Docetaxel-Filaxis - instructions for use, doses, 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. It is active against some, though not all, of cells that produce in excess p-glycoprotein, which is encoded by a gene of multiple resistance.

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. The connection with plasma proteins is more than 95%.

Within 7 days docetaxel is excreted in urine and feces after oxidation of the tert-butyl ester group with the participation of cytochrome P450 (6% and 75% of the administered dose, respectively).Approximately 80% of the drug being 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 on the age and sex of the patient. In patients with signs of easily expressed violations of the liver (ALT levels and ACT ≥1.5 norms in combination with increased activity of alkaline phosphatase ≥2.5 norms), the overall clearance was reduced by 27% compared with the average. Docetaxel clearance does not change in patients with mild or moderate fluid retention; information about the clearance of the drug in patients with severe fluid retention is not present.

Indications:

- Locally advanced or metastatic breast cancer as a primary chemotherapy treatment (1st line) or with ineffective prior therapy, including anthracyclines (2nd line);

- locally advanced or metastatic non-small cell lung cancer with ineffectiveness of previous therapy with the inclusion of platinum drugs;

- metastatic ovarian cancer with ineffectiveness of previous therapy with the inclusion of platinum drugs

Contraindications:

- Severe hypersensitivity reactions to docetaxel or polysorbate-80 in the anamnesis;

- initial number of neutrophils <1500 / μl;

- pronounced violations of the liver function;

- Pregnancy and the period of breastfeeding.

Dosing and Administration:

To prevent hypersensitivity reactions, as well as to reduce fluid retention, all patients before the introduction of the drug undergo glucocorticosteroid premedication, for example, dexamethasone inside at a dose of 16 mg / day. (8 mg twice daily) inside, for 3 days, starting 1 day before docetaxel administration. Docetaxel-Filaxis is administered as a one-hour intravenous infusion.

When choosing the dose and mode of administration of the drug in each individual case, you should refer to the special literature.

Mammary cancer

The recommended dose of Docetaxel-Filaxis is 60-100 mg / m² every 3 weeks.

Non-small cell lung cancer

Docetaxel-Filaxis is administered at a dose of 75-100 mg / m² every 3 weeks.

Metastatic ovarian cancer

Docetaxel-Filaxis is administered at a dose of 100 mg / m² every 3 weeks.

Correction of dose

With a drop 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 docetaxel at a dose of 60 mg / m², treatment should be discontinued.

Special groups of patients

Patients with impaired liver function

In patients with the level of transaminases in the blood plasma (ALT and / or ACT), exceeding in more than 1,5 times the upper limit of the norm (VGN), or alkaline phosphatase, exceeding more than 2,5 VHN, the recommended dose of Docetaxel-Filaxis is 75 mg / m². In patients with elevated levels of bilirubin and / or increased activity of ALT and ACT (> 3.5 UGN) in combination with an increase in alkaline phosphatase levels more than 6 times that of UHN, Docetaxel-Filaxis is not recommended.

Children

Security and the effectiveness of docetaxel in children is not well understood.

Aged people

Special instructions for the use of docetaxel in the elderly are not available.

Instructions for preparing a solution for intravenous administration

a) Preparation of the premixed solution

Before reconstitution, the bottles with the preparation and the solvent should be held at room temperature for 5 minutes.

All contents of the vial with the solvent are added to the vial with concentrate.

The vial with the resulting mixture is flipped for 45 seconds. (Do not shake!) And left for 5 minutes at room temperature, after which the solution is checked for homogeneity and transparency (the presence of foam even after 5 minutes is the norm).

The pre-mixed solution should be used to prepare the infusion solution immediately.

b) Preparation of a solution for infusion

The required volume of the premixed solution containing 10 mg / ml of docetaxel, according to the required dose, is diluted with 5% dextrose solution or 0.9% sodium chloride solution to a concentration of not more than 0.74 mg / ml. The resulting infusion solution should be mixed. The resulting solution should be used within 4 hours.

The solution for infusion before administration must be inspected; In the presence of sediment, the solution should be destroyed.

Side effects:

From the 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,previously received 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 infusion and are easy to moderate (flushing, rash, in conjunction with itching, tightness in chest, back pain, dyspnoea and drug fever or chills). Very rarely develops bullous rash (Lyell's syndrome or Stevens-Johnson syndrome). Severe reactions characterized by a reduction in blood pressure and / or bronchospasm or generalized rash / erythema usually disappear after discontinuation of the infusion and the appointment of 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. 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 limbs, and then can become generalized, resulting in an increase in body weight of 3 kg or more. The frequency and severity of fluid retention increases with repeated administration of the drug. 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.

On the part of the digestive system: nausea, vomiting, diarrhea, anorexia, constipation, stomatitis, a taste disorder, esophagitis, pain in the stomach, rarely gastrointestinal bleeding, extremely rarely - intestinal obstruction; increased serum activity ACT, ALT, alkaline phosphatase and serum bilirubin concentration.

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 pass independently on average for 3 months.Very rarely there is a development of seizures and a passing loss of consciousness.

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

From the respiratory system: very rarely there is an acute respiratory distress syndrome and interstitial pneumonia, pulmonary fibrosis.

On the part of the organs of vision: rarely - lacrimation in conjunction with conjunctivitis (or without it), transient visual disorders (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; very rarely (mainly in patients receiving concomitantly other antitumoral drugs) may develop occlusion of the lacrimal canal.

Local reactions: hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage or edema of the vein.

Other: asthenia, arthralgia, myalgia, muscle weakness, shortness of breath, generalized or local pain,including pain in the chest, not related to heart and lung diseases, sepsis, increased reactions to irradiation.

Overdose:

Expected symptoms: suppression of the bone marrow, peripheral neuropathy and inflammation of the mucous membranes.

Activities in case of overdose: hospitalization of the patient, careful monitoring of the functions of vital organs, preventive administration of colony-stimulating factors, symptomatic therapy. The antidote to docetaxel is not currently known.

Interaction:

Research in vitro showed that biotransformation of the drug can change with the simultaneous use of substances: inducing, inhibiting or metabolized by the cytochrome P450-3A system, such as ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, care must be taken with the simultaneous administration of such drugs, given the possibility of pronounced interaction.

In vitro drugs that bind strongly to proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate, did not affect the binding of docetaxel to 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. In this case, the clearance of doxorubicin and the level of doxorubicinol (metabolite of doxorubicin) in plasma does not change.

With combined therapy with cisplatin or carboplatin, the pharmacokinetic profiles of the drugs do not change.

Special instructions:

Docetaxel-Filaxis treatment is performed only under the supervision of a doctor who has experience in the use of antitumor drugs, in the conditions of a specialized hospital. Careful monitoring of the clinical blood test should be carried out. With the development of severe neutropenia (<500 / μL for 7 days or more) during the course of therapy with Docetaxel-Filaxis, it is recommended to reduce the dose of the drug at 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.The development of hypersensitivity reactions is possible at the very first minutes of infusion of Docetaxel-Phylaxis. 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 medical measures. Reuse of Docetaxel-Filaxis in such patients is not permitted.

With a high activity of serum transaminases (ALT and / or ACT) - more than 1.5 times higher than IGN, in combination with an increase in serum alkaline phosphatase more than 2.5 times higher than IGN, there is an extremely high risk of serious side effects: sepsis, gastrointestinal bleeding, febrile neutropenia, infection, thrombocytopenia, stomatitis and asthenia. In this regard, functional liver samples should be determined before the start of therapy and before each subsequent cycle of Docetaxel-Filaxis therapy. In patients with elevated levels of bilirubin and / or increased activity, ALT and ACT (> 3.5 UGN) in combination with increased levelsalkaline phosphatase more than 6 times that of UHN, docetaxel-phylaxis is not recommended.

In connection with the possibility of fluid retention, careful monitoring of patients with effusion to the pleural cavity, pericardium or having ascites is necessary. With the appearance of edema - the restriction of salt and drinking regimen and the appointment of diuretics.

During and for at least three months after cessation of therapy, reliable methods of contraception should be used.

Care should be taken when applying and preparing Docetaxel-Filaxis solutions. It is recommended to use gloves. If the concentrate, premixed solution or infusion solution enters the skin, then immediately wash it thoroughly with soap and water. If ingested, mucous membranes should be rinsed immediately with water.

Form release / dosage:Concentrate for the preparation of a solution for infusions, 40 mg / ml.

Packaging:

For 20 mg / 0.5 ml and 80 mg / 2 ml in vials.

20 mg / 0.5 ml concentrate in a 5 ml glass vial sealed with Teflon-coated stopper and cap together with 1.5 ml of solvent in a 5 ml glass vial,sealed with Teflon cap and cap, with instructions for use in a plastic pallet, then packed in a pack of cardboard or 80 mg / 2 ml concentrate in a 15 ml glass vial sealed with Teflon-coated stopper and cap together with 6 ml of solvent in a glass a 15 ml vial capped with Teflon-coated stopper and cap, with instructions for use in a plastic tray, then packaged in a pack of cardboard.

Storage conditions:

At a temperature of 15 to 25 ° C, in a place protected from light and inaccessible to 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-001498

Date of registration:25.05.2010

The owner of the registration certificate:Laboratory of Philaxis S.A.Laboratory of Philaxis S.A. Argentina

Manufacturer: & nbsp

ZIO-HEALTH, JSC Russia

ROSFARM, LLC Russia

Information update date: & nbsp23.01.2016

Illustrated instructions

Instructions

Docetaxel-Phylaxis (Docetaxel-Filaxis)