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

An antitumor agent of plant origin obtained semi-synthetically from a plant Taxus Baccata. The mechanism of action is associated with the ability to stimulate the "assembly" of microtubules from dimeric tubulin molecules, stabilize, prevent depolymerization, their structure and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell. Besides, paclitaxel induces the formation of abnormal clusters or "bundles" of microtubules throughout the entire cell cycle and a variety of star clusters (asters) during mitosis.

Causes a dose-dependent suppression of bone marrow hematopoiesis. According to experimental data it has mutagenic and embryotoxic properties, it causes a decrease in reproductive function.

Pharmacokinetics:

With intravenous (IV) infusion for 3 hours at a dose of 135 mg / m² the maximum concentration (Сmах) is 2170 ng / ml, the area under the curve "concentration-time" (AUC) - 7952 ng / h / ml: when administered at the same dose for 24 hours, 195 ng / ml and 6300 ng / h / ml, respectively. FROM_max and AUC dose-dependent: with a 3-hour infusion, increasing the dose to 175 mg / m² leads to an increase in these parameters by 68% and 89%, and at 24 hours introduction - by 87% and 26%, respectively.

The connection with plasma proteins is 88-98%. The time of half-distribution from the blood in the tissue is 30 minutes. Easily penetrates and adsorbed by tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles. Metabolized in the liver by hydroxylation with the participation of cytochrome P450 isoenzymes CYP2D8 (with the formation of a metabolite - 6-alpha-hydroxypaclitaxel) and CYP3CA4 (from formation of metabolites of 3-para-hydroxy-paclitaxel and 6-alpha, 3-paradihydroxy paclitaxel). The half-life and total clearance are variable and depend on the dose and duration of IV administration: 13.1-52.7 h and 12.2-23.8 l / h / m², respectively. 90% of the drug is excreted with bile in the form of metabolites.In a small amount (from 1.3 to 12.6%, depending on the level of the administered dose) is excreted unchanged in the urine.

Indications:

- Ovarian cancer (first-line therapy of patients with a common form of disease or residual tumor (more than 1 cm) after laparotomy (in combination with cisplatin) and second-line therapy with metastases after standard therapy, which did not give a positive result).

- Breast cancer (the presence of affected lymph nodes after standard combination therapy (adjuvant treatment), after relapse, within 6 months after initiation of adjuvant therapy - first-line therapy, metastatic breast cancer after ineffective standard therapy - second-line therapy).

- Non-small cell lung cancer (first-line therapy for patients who do not plan surgical treatment and / or radiation therapy (in combination with cisplatin).

Contraindications:

- Hypersensitivity to paclitaxel or other constituents of the drug (including polyoxyethylated castor oil).

- The initial content of neutrophils is less than 1500 / μL.

- Pregnancy and lactation.

Carefully:Carefully: thrombocytopenia (less than 100,000 / μl), liver failure, acute infectious diseases (including herpes zoster, chicken pox, herpes), severe course of coronary heart disease, myocardial infarction (in history), arrhythmias.

Application in pediatrics. The safety and effectiveness of paclitaxel in children is not established.

Dosing and Administration:

To prevent the development of severe allergic reactions, all patients before the start of infusion should undergo premedication with glucocorticosteroids, antihistamines and antagonists H_2-histamine receptors: 20 mg of dexamethasone (or its equivalent) orally or intramuscularly 12 and 6 hours before the administration of Mitotax®, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30 to 60 minutes before administration preparation Mitotaks®.

When choosing the regimen and doses in each individual case, one should be guided by the literature data.

Mitotax® is administered intravenously as a 3-hour or 24-hour infusion at a dose of 175 mg / m³ or 135 mg / m, respectively, with an interval between administrations of 3 weeks.The drug is used in the form of monotherapy or in combination with cisplatin (ovarian cancer and non-small cell lung cancer) or doxorubicin (breast cancer).

Repeated administration of Mitotax® is carried out at a neutrophil count in peripheral blood ≥ 1500 / μL of blood and platelets - ≥ 00000 / μl.

Patients who had experienced severe neutropenia after previous paclitaxel injections (neutrophil count <500 / μL blood for 7 days or more long-term) or severe form of peripheral neuropathy, the dose of Mitotax® should be reduced by 20% during subsequent courses of treatment.

The rules for preparation, introduction and storage of the solution:

Solution for infusion is prepared immediately before the introduction. Concentrate is diluted with 0.9% sodium chloride solution, or 5% dextrose solution, or a combination of 5% dextrose solution with 0.9% sodium chloride solution, or a combination of 5% dextrose solution in Ringer's solution. The final concentration of paclitaxel in the solution should be from 0.3 to 1.2 mg / ml. The prepared solutions may be opalescent due to the carrier base present in the formulation, and after filtration, the opalescence of the solution may persist.

When preparing, storing and administering Mitotax®, you should use equipment that does not contain PVC parts.

Mortar Mitotax® solutions should be prepared and stored in glass, polypropylene or polyolefin systems and injected through infusion systems with an internal surface of polyethylene, and also through a membrane filter connected to the system with a pore size of not more than 0.22 microns.

Side effects:

The frequency and severity of side effects are dose-dependent.

From the hematopoiesis: neutropenia, thrombocytopenia, anemia. Suppression of bone marrow function, mainly granulocyte germ, was the main toxic effect limiting the dose of the drug. The maximum decrease in the level of neutrophils is usually observed on day 8-11, normalization occurs on day 22.

Allergic reactions: skin rash, "hot flashes" of blood to the skin of the face and upper chest, angioedema, bronchospasm, generalized urticaria, lowering of arterial pressure, pain behind the sternum. Single cases of chills and pains in the back are described.

From the cardiovascular system: lowering blood pressure (BP), less often - increasing blood pressure, bradycardia or tachycardia, rhythm disturbance, atrioventricular blockade, ventricular bigemia, changes in ECG, thrombosis of venous vessels.

From the respiratory system: interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, and more frequent development of radiation pneumonitis in patients concomitant with radiotherapy.

From the nervous system: peripheral neuropathy (mainly paresthesia). Rarely - convulsive seizures of the type grand mal, ataxia, encephalopathy, optic nerve damage, autonomic neuropathy, manifested by paralytic intestinal obstruction and orthostatic hypotension.

From the musculoskeletal system: arthralgia, myalgia.

On the part of the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation; there are isolated reports of acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis; increased activity of "liver" transaminases (more often ACT), alkaline phosphatase and bilirubin in serum. The cases of development of hepatonecrosis and hepatic encephalopathy are described.

From the skin and skin appendages: alopecia, rarely a violation of pigmentation or discoloration of the nail bed.

From the sense organs: decreased visual acuity, conjunctivitis, increased lacrimation.

Local reactions: thrombophlebitis, pain, swelling, erythema, induration and skin pigmentation at the injection site; Extravasation can cause inflammation and necrosis of subcutaneous tissue.

Other: asthenia and general malaise, decreased tolerance to infections (any etiology).

Overdose:

Symptoms: aplasia of the bone marrow, peripheral neuropathy, mucositis.

Treatment: symptomatic. The antidote to paclitaxel is not known.

Interaction:

Cisplatin reduces the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when paclitaxel injected after cisplatin). Inhibitors of microsomal oxidation (incl. ketoconazole, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel.

Simultaneous use with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins.Polyoxyethylated castor oil, which is a part of paclitaxel, can cause extraction of DEHGT [di- (2-hexyl) phthalate] from plasticized polyvinylchloride (PVC) containers, where the degree of leaching of the DEHP increases with increasing solution concentration and with time.

Special instructions:

Treatment with Mitotax® should be performed under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs.

If Mitotax® is used in combination with cisplatin, first enter Mitotax® and then cisplatin.

During treatment it is necessary to regularly monitor the picture of peripheral blood, blood pressure, heart rate and the number of breaths (especially during the first hour of infusion), ECG control (and before treatment).

In case of development of severe hypersensitivity reactions, the infusion of Mitotax® should be stopped immediately and symptomatic treatment should be started, and the drug should not be injected again.

In cases of development of violations of atrioventricular conduction, with repeated administration it is necessary to carry out continuous cardiomonitoring.

Patients should be provided with reliable contraceptive methods during treatment with Mitotax® and at least 3 months after the end of therapy.

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Mitotax® is a cytotoxic substance that should be used with caution, use gloves and avoid contact with skin or mucous membranes, which in such cases must be thoroughly washed with soap and water or (eyes) with plenty of water.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 6 mg / ml.

Packaging:Concentrate for the preparation of a solution for infusions of 6 mg / ml: 30 mg / 5 ml, 100 mg / 16.7 ml, 250 mg / 41.7 ml and 300 mg / 50 ml in colorless glass bottles sealed with rubber stopper and crimped aluminum cap with a protective plastic lid gray for vials of 5 ml, red for vials of 16.7 ml, violet for bottles of 41.7 ml and green for bottles of 50 ml.
For 1 bottle of 5 ml, 16.7 ml, 41.7 ml and 50 ml, along with instructions for use in a pack of cardboard. For 1 vial (16.7 ml, 41.7 ml and 50 ml) in a contiguous cell Packing together with instructions for use in a pack of cardboard.

Storage conditions:

List B.

In a dry, the dark place at a temperature of no higher than 25 ° C. Do not freeze. Keep 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:П N013321 / 02

Date of registration:22.10.2007

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDr. Reddy`c Laboratoris Ltd.Dr. Reddy`c Laboratoris Ltd.

Information update date: & nbsp16.10.2015

Illustrated instructions

Instructions

Mitotax® (Mitotax)