Paxen - instructions for use, doses, 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, a decrease in reproductive function.

Pharmacokinetics:

With intravenous (IV) administration 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" (АUC) -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. The connection with plasma proteins is 88-98%. The average volume of distribution is 198-688 l / m. 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 3-para-hydroxypaclitaxel and 6-alpha, 3-paradihydroxy paclitaxel). It is excreted mainly with bile - 90%. When repeated infusions are not cumulated.

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.After intravenous infusion (1-24 hours), the total excretion by the kidneys is 1.3-12.6% of the dose (15-275 mg / m²), which indicates the presence of intensive extrarenal clearance. The total ground clearance is 11-24 l / sq.m.

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 is adjuvant treatment, after relapse, within 6 months after the 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).

- 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 whose dosage form includes polyoxylated 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. The safety and effectiveness of Paxen in children is not established.

Dosing and Administration:

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, antihistamines and H antagonists₂ histamine receptors. For example, 20 mg of dexamethasone (or its equivalent) orally within about 12 and 6 hours before the administration of Paxen, 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 Paxen.

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

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

The administration of Paxen should not be repeated until the neutrophil count is at least 1500 / μl of blood and the platelet count is at least 100,000 / μl of blood. Patients who experienced severe neutropenia after administration of Paxen (neutrophil count <500 / mm³ blood for 7 days or longer) or a severe form of peripheral neuropathy during subsequent courses of treatment, the dose of Paxen should be reduced by 20 % .

The drug solution is prepared immediately before administration, diluting the concentrate with 0.9% sodium chloride solution, 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 from 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 drug Paksen should use the equipment, which does not contain PVC parts.

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 Paxen's administration, there may be reactions of increased sensitivity, manifested by bronchospasm, lowering of arterial pressure, pain behind the sternum, flushing of the face, skin rashes, 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 mal, 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.

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

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

Other adverse reactions: 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 administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the association of paclitaxel with plasma proteins.

Inhibitors of microsomal oxidation (incl. ketoconazole, cimetidine, dexamethasone, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel. This interaction in the appointment of drugs in therapeutic doses of clinical importance.

Special instructions:

The use of Paxen should be carried out under the supervision of a doctor who has experience working with antitumoral chemotherapeutic drugs.

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, antihistamines and antagonists of Hg histamine receptors: 20 mg of dexamethasone (or its equivalent) orally for about 12 and 6 hours before administration of Paxen, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes prior to administration of Paxen.

In case of severe hypersensitivity reactions, the infusion of Paxen should be stopped immediately and symptomatic treatment should be started, and the drug should not be re-administered.

Polyoxyethylated castor oil, which is part of the Paxen preparation, can cause extraction of DEHP [di- (2-hexyl) phthalate] from plasticized polyvinylchloride (PVC) containers, and the degree of leaching of the DEHP increases with increasing solution concentration and with time. Therefore, when preparing, storing and administering the drug Paksen should use the equipment,which does not contain PVC parts.

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

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

If Paxen is used in combination with cisplatin, you should first administer Paxen, and then cisplatin.

Patients during treatment with Paxen and at least 3 months after the end of therapy should use reliable methods of contraception.

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.

Paxen 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 a large amount of water.

Form release / dosage:Concentrate for the preparation of solution for infusion.

Packaging:

Concentrate in vials of 30 mg / 5 ml, 100 mg / 16.7 ml, 150 mg / 25 ml and 300 mg / 50 ml.

1 bottle per pack with the enclosed instructions for use.

Storage conditions:

In the dark place at a temperature of + 10 ° to + 25 ° C. KEEP OUT OF THE REACH OF CHILDREN

Shelf life:

3 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N014957 / 01-2003

Date of registration:13.05.2009

The owner of the registration certificate:AIVEX-CR as.AIVEX-CR as. Czech Republic

Manufacturer: & nbsp

IVAX-CR, a.s. Czech Republic

Information update date: & nbsp15.10.2015

Illustrated instructions

Instructions

Paxen® (Paxene®)