Paclitaxel-Filaxis - instructions for use, dose, side effects, contraindications

The mechanism of action is associated with the ability to stimulate the "assembly" of microtubules from dimeric tubulin molecules, stabilize their structure and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.

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) administration for 3 hours at a dose of 135 mg / m²the maximum concentration (Cmax) is 2170 ng / ml, the area under the curve "concentration-time" (AUC) - 7952 ng / h / ml; with the same dose administered for 24 hours at 195 ng / ml and 6300 ng / h / ml, respectively. Stam 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%, respectively, at 24 hours - by 87% and 26%, respectively.

With repeated infusions do not cumulate.

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 (with the formation of metabolites of 3-para-hydroxy-paclitaxel and 6-alpha, 3-para-dihydroxy 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 for surgical treatment and / or radiation therapy (in combination with cisplatin)).

- Kaposi's sarcoma in AIDS patients (second-line therapy, after ineffective therapy with liposomal anthracyclines)

Contraindications:

- Hypersensitivity to the drug, as well as other drugs, the dosage form of which includes polyoxyethylated castor oil.

- Pregnancy and lactation.

- The initial content of neutrophils is less than 1500 / μl in patients with solid tumors.

- The initial (or registered in the treatment) neutrophil count is less than 1000 / μl in patients with Kaposi's sarcoma in AIDS patients.

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. Safety and efficacy of the drug Paclitaxel in children is not established.

Dosing and Administration:

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, antihistamines and H antagonists₂-gistamine receptors: 20 mg dexamethasone (or its equivalent) orally approximately 12 and 6 hours before the administration of paclitaxel, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30 to 60 minutes before the administration of paclitaxel.

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

Paclitaxel is administered intravenously in the form of a 3-hour or 24-hour infusion at a dose of 135-175 mg / m² with an interval between courses 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).

The recommended dose of paclitaxel for the treatment of Kaposi's Sarcoma in AIDS patients is 100 mg / m² in the form of a 3-hour infusion every 2 weeks.

Administration of the drug paclitaxel should not be repeated until the neutrophil count is at least 1500 / μL blood, and the platelet count is at least 100,000 / μL blood. Patients who had severe neutropenia (neutrophil count <500 / μL blood for 7 days or longer) or severe form of peripheral neuropathy after subsequent administration of paclitaxel should be reduced by 20% after administration of paclitaxel.

The drug solution is prepared immediately before administration, diluting the concentrate with a 0.9% solution sodium chloride, or 5% dextrose solution, or 5% dextrose solution in a 0.9% solution of sodium chloride for injection, or 5% dextrose solution in Ringer's solution to a final concentration of 0.3 to 1.2 mg / ml.The prepared solutions may be opalescent due to the carrier base present in the formulation, after which the opalescence of the solution is retained.

When preparing, storing and administering the preparation paclitaxel Use equipment that does not contain PVC parts.

Paclitaxel should be administered via a system with an integrated membrane filter (pore size 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: in the first hours after administration of paclitaxel may experience hypersensitivity reactions manifested by bronchospasm, decreased blood pressure, pain in the chest, flushing, skin rash, generalized urticaria, angioedema.Single cases of chills and pains in the back are described.

From the cardiovascular system: lowering blood pressure, less often - raising blood pressure, bradycardia, tachycardia, atrioventricular blockade, ECG changes, vascular thrombosis and thrombophlebitis are possible.

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: mainly paresthesia. Rarely - convulsive seizures of the type grand trial, visual impairment, ataxia, encephalopathy, vegetative neuropathy, manifested by paralytic intestinal obstruction and orthostatic hypotension.

From the musculoskeletal system: arthralgia, myalgia.

From the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation. Single reports of acute intestinal obstruction, perforation of the intestine, thrombosis of the mesenteric artery, ischemic colitis.

On the part of the liver: 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.

Local reactions: 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.

Overdose:

Symptoms: bone marrow aplasia, 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). Simultaneous use with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins.

Inhibitors of microsomal oxidation (incl. ketoconazole, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel.

Polyoxyethylated castor oil, which is a part of the preparation Paclitaxel, can cause the extraction of DEHP [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:

The use of paclitaxel should be carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs.

If paclitaxel is used in combination with cisplatin, paclitaxel, 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 the case of severe hypersensitivity reactions, the infusion of the drug paclitaxel should immediately stop and start symptomatic treatment, and the drug should not be re-administered.

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

Patients should be treated with paclitaxel and at least 3 months after the end of therapy, reliable methods of contraception should be used.

During the treatment period, it is necessary to refrain from engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.

Paclitaxel is a cytotoxic substance that should be used with care, 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 infusion of 30 mg / 5 ml and 100 mg / 16.7 ml and 300 mg / 50 ml (6 mg / ml) in vials of colorless glass.

Packaging:For 1 bottle 100mg / 16.7ml and 300mg / 50ml concentrate, together with instructions for use. For 1 or 2 bottles of 30mg / 5ml concentrate, in a plastic pallet, together with instructions for use. For 2 vials of 100mg / 16.7ml of concentrate, in a plastic pallet, together with the instructions on application.

In packs cardboard.

Storage conditions:

List B. At a temperature not higher than + 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-001499

Date of registration:18.05.2010

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

Manufacturer: & nbsp

Laboratorios FILAXIS, S.A. Argentina

Information update date: & nbsp11.10.2015

Illustrated instructions

Instructions

Paclitaxel-Phylaxis (Paclitaxel-Filaxis)