Docetaxel - instructions for use, dose, side effects, contraindications

An antineoplastic agent, a semi-synthetic analogue of paclitaxel. The mechanism of action is associated with the accumulation of tubulin in the microtubules of the mitotic spindle, which leads to disruption in the processes of their assembly and disassembly. Violates cell division in G phases₂ and M of the cell cycle.

Pharmacokinetics:

After a single intravenous injection at a dose of 100 mg / m² average C_max docetaxel in plasma is 3.7 μg / ml. The average value of V_d in the equilibrium state is 113 liters. Binding to plasma proteins - 90%. Docetaxel is metabolized.

The average system clearance is 21 l / h / m². About 6% is excreted by the kidneys, 75% - through the intestine, mainly in the form of metabolites and only a small part - unchanged.

Indications:

The agent of the first line for breast cancer, as well as ineffective therapy with anthracycline-based drugs; non-small cell lung cancer (including with ineffectiveness of other antitumour agents); malignant tumors of the head and neck; ovarian cancer; metastatic hormone-resistant prostate cancer (in combination with prednisone or prednisolone); Metastatic stomach cancer, including the cardiac department (in combination with cisplatin and 5-fluorouracil), as a therapy for the 1st line.

ICD-10

II.C60-C63.C61 Malignant neoplasm of prostate

II.C50 Malignant neoplasm of breast)

II.C30-C39.C34 Malignant neoplasm of bronchi and lungs

II.C15-C26.C16 Malignant neoplasm of stomach

Contraindications:

Hypersensitivity, neutropenia (initial number of neutrophils in peripheral blood <1.5×10⁹/ l), expressed violations of the liver (increased levels of bilirubin, transaminases, alkaline phosphatase).

Carefully:

Children's age (safety and effectiveness of the application has been studied insufficiently, there is limited experience in children).

Pregnancy and lactation:

Contraindicated in pregnancy. The action category for the fetus by FDA is D.

For the duration of treatment, breastfeeding should be discontinued (it is not known whether docetaxel in breast milk).

Dosing and Administration:

Intravenously slow (for one hour), once, every 3 weeks, at a dose of 75-100 mg / m² (depending on the indications and scheme of chemotherapy).

Side effects:

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): neutropenia, thrombocytopenia, anemia; heart rhythm failure, heart failure, a decrease or increase in blood pressure, cases of venous thromboembolism and myocardial infarction.

On the part of the digestive system: nausea, vomiting, diarrhea / constipation, anorexia, stomatitis, taste disorder, esophagitis, pain in the stomach, increased serum levels transaminase, alkaline phosphatase, hyperbilirubinemia; cases of gastrointestinal bleeding.

From the skin: alopecia; skin rash, often accompanied by itching, sometimes followed by desquamation, leading in some cases to interruption or discontinuation of docetaxel therapy; hypo- or hyperpigmentation of nails and onycholysis.

Allergic reactions: hypersensitivity reactions of mild to moderate severity (flushing to the face, rash combined with itching, chest tightness, back pain, dyspnea and drug fever or chills), severe reactions (accompanied by arterial hypotension and / or bronchospasm or generalized rash / erythema ).

Other: peripheral neuropathy (paresthesia, dysesthesia or pain, weakness), peripheral edema (initially usually appear on the lower extremities), ascites, asthenia, arthralgia and myalgia, reactions at the injection site (hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage or swelling veins).

Overdose:

Symptoms: myelosuppression, peripheral neurotoxicity, inflammation of the mucous membranes.

Treatment: hospitalization of the patient in a specialized department, careful monitoring of vital functions, symptomatic therapy is necessary. Patients should be assigned a granulocyte colony-stimulating factor as soon as possible. The specific antidote is unknown.

Interaction:

Immunosuppressants (azathioprine, mercaptopurine, muroomonab, tacrolimus, chlorambucil, glucocorticoids, ciclosporin, cyclophosphamide) - increased risk of infectious complications.

Inhibitors of cytochrome P450 activity (ketoconazole, midazolam, orfenadrine, testosterone, erythromycin) - a significant slowing of the metabolism of docetaxel.

Paclitaxel and other drugs metabolized by isoforms CYP3A - change in the metabolism of docetaxel (in experiments in vitro suppression of paclitaxel metabolism of docetaxel; in its turn docetaxel inhibits the formation of a minor metabolite of paclitaxel in a reaction involving cytochrome CYP3A, but not CYP2C).

Topotecan - with the introduction of docetaxel after four days of topotecan administration, a significant reduction in the clearance of docetaxel and an increase in neutropenia (compared with the administration of docetaxel after topotecan treatment for one day) are possible.

Special instructions:

Treatment is carried out only with the participation of an experienced specialist in antitumor therapy in the presence of conditions necessary for relief of complications (in a specialized hospital).

Caution should be exercised when using and preparing solutions of docetaxel (as with other antitumor drugs). When preparing solutions it is recommended to use gloves. In case of contact with the skin or mucous membranes, the mucous membranes should be thoroughly washed with water and the skin with water and soap. It is necessary to prepare anti-shock stowage (including epinephrine and oxygen) for relief of possible anaphylactic reactions.

To prevent hypersensitivity reactions, and to reduce fluid retention, all patients before the introduction of docetaxel are premedicated with glucocorticoids, for example, dexamethasone at a dose of 16 mg per day (8 mg twice daily) inside, for 3 days starting one day before the administration of docetaxel.

In patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, dexamethasone is premedicated at a dose of 8 mg for 12, 3 and 1 hour before the onset of docetaxel administration.

To reduce the risk of development of hematological complications, preventive administration of the colony-stimulating factor is recommended.

Careful observation of patients is necessary, especially during the first and second infusions of docetaxel, because hypersensitivity reactions may develop. Light manifestations of hypersensitivity (redness of the face or localized skin reactions) do not require an interruption in the administration of the drug. With the development of severe hypersensitivity reactions (arterial hypotension and / or bronchospasm, generalized rash / erythema), discontinuation of infusion and appropriate treatment for complications are necessary. Reuse of docetaxel in these patients is not permitted.

In all patients with docetaxel therapy, careful regular monitoring of peripheral blood parameters is necessary. With the development of serious adverse reactions (neutropenia <0.5×10⁹/ l, persisting for more than 7 days, or febrile neutropenia, or development of severe skin reactions, or severe peripheral neuropathy) during docetaxel therapy, the dose for the following administration should be reduced from 100 to 75 mg / m² and / or from 75 to 60 mg / m². If similar complications occur with docetaxel at a dose of 60 mg / m², treatment should be discontinued.

Before the start of therapy and before each subsequent cycle of therapy with docetaxel, functional tests of the liver should be determined.

In patients receiving monotherapy with docetaxel at a dose of 100 mg / m² and having a high activity of serum transaminases more than 1.5 times higher than the upper limit of the norm, in combination with an increase in serum alkaline phosphatase level more than 2.5 times higher than the upper limit of the norm, the risk of side effects increased: gastrointestinal bleeding, grade IV neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, sepsis. In this regard, in such patients with elevated liver function parameters, the recommended dose of docetaxel is 75 mg / m². In patients with elevated levels of bilirubin and / or increased activity of hepatic transaminases (> 3.5 from the upper limit of normal), in combination with an increase in alkaline phosphatase, more than 6 times the upper limit of the norm, docetaxel is not recommended.Currently, there is no data on the use of docetaxel in combination with other drugs in patients with impaired liver function.

In connection with the possibility of fluid retention, careful monitoring of patients with effusion to the pleural cavity, pericardium or ascites is necessary.

During treatment and for at least 3 months after discontinuation of therapy, men and women of childbearing age should avoid conception using reliable contraceptive methods.

As of July 31, 2012, the Ministry of Health of Canada received 31 reports of respiratory adverse reactions, possibly associated with the use of docetaxel, including pneumonitis, interstitial lung disease, pulmonary infiltration or respiratory failure - 23 patients required hospitalization. In 9 cases, a lethal outcome was reported.

In the literature, several cases of severe respiratory adverse reactions have been described in patients using docetaxel either alone or in combination with other antineoplastic agents. These adverse reactions include, for example, pneumonitis or interstitial pneumonitis, pulmonary infiltrates,acute respiratory distress syndrome, respiratory failure, interstitial lung diseases, interstitial infiltrates and pneumocystis pneumonia. Some of these cases resulted in death.

Instructions

Docetaxel (Docetaxelum)