persists at the time the next docetaxel/capecitabine dose is due, treatment should be withheld until toxicity resolves to grade 0–1, then resumed at 100% of the initial dose.
- For patients who experience a second occurrence of grade 2 toxicity at any time during the treatment cycle, or a first occurrence of grade 3 toxicity, therapy should be withheld until toxicity resolves to grade 0–1, then resumed with docetaxel at a dose of 55 mg/m².
- If further toxicity occurs or if grade 4 toxicity develops, docetaxel treatment should be discontinued.
Details on trastuzumab dose adjustments are provided in the "Summary of Product Characteristics" for trastuzumab.
In Combination with Cisplatin and 5-Fluorouracil
If a patient develops an episode of febrile neutropenia, prolonged neutropenia, or infection despite G-CSF administration, the docetaxel dose should be reduced from 75 to 60 mg/m². If further episodes of complicated neutropenia occur, the dose should be further reduced from 60 to 45 mg/m². If a patient develops grade IV thrombocytopenia, the docetaxel dose should be reduced from 75 to 60 mg/m². The next treatment cycle should not be repeated until the neutrophil count recovers to >1500 cells/mm³ and platelet count to >100,000 cells/mm³. If toxicities persist despite these measures, docetaxel therapy should be discontinued (see section "Special Instructions").
Table 1
Recommended dose modification measures for patients receiving the combination of docetaxel, cisplatin, and 5-fluorouracil:
| Toxicity manifestations |
Dose adjustments |
| Grade 3 diarrhea |
First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: reduce the dose of docetaxel by 20%. |
| Grade 4 diarrhea |
First episode: reduce the doses of docetaxel and 5-fluorouracil by 20%. Second episode: discontinue treatment. |
| Stomatitis or other mucosal inflammatory processes, grade 3 |
First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: discontinue 5-fluorouracil for all subsequent treatment cycles. Third episode: reduce the dose of docetaxel by 20%. |
| Stomatitis or other mucosal inflammatory processes, grade 3 |
First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: discontinue 5-fluorouracil for all subsequent treatment cycles. Third episode: reduce the dose of docetaxel by 20%. |
| Stomatitis or other mucosal inflammatory processes, grade 4 |
First episode: discontinue 5-fluorouracil for all subsequent treatment cycles. Second episode: reduce the dose of docetaxel by 20%. |
Specific dose adjustments for cisplatin and 5-fluorouracil are described in the respective "Summary of Product Characteristics".
In the pivotal clinical trial of docetaxel, patients who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infectious diseases) during therapy with G-CSF were advised to receive prophylactic G-CSF (e.g., from day 6 to day 15 of the cycle) in all subsequent chemotherapy cycles.
Special patient groups
Patients with hepatic impairment
According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel is 75 mg/m² for patients with elevated transaminase levels (ALT and/or AST) greater than 1.5 times the ULN and alkaline phosphatase levels greater than 2.5 times the ULN. For patients with increased serum bilirubin (>ULN) and/or ALT and AST levels greater than 3.5 times the ULN, accompanied by alkaline phosphatase levels greater than 6 times the ULN, dose reduction is not recommended; however, docetaxel should not be administered at all unless absolutely necessary.
In the pivotal clinical trial of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated levels of ALT and/or AST greater than 1.5 times the ULN, alkaline phosphatase greater than 2.5 times the ULN, and bilirubin greater than ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended for such patients. The drug should not be administered to these patients unless absolutely necessary.
There are no data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment.
Elderly patients
According to population pharmacokinetic analysis data, there are no specific recommendations for dose adjustment in elderly patients.
When docetaxel is used in combination with capecitabine in patients aged 60 years and older, it is recommended to reduce the initial dose of capecitabine to 75% (see the "Summary of Product Characteristics" for capecitabine).
Children.
Docetaxel is not recommended for use in children due to limited evidence on safety and/or efficacy in this patient population.
Results from studies on the efficacy and safety of docetaxel for the treatment of children have not been obtained.
The safety and efficacy of docetaxel for the treatment of nasopharyngeal carcinoma in children aged 1 month to 18 years have not yet been established.
There is a lack of substantial evidence supporting the use of docetaxel in children for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, and head and neck cancers, except for undifferentiated nasopharyngeal carcinoma types II and III.
Overdose.
There have been several reports of docetaxel overdose.
In case of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions.
An overdose is expected to intensify the drug's adverse effects. The most likely complications include bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation.
Following confirmation of overdose, therapeutic doses of G-CSF should be administered to the patient as soon as possible. Other necessary symptomatic measures should be taken if required.
There is currently no specific antidote for docetaxel.
Adverse reactions.
Summary of safety profile data for all indications
Data on adverse reactions considered likely related to docetaxel administration were obtained from studies involving the following patients:
- 1312 and 121 patients receiving docetaxel as monotherapy at doses of 100 mg/m² and 75 mg/m², respectively;
- 258 patients receiving docetaxel in combination with doxorubicin;
- 406 patients receiving docetaxel in combination with cisplatin;
- 92 patients receiving docetaxel in combination with trastuzumab;
- 255 patients receiving docetaxel in combination with capecitabine;
- 332 patients receiving docetaxel in combination with prednisone or prednisolone (clinically significant treatment-related adverse reactions are listed);
- 1276 patients (744 and 532 patients in studies TAX 316 and GEICAM 9805, respectively) receiving docetaxel in combination with doxorubicin and cyclophosphamide (clinically significant treatment-related adverse reactions are listed);
- 300 patients with gastric adenocarcinoma (221 patients from the phase III portion and 79 patients from the phase II portion of the clinical study) receiving docetaxel in combination with cisplatin and 5-fluorouracil (clinically significant treatment-related adverse reactions are listed);
- 174 and 251 patients with head and neck cancer receiving docetaxel in combination with cisplatin and 5-fluorouracil (clinically significant treatment-related adverse reactions are listed).
These reactions were described using the National Cancer Institute (NCI) Common Toxicity Criteria [grade 3 = G3; grade of severity 3–4 = G3/4; grade of severity 4 = G4], Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), and Medical Dictionary for Regulatory Activities (MedDRA) terminology.
The frequency of adverse effects was defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).
Within each group, adverse effects are listed in decreasing order of frequency.
The most common adverse reactions observed during docetaxel monotherapy were: neutropenia (reversible and noncumulative; the nadir of neutrophil count typically occurs on day 7; the mean duration of severe neutropenia (<500 cells/mm³) is approximately 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhea, and asthenia. The severity of adverse events associated with docetaxel may increase when the drug is combined with other chemotherapeutic agents.
When docetaxel was used in combination with trastuzumab, adverse effects (of any grade) were observed in ≥10% of patients. Compared to docetaxel monotherapy, this combination increased the frequency of serious adverse effects (40 vs 31%) and the frequency of grade 4 adverse effects (34 vs 23%).
The most common (≥5%) adverse effects of the docetaxel and capecitabine combination observed in a phase III clinical trial in patients with breast cancer who had failed prior anthracycline therapy are listed in the "General characteristics" section of the capecitabine product information.
The following adverse events were most frequently reported with docetaxel administration.
Immune system disorders
Hypersensitivity reactions usually occurred within minutes after the start of docetaxel infusion and ranged from mild to moderate in severity. The most commonly reported symptoms included skin flushing, rash (with or without pruritus), chest tightness, back pain, dyspnea, fever, or chills. Severe adverse reactions manifested as hypotension and/or bronchospasm or generalized rash/erythema (see section "Special warnings and precautions for use").
Nervous system disorders
Severe peripheral neurotoxic reactions require dose reduction of the drug (see sections "Dosage and administration" and "Adverse reactions"). Mild to moderate neurosensory reactions included paresthesia, dysesthesia, or pain sensations, including burning sensations. Neuromotor reactions were manifested as generalized weakness.
Skin and subcutaneous tissue disorders
Reversible skin reactions, generally mild or moderate in severity, were observed. These reactions included rash, often localized on the palms and soles (including severe palmar-plantar erythrodysesthesia or hand-foot syndrome), as well as on the arms, face, or chest, frequently accompanied by pruritus. Rash most commonly appeared within one week after docetaxel infusion. Severe manifestations occurred less frequently, such as rash with subsequent epithelial desquamation, sometimes necessitating treatment interruption or complete discontinuation of docetaxel (see sections "Dosage and administration" and "Special warnings and precautions for use"). Serious nail disorders included hypo- or hyperpigmentation, and in some cases pain and onycholysis.
General disorders and administration site conditions
Reactions at the site of drug administration were predominantly mild and included hyperpigmentation, inflammation, erythema, or dryness of the skin, phlebitis or hemorrhage, and venous swelling at the infusion site.
Cases of fluid retention included peripheral edema, less frequently pleural or pericardial effusion, ascites, and weight gain. Peripheral edema usually began in the lower limbs and could become generalized, leading to an increase in total body weight of 3 kg or more. Fluid retention is cumulative both in frequency and severity (see section "Special warnings and precautions for use").
Table 2
Adverse reactions observed in patients with breast cancer treated with docetaxel as monotherapy at a dose of 100 mg/m²
| MedDRA System Organ Classes |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7% of cases) |
Infections associated with G4 neutropenia (G3/4: 4.6%) |
|
| Blood and lymphatic system disorders |
Neutropenia (G4: 76.4%); anemia (G3/4: 8.9%); febrile neutropenia |
Thrombocytopenia (G4: 0.2%) |
|
| Immune system disorders |
Hypersensitivity reactions (G3/4: 5.3%) |
||
| Metabolism and nutrition disorders |
Anorexia |
||
| Nervous system disorders |
Peripheral sensory neuropathy (G3: 4.1%); peripheral motor neuropathy (G3/4: 4%); |
||
| Cardiac disorders |
Arrhythmia (G3/4: 0.7%) |
Heart failure |
|
| Vascular disorders |
Arterial hypotension; |
||
| Respiratory, thoracic and mediastinal disorders |
Dyspnea (severe: 2.7%) |
||
| Gastrointestinal disorders |
Stomatitis (G3/4: 5.3%); |
Constipation (severe: 0.2%); |
Esophagitis (severe: 0.4%) |
| Skin and subcutaneous tissue disorders |
Alopecia; skin reactions (G3/4: 5.9%); nail disorders (severe: 2.6%) |
||
| Musculoskeletal and connective tissue disorders |
Myalgia (severe: 1.4%) |
Arthralgia |
|
| General disorders and administration site conditions |
Fluid retention (severe: 6.5%); |
Local reactions after drug administration; |
|
| Investigations |
G3/4 increased blood bilirubin levels (<5%); |
From blood and lymphatic system
Rare: bleeding or hemorrhage on the background of grade III/IV thrombocytopenia.
From nervous system
There is evidence of reversibility of nervous system disorders in 35.3% of patients in whom these disorders developed after monotherapy with docetaxel at a dose of 100 mg/m². These disorders spontaneously resolved within 3 months.
From skin and subcutaneous tissue
Very rare: one case of irreversible alopecia reported at the end of the study.
73% of skin reactions were reversible and disappeared within 21 days.
General disorders and administration site reactions
The median cumulative dose at the time of drug discontinuation was greater than 1000 mg/m², and the median time to reversible development of fluid retention was 16.4 weeks (range: 0 to 42 weeks). The onset of moderate to severe fluid retention was delayed in patients who received premedication (median cumulative dose: 818.9 mg/m²) compared to those who did not receive premedication (median cumulative dose: 489.7 mg/m²); however, several cases of this adverse reaction were reported during early treatment cycles.
Table 3
Adverse reactions observed in patients with non-small cell lung cancer treated with docetaxel as monotherapy at a dose of 75 mg/m²
| MedDRA System Organ Classes |
Very common |
Common |
| Infections and infestations |
Infections (G3/4: 5%) |
|
| Blood and lymphatic system disorders |
Neutropenia (G4: 54.2%); |
Febrile neutropenia |
| Immune system disorders |
Hypersensitivity reactions (no severe cases) |
|
| Metabolism and nutrition disorders |
Anorexia |
|
| Nervous system disorders |
Peripheral sensory neuropathy (G3/4: 0.8%) |
Peripheral motor neuropathy (G3/4: 2.5%) |
| Cardiac disorders |
Arrhythmia (no severe cases) |
|
| Vascular disorders |
Arterial hypotension |
|
| Gastrointestinal disorders |
Nausea (G3/4: 3.3%); |
Constipation |
| Skin and subcutaneous tissue disorders |
Alopecia; |
Nail disorders |
| Musculoskeletal and connective tissue disorders |
Myalgia |
|
| General disorders and administration site conditions |
Asthenia (severe: 12.4%); |
|
| Investigations |
G3/4 increased blood bilirubin (<2%) |
Table 4
Adverse reactions recorded in patients with breast cancer treated with docetaxel at a dose of 75 mg/m² in combination with doxorubicin
| System organ classes according to MedDRA |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 7.8%) |
||
| Blood and lymphatic system disorders |
Neutropenia (G4: 91.7%); anemia (G3/4: 9.4%); febrile neutropenia; thrombocytopenia (G4: 0.8%) |
||
| Immune system disorders |
Hypersensitivity reactions (G3/4: 1.2%) |
||
| Metabolism and nutrition disorders |
Anorexia |
||
| Nervous system disorders |
Peripheral sensory neuropathy (G3: 0.4%) |
Peripheral motor neuropathy (G3/4: 0.4%) |
|
| Cardiac disorders |
Heart failure; arrhythmia (no severe cases) |
||
| Vascular disorders |
Arterial hypotension |
||
| Gastrointestinal disorders |
Nausea (G3/4: 5%); stomatitis (G3/4: 7.8%); diarrhea (G3/4: 6.2%); vomiting (G3/4: 5%); constipation |
||
| Skin and subcutaneous tissue disorders |
Alopecia; nail disorders (severe: 0.4%); skin reactions (no severe cases) |
||
| Musculoskeletal and connective tissue disorders |
Myalgia |
||
| General disorders and administration site conditions |
Asthenia (severe: 8.1%); fluid retention (severe: 1.2%); pain |
Local reactions after drug administration |
|
| Investigations |
G3/4 Increased blood bilirubin level (<2.5%); G3/4 increased alkaline phosphatase level (<2.5%) |
G3/4 Increased AST level (<1%); G3/4 increased ALT level (<1%) |
Table 5
Adverse reactions recorded in patients with non-small cell lung cancer treated with docetaxel 75 mg/m² in combination with cisplatin
| System organ classes according to MedDRA |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 5.7%) |
||
| Blood and lymphatic system disorders |
Neutropenia (G4: 51.5%); anemia (G3/4: 6.9%); thrombocytopenia (G4: 0.5%) |
Febrile neutropenia |
|
| Immune system disorders |
Hypersensitivity reactions (G3/4: 2.5%) |
||
| Metabolism and nutrition disorders |
Anorexia |
||
| Nervous system disorders |
Peripheral sensory neuropathy (G3: 3.7%); peripheral motor neuropathy (G3/4: 2%) |
||
| Cardiac disorders |
Arrhythmia (G3/4: 0.7%) |
Heart failure |
|
| Vascular disorders |
Arterial hypotension (G3/4: 0.7%) |
||
| Gastrointestinal disorders |
Nausea (G3/4: 9.6%); vomiting (G3/4: 7.6%); diarrhea (G3/4: 6.4%); stomatitis (G3/4: 2%) |
Constipation |
|
| Skin and subcutaneous tissue disorders |
Alopecia; nail disorders (severe: 0.7%); skin reactions (G3/4: 0.2%) |
||
| Musculoskeletal and connective tissue disorders |
Myalgia (severe: 0.5%) |
||
| General disorders and administration site conditions |
Asthenia (severe: 9.9%); fluid retention (severe: 0.7%); |
Local reactions after drug administration; pain |
|
| Investigations |
G3/4 Increased blood bilirubin (2.1%); G3/4 Increased ALT (1.3%) |
G3/4 Increased AST (0.5%); G3/4 Increased alkaline phosphatase (0.3%) |
Table 6
Adverse reactions recorded in patients with breast cancer receiving docetaxel at a dose of 100 mg/m² in combination with trastuzumab
| MedDRA system organ classes |
Very common |
Common |
| Blood and lymphatic system disorders |
Neutropenia (G3/4: 32%); febrile neutropenia (including neutropenia associated with fever and antibiotic use) or neutropenic sepsis |
|
| Metabolism and nutrition disorders |
Anorexia |
|
| Psychiatric disorders |
Insomnia |
|
| Nervous system disorders |
Paresthesia; headache; dysgeusia; hypoesthesia |
|
| Eye disorders |
Lacrimation, conjunctivitis |
|
| Cardiac disorders |
Heart failure |
|
| Vascular disorders |
Lymphedema |
|
| Respiratory, thoracic and mediastinal disorders |
Nosebleeds; pharyngolaryngeal pain; nasopharyngitis; dyspnea; cough; rhinorrhea |
|
| Gastrointestinal disorders |
Nausea; diarrhea; vomiting; constipation; stomatitis; dyspepsia; abdominal pain |
|
| Skin and subcutaneous tissue disorders |
Alopecia; erythema; rash; nail disorders |
|
| Musculoskeletal and connective tissue disorders |
Myalgia; arthralgia; limb pain; bone pain; back pain |
|
| General disorders and administration site conditions |
Asthenia; peripheral edema; fever; increased fatigue; mucosal inflammation; pain; acute respiratory illness; chest pain; chills |
Lethargy |
| Investigations |
Weight increased |
Description of individual adverse reactions observed in breast cancer patients treated with docetaxel at a dose of 100 mg/m² in combination with trastuzumab
Blood and lymphatic system disorders
Very common. Hematologic toxicity with combination therapy using trastuzumab and docetaxel increased compared to docetaxel monotherapy (32% of cases of grade III/IV neutropenia vs 22%, according to NCI-CTC [National Cancer Institute – Common Toxicity Criteria] criteria). It should be noted that the incidence of this adverse event in this patient population may be underestimated, as even with docetaxel monotherapy at a dose of 100 mg/m², neutropenia occurs in 97% of patients, with 76% experiencing grade IV neutropenia (based on nadir neutrophil count). The incidence of febrile neutropenia or neutropenic sepsis also increases in patients receiving the combination of trastuzumab and docetaxel (23% vs 17% in patients receiving docetaxel monotherapy).
Cardiac disorders
Symptomatic heart failure occurred in 2.2% of patients receiving the combination of trastuzumab and docetaxel, compared to 0% in patients receiving docetaxel monotherapy. In the study group receiving the combination of docetaxel and trastuzumab, 64% of patients had previously received anthracyclines as adjuvant therapy, compared to 55% in the docetaxel monotherapy group.
Table 7
Adverse reactions observed in breast cancer patients treated with docetaxel at a dose of 75 mg/m² in combination with capecitabine
| System organ classes according to MedDRA |
Very common |
Common |
| Infections and infestations |
Oral mucosal candidiasis (G3/4: <1 %) |
|
| Blood and lymphatic system disorders |
Neutropenia (G3/4: 63 %); anemia (G3/4: 10 %) |
Thrombocytopenia (G3/4: 3 %) |
| Metabolism and nutrition disorders |
Anorexia (G3/4: 1 %); |
Dehydration (G3/4: 2 %) |
| Nervous system disorders |
Dysgeusia (G3/4: <1 %); |
Dizziness; peripheral neuropathy |
| Eye disorders |
Lacrimation |
|
| Respiratory, thoracic and mediastinal disorders |
Pharyngolaryngeal pain (G3/4: 2 %) |
Dyspnea (G3/4: 1 %); |
| Gastrointestinal disorders |
Stomatitis (G3/4: 18 %); |
Upper abdominal pain; dry mouth |
| Skin and subcutaneous tissue disorders |
Palmar-plantar erythrodysesthesia syndrome (G3/4: 24 %); alopecia (G3/4: 6 %); nail disorders (G3/4: 2 %) |
Dermatitis; nail discoloration; |
| Musculoskeletal and connective tissue disorders |
Myalgia (G3/4: 2 %); |
Limb pain (G3/4: <1 %); back pain (G3/4: 1 %) |
| General disorders and administration site conditions |
Asthenia (G3/4: 3 %); peripheral edema (G3/4: 1 %) |
Lethargy; pain |
| Investigations |
Weight increased; |
Table 8
Adverse reactions observed in patients with prostate cancer treated with docetaxel at a dose of 75 mg/m² in combination with prednisone or prednisolone
| MedDRA system organ classes |
Very common |
Common |
| Infections and infestations |
Infections (G3/4: 3.3%) |
|
| Blood and lymphatic system disorders |
Neutropenia (G3/4: 32%); |
Thrombocytopenia (G3/4: 0.6%); febrile neutropenia |
| Immune system disorders |
Hypersensitivity reactions (G3/4: 0.6%) |
|
| Metabolism and nutrition disorders |
Anorexia (G3/4: 0.6%) |
|
| Nervous system disorders |
Peripheral sensory neuropathy (G3/4: 1.2%); dysgeusia (G3/4: 0%) |
Peripheral motor neuropathy (G3/4: 0%) |
| Eye disorders |
Lacrimation (G3/4: 0.6%) |
|
| Cardiac disorders |
Left ventricular dysfunction (G3/4: 0.3%) |
|
| Respiratory, thoracic and mediastinal disorders |
Nosebleeds (G3/4: 0%); |
|
| Gastrointestinal disorders |
Nausea (G3/4: 2.4%); |
|
| Skin and subcutaneous tissue disorders |
Alopecia; nail disorders (no severe cases) |
Exfoliative rash (G3/4: 0.3%) |
| Musculoskeletal and connective tissue disorders |
Arthralgia (G3/4: 0.3%); |
|
| General disorders and administration site conditions |
Increased fatigue (G3/4: 3.9%); fluid retention (severe: 0.6%) |
Table 9
Adverse reactions recorded during administration of docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with lymph node metastatic breast cancer (study TAX 316) and without lymph node metastases (study GEICAM 9805) – pooled data
| MedDRA System Organ Classes |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 2.4%); neutropenic infections (G3/4: 2.6%). |
||
| Blood and lymphatic system disorders |
Anemia (G3/4: 3%); neutropenia (G3/4: 59.2%); thrombocytopenia (G3/4: 1.6%); febrile neutropenia |
||
| Immune system disorders |
Hypersensitivity reactions (G3/4: 0.6%) |
||
| Metabolism and nutrition disorders |
Anorexia (G3/4: 1.5%) |
||
| Nervous system disorders |
Dysgeusia (G3/4: 0.6%); peripheral sensory neuropathy (G3/4: <0.1%) |
Peripheral motor neuropathy (G3/4: 0%); |
Syncope (G3/4: 0%); neurotoxicity manifestations (G3/4: 0%); somnolence (G3/4: 0%) |
| Eye disorders |
Conjunctivitis (G3/4: <0.1%) |
Lacrimation (G3/4: <0.1%) |
|
| Cardiac disorders |
Arrhythmia (G3/4: 0.2%); congestive heart failure |
||
| Vascular disorders |
Vasodilation (G3/4: 0.5%) |
Arterial hypotension (G3/4: 0%); phlebitis (G3/4: 0%) |
Lymphedema (G3/4: 0%) |
| Respiratory, thoracic and mediastinal disorders |
Cough (G3/4: 0%) |
||
| Gastrointestinal disorders |
Nausea (G3/4: 5%); |
Abdominal pain (G3/4: 0.4%) |
Colitis/ enteritis/ colorectal perforation |
| Skin and subcutaneous tissue disorders |
Alopecia (G3/4: <0.1%); (G3/4: 0.6%); nail disorders (G3/4: 0.4%) |
||
| Musculoskeletal and connective tissue disorders |
Myalgia (G3/4: 0.7%); |
||
| General disorders and administration site conditions |
Asthenia (G3/4: 10%); peripheral edema (G3/4: 0.2%) |
||
| Reproductive system and breast disorders |
Amenorrhea |
||
| Investigations |
Weight increased (G3/4: 0%), weight decreased (G3/4: 0.2%) |
Description of individual adverse reactions observed during administration of docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with node-positive (study TAX 316) and node-negative (study GEICAM 9805) breast cancer
Nervous system
During the study in patients with breast cancer and regional lymph node involvement (TAX316), peripheral sensory neuropathy persisted during the follow-up period in 10 out of 84 patients who developed this disorder at the end of chemotherapy.
Cardiac
In the TAX316 study, congestive heart failure (CHF) occurred in 26 patients (3.5%) in the group receiving treatment with the TAC regimen and in 17 patients (2.3%) in the group receiving treatment with the FAC regimen. In all but one patient in each group, CHF was diagnosed more than 30 days after treatment. Two patients in the TAC group and four patients in the FAC group died from heart failure.
In the GEICAM 9805 study, congestive heart failure developed during the follow-up period in 3 patients (0.6%) in the TAC regimen group and in 3 patients (0.6%) in the FAC regimen group. One patient in the TAC regimen group died from dilated cardiomyopathy.
Skin and subcutaneous tissue
In the TAX316 study, alopecia that occurred at the end of chemotherapy and persisted during the follow-up period was recorded in 687 out of 744 patients in the TAC group and in 645 out of 736 patients in the FAC group.
At the end of the follow-up period, alopecia persisted in 29 (4.2%) patients in the TAC group and in 16 (2.4%) patients in the FAC group.
At the end of the follow-up period (actual median follow-up duration was 96 months), alopecia remained in 29 patients in the TAC regimen group (3.9%) and in 16 patients in the FAC regimen group (2.2%).
In the GEICAM 9805 study, alopecia that persisted after completion of chemotherapy and throughout the follow-up period (median follow-up duration was 10 years and 5 months) was documented in 49 patients (9.2%) in the TAC regimen group and in 35 patients (6.7%) in the FAC regimen group.
Alopecia related to the investigational drug started or worsened during the follow-up period in 42 patients (7.9%) in the TAC regimen group and in 30 patients (5.8%) in the FAC regimen group.
Reproductive system and breast
In the TAX316 study, amenorrhea that developed at the end of chemotherapy and persisted during the follow-up period was observed in 121 out of 202 patients who had amenorrhea at the end of chemotherapy.
General disorders and administration site conditions
In the TAX316 study, peripheral edema persisted during the follow-up period in 19 out of 119 patients with peripheral edema in the TAC group and in 4 out of 23 patients in the FAC group.
In the GEICAM 9805 study, lymphedema persisted in 4 out of 5 patients who had lymphedema at the end of chemotherapy.
In the GEICAM 9805 study, lymphedema was observed at the end of chemotherapy in 4 out of 5 patients in the TAC regimen group and in 1 out of 2 patients in the FAC regimen group and did not resolve during the follow-up period (median follow-up duration was 10 years and 5 months). Asthenia persisted during the follow-up period (median follow-up duration was 10 years and 5 months) in 12 patients (2.3%) in the TAC regimen group and in 4 patients (0.8%) in the FAC regimen group.
Acute leukemia/myelodysplastic syndrome
During the 10-year follow-up period in the TAX316 study, acute leukemia was reported in 4 out of 744 patients in the TAC group and in 1 out of 736 patients in the FAC group. Myelodysplastic syndrome was reported in 2 out of 744 patients in the TAC group and in 1 out of 736 patients in the FAC group.
During the GEICAM 9805 study, with a median follow-up duration of 10 years, acute leukemia occurred in 1 out of 532 (0.2%) patients receiving docetaxel, doxorubicin, and cyclophosphamide. No cases of acute leukemia were recorded in patients receiving fluorouracil, doxorubicin, and cyclophosphamide. Myelodysplastic syndrome was not diagnosed in any patient in either study group.
Neutropenic complications
The table below shows that in the GEICAM study, among patients in the TAC group who received primary prophylaxis with G-CSF, grade 4 neutropenia, febrile neutropenia, and neutropenic infection occurred less frequently after this prophylaxis became mandatory.
Table 10
Neutropenic complications in patients receiving TAC with or without primary prophylaxis with G-CSF (GEICAM 9805 study)
| Complications |
Without primary prophylaxis with G-CSF (n = 111) n (%) |
With primary prophylaxis with G-CSF (n = 421) n (%) |
| Neutropenia (Grade 4) |
104 (93.7) |
135 (32.1) |
| Febrile neutropenia |
28 (25.2) |
23 (5.5) |
| Neutropenic infection |
14 (12.6) |
21 (5.0) |
| Neutropenic infection (Grade 3-4) |
2 (1.8) |
5 (1.2) |
Table 11
Adverse reactions recorded in patients with gastric adenocarcinoma treated with docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil
| MedDRA System Organ Classes |
Very common |
Common |
| Infections and infestations |
Neutropenic infections; infectious disorders (G3/4: 11.7%) |
|
| Blood and lymphatic system disorders |
Anaemia (G3/4: 20.9%); neutropenia (G3/4: 83.2%); thrombocytopenia (G3/4: 8.8%); febrile neutropenia |
|
| Immune system disorders |
Hypersensitivity reactions (G3/4: 1.7%) |
|
| Metabolism and nutrition disorders |
Anorexia (G3/4: 11.7%) |
|
| Nervous system disorders |
Peripheral sensory neuropathy (G3/4: 8.7%) |
Dizziness (G3/4: 2.3%); peripheral motor neuropathy (G3/4: 1.3%) |
| Eye disorders |
Lacrimation (G3/4: 0%) |
|
| Ear and labyrinth disorders |
Hearing impairment (G3/4: 0%) |
|
| Cardiac disorders |
Arrhythmia (G3/4: 1%) |
|
| Gastrointestinal disorders |
Diarrhoea (G3/4: 19.7%); nausea (G3/4: 16%); stomatitis (G3/4: 23.7%); vomiting (G3/4: 14.3%) |
Constipation (G3/4: 1%); abdominal pain (G3/4: 1%); oesophagitis/dysphagia/ odynophagia (G3/4: 0.7%) |
| Skin and subcutaneous tissue disorders |
Alopecia (G3/4: 4%) |
Rash with pruritus (G3/4: 0.7%); nail disorders (G3/4: 0.7%); increased desquamation of skin epithelium (G3/4: 0%) |
| General disorders and administration site conditions |
Lethargy (G3/4: 19%); pyrexia (G3/4: 2.3%); |
Description of individual adverse reactions observed in patients with gastric adenocarcinoma treated with docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil.
Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infections occurred in 17.2% and 13.5% of patients, respectively, regardless of whether G-CSF was administered. G-CSF was administered for secondary prophylaxis in 19.3% of patients (10.7% of all chemotherapy cycles). Febrile neutropenia and neutropenic infections developed in 12.1% and 3.4% of patients who received G-CSF, respectively, compared to 15.6% and 12.9% of patients who did not receive G-CSF prophylaxis.
Table 12
Adverse reactions observed in patients with head and neck cancer treated with docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil
Induction chemotherapy followed by radiotherapy (TAX 323 study)
| MedDRA System Organ Classes |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 6.3%); |
||
| Benign, malignant and unspecified neoplasms (incl. cysts and polyps) |
Pain due to malignant tumor (G3/4: 0.6%) |
||
| Blood and lymphatic system disorders |
Neutropenia (G3/4: 76.3%); |
Febrile neutropenia |
|
| Immune system disorders |
Hypersensitivity reactions (no severe cases) |
||
| Metabolism and nutrition disorders |
Anorexia (G3/4: 0.6%) |
||
| Nervous system disorders |
Dysgeusia/parosmia; |
Dizziness |
|
| Eye disorders |
Lacrimation; conjunctivitis |
||
| Ear and labyrinth disorders |
Hearing impairment |
||
| Cardiac disorders |
Myocardial ischemia (G3/4: 1.7%) |
Arrhythmia (G3/4: 0.6%) |
|
| Vascular disorders |
Venous disorders (G3/4: 0.6%) |
||
| Gastrointestinal disorders |
Nausea (G3/4: 0.6%); |
Constipation; esophagitis/dysphagia/odynophagia (G3/4: 0.6%); |
|
| Skin and subcutaneous tissue disorders |
Alopecia (G3/4: 10.9%) |
Rash with pruritus; |
|
| Musculoskeletal and connective tissue disorders |
Myalgia (G3/4: 0.6%) |
||
| General disorders and administration site conditions |
Lethargy (G3/4: 3.4%); |
||
| Investigations |
Increased body weight |
Table 13
Induction chemotherapy followed by chemoradiotherapy (TAX 324 study)
| System organ classes according to MedDRA |
Very common |
Common |
Uncommon |
| Infections and infestations |
Infections (G3/4: 3.6%) |
Neutropenic infections |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Pain due to malignant tumor (G3/4: 1.2%) |
||
| Blood and lymphatic system disorders |
Neutropenia (G3/4: 83.5%); anemia (G3/4: 12.4%); thrombocytopenia (G3/4: 4%); febrile neutropenia |
||
| Immune system disorders |
Hypersensitivity reactions |
||
| Metabolism and nutrition disorders |
Anorexia (G3/4: 12%) |
||
| Nervous system disorders |
Dysgeusia/parosmia (G3/4: 0.4%); peripheral sensory neuropathy (G3/4: 1.2%) |
Dizziness (G3/4: 2%); peripheral motor neuropathy (G3/4: 0.4%) |
|
| Eye disorders |
Lacrimation |
Conjunctivitis |
|
| Ear and labyrinth disorders |
Hearing impairment (G3/4: 1.2%) |
||
| Cardiac disorders |
Arrhythmia (G3/4: 2.0%) |
Myocardial ischemia |
|
| Vascular disorders |
Venous disorders |
||
| Gastrointestinal disorders |
Nausea (G3/4: 13.9%); stomatitis (G3/4: 20.7%); vomiting (G3/4: 8.4%); diarrhea (G3/4: 6.8%); esophagitis/dysphagia/odynophagia (G3/4: 12%); constipation (G3/4: 0.4%) |
Dyspepsia (G3/4: 0.8%); abdominal pain (G3/4: 1.2%); gastrointestinal hemorrhage (G3/4: 0.4%) |
|
| Skin and subcutaneous tissue disorders |
Alopecia (G3/4: 4%); rash with pruritus |
Increased skin dryness; increased desquamation of skin epithelium |
|
| Musculoskeletal and connective tissue disorders |
Myalgia (G3/4: 0.4%) |
||
| General disorders and administration site conditions |
Lethargy (G3/4: 4%); fever (G3/4: 3.6%); fluid retention (G3/4: 1.2%); edema (G3/4: 1.2%) |
||
| Investigations |
Decreased body weight |
Increased body weight |
Post-marketing surveillance data
Benign, malignant and unspecified neoplasms (including cysts and polyps)
The use of docetaxel in combination with other chemotherapeutic agents and/or radiotherapy has been associated with very rare cases of acute myeloid leukemia and manifestation of myelodysplastic syndrome.
Blood and lymphatic system disorders
Bone marrow suppression and other hematological adverse effects have been reported. Cases of disseminated intravascular coagulation syndrome have also been reported, often in association with sepsis or multiorgan failure.
Immune system disorders
Several cases of anaphylactic shock, sometimes fatal, have been reported.
Nervous system disorders
Docetaxel administration has led to rare cases of seizures or transient loss of consciousness. These reactions were sometimes observed during drug infusion.
Eye disorders
Very rare cases of transient visual disturbances (flashes, flickering lights in front of the eyes, scotoma) have been reported, which typically developed during drug infusion and were accompanied by hypersensitivity reactions. These disorders resolved spontaneously after infusion was stopped. There have been reports of rare cases of lacrimation, with or without accompanying conjunctivitis, resulting from obstruction of the lacrimal duct and causing increased tearing.
Cases of cystoid macular edema (CME) have been observed in patients receiving docetaxel.
Ear and labyrinth disorders
Rare cases of ototoxicity, worsening and/or hearing loss have been reported.
Cardiac disorders
Rare cases of myocardial infarction have been reported.
Vascular disorders
Rare cases of venous thromboembolic events have been reported.
Respiratory, thoracic and mediastinal disorders
Rare cases of acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis, and respiratory failure, sometimes fatal, have been reported. In patients receiving concomitant radiotherapy, rare cases of radiation pneumonitis have occurred.
Gastrointestinal disorders
Rare cases of dehydration due to gastrointestinal disorders, gastrointestinal tract perforations, ischemic colitis, colitis of other etiology, and neutropenic enterocolitis have been reported. There have also been reports of rare cases of intestinal obstruction and bowel obstruction.
Hepatobiliary disorders
Very rare cases of hepatitis, sometimes fatal (mainly in patients with pre-existing liver dysfunction prior to initiation of chemotherapy), have been reported.
Renal and urinary disorders
Cases of renal dysfunction and renal failure have been reported. In approximately 20% of these cases, no risk factors for acute renal failure were identified, such as concomitant use of nephrotoxic drugs or gastrointestinal disorders.
Skin and subcutaneous tissue disorders
Very rare cases of systemic lupus erythematosus and bullous skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis associated with docetaxel administration have been reported. In some cases, these adverse effects may have been influenced by concomitant factors. Cases of scleroderma-like skin lesions preceded by peripheral lymphedema have also been reported following docetaxel use. Cases of persistent alopecia (frequency unknown) have been reported.
General disorders and administration site conditions
Rare cases of the recall radiation reaction phenomenon (acute radiation reactions during chemotherapy administered several weeks, months, or years after radiotherapy) have been reported.
Fluid retention was not associated with acute episodes of oliguria or arterial hypotension.
Rare cases of dehydration and pulmonary edema have been reported.
Metabolic and nutritional disorders
Cases of electrolyte imbalance have been reported. Hyponatremia, mainly associated with dehydration, vomiting, and pneumonia, has been reported. Hypokalemia, hypomagnesemia, and hypocalcemia were observed, usually in association with gastrointestinal disorders, particularly diarrhea.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is an important procedure for regulatory authorities. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through national adverse reaction reporting systems.
Shelf life. 2 years.
After opening the vial
Each vial is intended for single use and should be used immediately after opening. If the drug is not used immediately, the user is responsible for the duration and storage conditions.
After reconstitution in infusion solution
From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the user is responsible for the duration and storage conditions.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
Docetaxel 20 mg
Concentrate for solution for infusion: 0.5 mL of the drug in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.
Solvent: 1.8 mL in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.
1 vial of Docetaxel 20 mg concentrate with 1 vial of solvent in a blister.
1 blister in a cardboard carton.
Docetaxel 80 mg
Concentrate for solution for infusion: 2.0 mL of the drug in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.
Solvent: 7.1 mL in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.
1 vial of Docetaxel 80 mg concentrate with 1 vial of solvent in a blister.
1 blister in a cardboard carton.
Prescription status. Prescription only.
Manufacturer.
MAYLAN LABORATORIES LIMITED (OTL)
MYLAN LABORATORIES LIMITED (OTL)
Manufacturer's address and place of business.
Plot No. 284-B, Bommasandra Jigani Link Road, Industrial Area, Anekal Taluk, Bangalore, Karnataka 560105, India
Plot No. 284-B, Bommasandra Jigani Link Road, Industrial Area, Anekal Taluk, Bangalore, Karnataka 560105, India
Marketing authorization holder.
M.Biotech Ltd
M.Biotech Ltd
Address of the marketing authorization holder.
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom