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

Docetaxel is an antitumor drug of plant origin (from the taxoid group). Accumulates tubulin in microtubules, prevents their disintegration, which disrupts the phase of mitosis and interfacial processes in tumor cells. Docetaxel long time is stored in cells, where its concentration reaches high values. Besides, docetaxel proved to be active against some, though not all, cells producing in excess P-glycoprotein, which is encoded by the gene of multiple resistance. In vivo docetaxel has a broad spectrum of activity against tumors of mice and transplanted human tumor cells.

Pharmacokinetics:

The kinetics of docetaxel is dose-dependent and corresponds to a three-phase pharmacokinetic model with a half-life of 4 minutes, 36 minutes and 11.4 hours, respectively. Docetaxel more than 95% binds to plasma proteins.

Within 7 days docetaxel is excreted in urine and feces after oxidation of tert-butyl ether group with participation of cytochrome-P450; Excretion in urine and feces is 6% and 75% of the dose, respectively. Approximately 80% of the drug, excreted with feces,is detected within 48 hours as a basic inactive metabolite and three less significant inactive metabolites and in a very small amount - unchanged.

The pharmacokinetics of docetaxel does not depend from age and sex patient.

At mildly expressed violations of liver function (levels of alanine aminotransferase (ALT) and aspartate aminotransaminase (ACT)> 1.5 norms in combination with an increase in alkaline phosphatase activity> 2.5 norms), the overall clearance is reduced by 27% compared with the average.

Docetaxel clearance does not change with mild or moderate fluid retention; there is no information on the clearance of the drug with a pronounced fluid retention.

Indications:

Mammary cancer:

- adjuvant therapy for operable breast cancer (breast cancer) with regional lymph node involvement in combination with doxorubicin and cyclophosphamide;

- operable breast cancer without affecting regional lymph nodes in patients who undergo chemotherapy according to established international screening criteria for primary chemotherapy of early breast cancer (with one or more risk factors for relapse);

- Locally advanced or metastatic breast cancer (in combination with doxorubicin as the first line of therapy or as second line therapy: in monotherapy, with ineffectiveness of the previous treatment, including anthracyclines or alkylating agents, and in combination with capecitabine, if the previous treatment included anthracyclines);

- metastatic breast cancer with tumor expression HER2 in combination with trastuzumab, in the absence of prior chemotherapy.

Non-small cell lung cancer:

- inoperable, topicallycommon or metastatic non-small cell lung cancer (in combination with cisplatin or carboplatin) as 1st line therapy or in monotherapy as 2nd line therapy for ineffective chemotherapy based on platinum drugs.

Ovarian Cancer:

- metastatic ovarian cancer with ineffectiveness of previous therapy of the 1st line (docetaxel in monotherapy, therapy of the 2nd line).

Head and neck cancer:

- Locally distributed squamous cell carcinoma of the head and neck (docetaxel in combination with cisplatin and fluorouracil, induction therapy).

Prostate cancer:

- metastatic, hormone-resistant prostate cancer (in combination with prednisone or prednisolone).

Stomach cancer:

- Metastatic stomach cancer, including the cardiac department, (in combination with cisplatin and fluorouracil) as first-line therapy.

Contraindications:

- Excessive sensitivity reactions to docetaxel or other components of the drug;

- initial number of neutrophils <1500 / μl;

- pronounced violations of the liver function;

- Pregnancy and the period of breastfeeding.

Carefully:Children's age (data on use in children is not enough).

Pregnancy and lactation:

The drug is contraindicated during pregnancy and breastfeeding.

During and for at least three months after discontinuing therapy, patients need to use reliable contraceptive methods.

Dosing and Administration:

When choosing a dose and the mode of administration of Tautakes, in each individual case, reference should be made to special literature.

Tautax is administered as a one-hour intravenous infusion every 3 weeks.

To prevent reactions of hypersensitivity, as well as to reduce fluid retention,all patients (excluding patients with prostate cancer) prior to the administration of the drug Tautax, it is necessary to premedicate with glucocorticosteroids, for example, dexamethasone inside at a dose of 16 mg / day (8 mg twice a day), for 3 days, 1 day before the administration of Tautakes.

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 initiation of Tautakes.

To reduce the risk of development of hematological complications, preventive administration of granulocyte colony-stimulating factor (G-CSF) is recommended.

Mammary cancer

With adjuvant therapy patients with an operable form of breast cancer, the recommended dose of Tautax is 75 mg / m² 1 hour after administration of doxorubicin (50 mg / m²) and cyclophosphamide (500 mg / m²) every 3 weeks. Only 6 cycles.

With monotherapy the recommended dose of Tautakes is 100 mg / m² every 3 weeks.

When combined with doxorubicin (50 mg / m²) or capecitabine (1250 mg / m² inside 2 times a day for 2 weeks with a subsequent weekly break) Tautax is administered at a dose of 75 mg / m² every 3 weeks.

When combined with trastuzumab the recommended dose of Tautax is 100 mg / m² every 3 weeks. For dose and route of administration of trastuzumab, see the instructions for the medical use of trastuzumab.

Non-small cell lung cancer

Tautax is administered with monotherapy and in combination with platinum preparations at a dose of 75 mg / m² every 3 weeks.

Metastatic ovarian cancer

Tautax is administered at a dose of 100 mg / m² every 3 weeks.

Locally spread squamous cell carcinoma of the head and neck

Tautax is administered at a dose of 75 mg / m². After infusion of Tautax on the same day, an infusion of cisplatin at a dose of 75 mg / m² for 1 hour, followed by fluorouracil infusion at a dose of 750 mg / m²/ day in the form of a 24-hour infusion for 5 days.

This mode is prescribed 1 time in 3 weeks and repeated up to 4 cycles.

After the chemotherapy course, radiotherapy is prescribed.

Metastatic squamous cell carcinoma of the head and neck

Tautax is administered at a dose of 100 mg / m² every 3 weeks.

Metastatic hormone-resistant prostate cancer

Tautax is administered at a dose of 75 mg / m² 1 time in 3 weeks.

Prednisone or prednisolone is administered orally 5 mg twice a day for the entire period of the course treatment with Tautax.

Metastatic stomach cancer, including the cardiac department

Tautax is administered at a dose of 75 mg / m² 1 time in 3 weeks.

After infusion of Tautax on the same day, an infusion of cisplatin at a dose of 75 mg / m² for 1-3 hours, followed by infusion of fluorouracil in a dose of 750 mg / m²/ day in the form of a 24-hour infusion for 5 days, starting from the end of the infusion of cisplatin.

Correction of dose

Tautax is administered at a neutrophil count of> 1500 / μL. With a decrease in the number of neutrophils <500 / μl, which was observed for more than a week, or development of 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 the use of Tautakes in a dose of 60 mg / m², treatment should be discontinued.

With combined therapy of breast cancer

Patients with an operable form of breast cancer who receive adjuvant therapy, with the development of febrile neutropenia should receive G-CSF on all subsequent cycles. With preservation of febrile neutropenia, it is necessary to reduce the dose of Tautax to 60 mg / m², continue to receive G-CSF. If G-CSF is not used, the dose of Tautax should be reduced from 75 mg / m² up to 60 mg / m².

In patients with grade 3 and 4 stomatitis (classification of toxicity of antitumor chemotherapy by WHO), a dose reduction of up to 60 mg / m².

When combined with Tautax and capecitabine at the first occurrence of grade 2 toxicity that persists before the next cycle of Tautax / capecitabine therapy, treatment may be delayed until toxicity drops to 0-1 degree, with 100% of the initial dose of Tautax administered during the next treatment cycle.

In patients with repeated development of grade 2 toxicity or the first episode of grade 3 toxicity at any time of the treatment cycle, treatment is postponed until toxicity is reduced to 0-1 degree, then treatment with Tautax is resumed at a dose of 55 mg / m².

With any subsequent manifestations of toxicity or the appearance of any toxicity type 4, the administration of Tautax should be discontinued.

Doses of capecitabine are reduced in accordance with its instruction for medical use.

With the combined treatment of non-small cell lung cancer

For patients who initially receive Tautax at a dose of 75 mg / m² in combination with cisplatin or carboplatin in which the platelet count in the previous cycle of treatment was reduced to <25,000 / ul (with cisplatin) and up to <75,000 / ul (carboplatin), or in patients who have developed a febrile neutropenia, or in patients with Serious manifestations of nonhematological toxicity dose of the drug Tautax in the next cycle should be reduced to 65 mg / m². For recommendations on correcting the dose of cisplatin, see its instructions for medical use.

With the combination of Tautax with cisplatin and fluorouracil in the case of infection of febrile neutropenia or attachment, despite receiving G-CSF, a dose Taytax preparation should be reduced to 60 mg / m².

With the subsequent development of episodes of complicated neutropenia, it is recommended to reduce the dose of Tautax with 60 mg / m²up to 45 mg / m².

With the development of thrombocytopenia of the 4th degree, the dose of Tautax should be reduced from 75 mg / m² up to 60 mg / m². Subsequent cycles are possible when the drug Taytax neutrophil count> 1500 / l and platelets> 100,000 / ul; If toxicity persists, treatment should be discontinued.

With the development of other types of toxicity, dose adjustment of Tautax is carried out in accordance with the following recommendations:

Toxicity

Correction of dose

Diarrhea 3 degrees

The first episode: reduce the dose of fluorouracil by 20%.

Secondary episode: reduce the dose of Tautakes by 20%.

Diarrhea 4 degrees

The first episode: reduce the dose of fluorouracil and Tautakes by 20%.

Repeat episode: stop treatment.

Stomatitis 3 degrees

The first episode: reduce the dose of fluorouracil by 20%.

Repeat episode: undo fluorouracil at subsequent cycles.

Third episode: reduce the dose of Tautakes by 20%.

Stomatitis 4 degrees

The first episode: fluorouracil at subsequent cycles.

Secondary episode: reduce the dose of Tautakes by 20%.

For recommendations on correcting the dose of cisplatin, see its instructions for medical use.

Special groups of patients

Patients with impaired liver function

In patients with increased activity, transaminases in the blood plasma (ALT and / or ACT), exceeding the upper limit of the norm (IGN) and / or alkaline phosphatase exceeding more than 1.5 times the IGN, the recommended dose of Tautax is 75 mg / m².

In patients with increased bilirubin concentration and / or increased ALT activity and ACT (> 3.5 VGN) in combination with an increase in alkaline phosphatase activity more than 6 times that of UHN, Tautax is not recommended.

Data on the use of docetaxel in combination with other drugs in patients with impaired liver function are currently not available.

Children

The safety and efficacy of docetaxel in children have not been adequately studied, and there is limited experience in children.

Aged people

Given the analysis of pharmacokinetic data, there are no specific recommendations for the use of docetaxel in the elderly.

When combined with capecitabine in patients older than 60 years, a reduction in the starting dose of capecitabine is recommended (see the instructions for the medical use of capecitabine).

Preparation of a solution for infusion

The required volume of concentrate in accordance with the required dose is diluted in 250 ml of a 5% solution of dextrose or 0.9% solution of sodium chloride. If the required dose of docetaxel is greater than 200 mg, a larger volume of infusion fluid should be used so that the docetaxel concentration is not above 0.74 mg / ml.

The resulting solution should be gently mixed and used for 4 hours at room temperature and normal light conditions.

Solution Tautakes for infusion, as well as any other drugs for parenteral application must be inspected before administration; in the presence of a precipitate solution should be destroyed.

Side effects:

Below are listed the reactions depending on the frequency of development: very often (≥10%); often (≥1 and <10%); infrequently (≥0.1 and <1%); rarely (≥0.01 and <0.1%); very rarely (<0.1%).

On the part of the organs of hematopoiesis: the most common side effect is reversible neutropenia, in some cases accompanied by fever. The number of neutrophils is reduced to the minimum values on average after 7 days (in patients who received previous chemotherapy, this period may be shorter), the average duration of severe neutropenia (<500 / μL) is also 7 days. Possible development of thrombocytopenia and anemia.

Hypersensitivity reactions: usually occur within a few minutes after the start of the infusion and can be easily or mild ("hot flashes", rash combined with itching, chest tightness, back pain, dyspnea and drug fever or chills). Very rarely develops bullous rash (Lyell's syndrome or Stevens-Johnson syndrome). Severe reactions characterized by a decrease in blood pressure and / or bronchospasm or generalized rash / erythema usually stop after stopping the infusion and prescribing adequate therapy.

From the skin and skin appendages: alopecia, mild to moderate skin reactions. Less common are severe reactions, such as a rash accompanied by itching or limited erythema of the skin of the extremities (palms and feet) with swelling and subsequent desquamation of the epithelium. Hypo-or hyperpigmentation of nails, severe nail lesions (onycholysis) are rare.

Fluid retention: cases of peripheral edema and, less often, pleural and pericardial effusions, ascites and weight gain are described. Peripheral edema initially appears on the lower extremities, and then can become generalized, leading to an increase in body weight of 3 kg or more. The frequency and severity of fluid retention increases with repeated administration of the drug; the average total docetaxel dose at which fluid retention was observed was 818.9 mg / m3 during premedication² and without premedication - 489.7 mg / m²; in some cases, fluid retention may develop during the first course of therapy. The fluid retention is not accompanied by acute episodes of oliguria or a decrease in blood pressure.In rare cases, the development of dehydration and pulmonary edema was reported.

From the gastrointestinal tract: nausea, vomiting, diarrhea, anorexia, constipation, stomatitis, taste disorder, esophagitis, pain in the stomach; rarely - gastrointestinal bleeding. Very rarely - intestinal obstruction.

From the nervous system: peripheral neuropathy in the form of easy or moderately expressed paresthesia, hyperesthesia, dysesthesia or pain, including burning. Motor disorders are characterized by weakness. These violations usually go away on their own within 3 months. Very rarely there is a development of seizures and a passing loss of consciousness.

From the cardiovascular system: disorders of the heart rhythm (sinus tachycardia, atrial fibrillation), unstable angina, heart failure, increase or decrease in blood pressure. Very rarely - cases of venous thromboembolism and myocardial infarction.

From the side of the liver and bile-excreting tracts: increased serum activity ACT, ALT, alkaline phosphatase and serum bilirubin concentration.

Other: asthenia, arthralgia, myalgia, muscle weakness, dyspnea,generalized or local pain, including pain in the chest, not related to heart and lung diseases, sepsis.

In rare cases, development of lachrymation in combination with conjunctivitis (or without it) is possible; very rarely, mainly in patients receiving other antitumoral drugs at the same time, it is possible to develop an occlusion of the lacrimal canal resulting in excessive lacrimation. In rare cases, transient visual disturbances (flashes of light in the eyes, the appearance of cattle), usually occurring during the administration of the drug and combined with the development of hypersensitivity reactions that disappear after the termination of infusion.

Reactions at the site of injection are moderately expressed and manifest as hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage or edema of the vein.

Very rarely there is an acute respiratory distress syndrome and interstitial pneumonia, pulmonary fibrosis and increased reaction to irradiation.

When docetaxel is used in combination with capecitabine, there is a more frequent development of adverse events from the gastrointestinal tract, palmar-plantar syndrome, dehydration, lacrimation,arthralgia, severe thrombocytopenia and anemia, hyperbilirubinemia, but more rare development of severe neutropenia, alopecia, disorders of the nails, asthenia, myalgia, edema of the lower extremities.

Patients aged> 60 years who received combination therapy with docetaxel and capecitabine, compared with patients of younger age, more frequent development of toxicity 3-4 degrees.

Overdose:

The main expected overdose manifestations include bone marrow suppression, peripheral neuropathy and mucosal inflammation.

The antidote of docetaxel is not known.

In case of an overdose, the patient should be hospitalized in a specialized department and carefully monitor the function of vital organs. Patients should be introduced as soon as possible G-CPS. Other symptomatic measures are taken when necessary.

Interaction:

Research in vitro showed that biotransformation of docetaxel can change with the simultaneous use of substances that induce, inhibit or metabolize isoenzyme CYP3A4, such as ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin.In this regard, care must be taken when using such drugs at the same time, given the possibility of pronounced interaction.

In vitro drugs that bind strongly to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and sodium valproate, did not affect the binding of docetaxel to plasma proteins. Docetaxel does not affect the binding to the protein digitoxin.

When docetaxel was used in combination with doxorubicin, clearance of docetaxel increased while maintaining its effectiveness. At the same time, the clearance of doxorubicin and the concentration of doxorubicinol (doxorubicin metabolite) in plasma did not change.

The clearance of docetaxel in combination therapy with cisplatin or carboplatin was similar to that observed with monotherapy with docetaxel.

The pharmacokinetic profile of cisplatin with itsimmediately after intravenous infusion of docetaxel was similar to that observed when administered one cisplatin.

Influences of docetaxel on pharmacokinetics (maximum concentration in blood plasma (FROM_max) and area under the concentration-time curve (AUC)) of the main metabolite capecitabine (5'-deoxy-5-fluorouridine) and the effect of capecitabine on pharmacokinetics (C_mOh and AUC) docetaxel is not detected.

Special instructions:

Treatment is conducted only under the supervision of a specialist with experienceantitumor therapy in a specialized hospital.

It should be closely monitored by clinical blood analysis in patients receiving Tautakes therapy. When development of severe neutropenia (<500 / μL for 7 days or more) during the course of therapy with Tautakes, it is recommended to reduce the dose of the drug in subsequent courses or to use adequate symptomatic measures.

To identify the reactions of hypersensitivity patients should be carefully monitored, especially during the first and second infusions. Light manifestations of hypersensitivity (redness of the face or localized skin reactions) do not require an interruption in the administration of the drug. Severe hypersensitivity reactions (lowering blood pressure, bronchospasm or generalized rash / erythema) require immediate withdrawal of the drug and the adoption of appropriate treatment measures to cure these complications.Reuse of Tautakes in these patients is not permitted.

In patients with impaired hepatic function, the risk of severe adverse effects (sepsis, gastrointestinal bleeding, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia) is extremely high, and therefore functional liver samples should be determined before the therapy is started and before each subsequent cycle of Tautakes therapy.

In connection with the possibility of fluid retention, careful monitoring of patients with effusion to the pleural cavity, pericardium or having ascites is necessary. When swelling occurs, you should limit the intake of salt and liquid and prescribe diuretics.

Tautax is an antitumor drug; as in the case of other potentially toxic substances, care must be taken when using it and preparing solutions. It is recommended to use gloves. If the product gets on the skin or mucous membranes, immediately wash the skin thoroughly with soap and water, mucous membranes - rinse with water.

Effect on the ability to drive transp. cf. and fur:

Studies on the effects of docetaxel on the ability to manage motor vehicles and mechanical equipment,not carried out.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

1 ml, 2 ml, 4 ml, 5 ml, 5.5 ml, 6 ml, 6.25 ml, 7.5 ml, 8 ml and 9 ml in vials.

1 bottle with instructions for use in a pack of cardboard.

For 3 or 5 bottles with instructions for use in a pack with partitions or special cardboard sockets.

By 20, 35, 50 bottles with an equal number of instructions for use in cardboard boxes (for hospitals).

Storage conditions:

At a temperature of 2 to 8 ° C out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000093

Date of registration:05.02.2010 / 10.11.2014

The owner of the registration certificate:LENS-PHARM, LLC LENS-PHARM, LLC Russia

Manufacturer: & nbsp

LENS-PHARM, LLC Russia

Information update date: & nbsp23.01.2016

Illustrated instructions

Instructions

Tautakes (Tautax)