Paklitera - 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, it causes a decrease in reproductive function.

Pharmacokinetics:

With intravenous (IV) administration for 3 hours at a dose of 135 mg / m² maximum concentration (С_mOh) 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. FROM_max and AUC dose-dependent: with 3-hour infusions, dose increase to 175 mg / m² leads to an increase in these parameters by 68% and 89%, and at 24 hours - 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 absorbs 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-up-hydroxy-paclitaxel) and CYP3CA4 (with the formation of metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-paradihydroxy paclitaxel). It is excreted mainly with bile - 90%. With repeated infusions do not cumulate.

The half-life and total clearance are variable and depend on the dose and duration in / in the introduction: 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.

Indications:

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

- Breast cancer (the presence of affected lymph nodes after standard combination therapy (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 (in combination with cisplatin).

- Kaposi's Sarcoma in AIDS patients (second-line therapy)

Contraindications:

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

- 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.

- Pregnancy and lactation.

Carefully:

Inhibition of bone marrow hemopoiesis (including after chemotherapy or radiation therapy), liver failure, acute infectious diseases (including herpes zoster, chickenpox, herpes), severe course of coronary heart disease, myocardial infarction (history), arrhythmias .

The safety and effectiveness of Pacliter's preparation in children is not established.

Dosing and Administration:

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, antihistamines and antagonists of Ng histamine receptors. For example, 20 mg of dexamethasone (or its equivalent) orally within 12 and 6 hours before the administration of the Pacliter preparation, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30 to 60 minutes prior to administration of the Pacliter preparation.

When choosing the mode and doses in each individual case, you should be guided by the dataspecial literature.

Pacifier is administered intravenously in the form of a 3-hour or 24-hour infusion at a dose of 175 mg / m² or 135 mg / m² 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). The recommended dose of the drug Paklitera 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.

The administration of Pacliter's preparation 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 have experienced severe neutropenia (neutrophil count <500 / μL blood for 7 days or longer) or severe peripheral neuropathy during subsequent courses of treatment should be reduced by 20%.

Solution for infusion 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 the 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 Pacliter, use equipment that does not contain PVC parts.

Pacifier should be introduced through 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.

From the immune system: in the first hours after the administration of Paklitera, reactions of hypersensitivity may occur, manifested by bronchospasm, lowering of arterial pressure, pain in the chest area, 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 (BP), less often - raising blood pressure, bradycardia, tachycardia, rhythm disturbance, atrioventricular blockade, ventricular bigemini, changes in ECG, thrombosis of venous vessels 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 gastrointestinal tract: 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, multiforme exudative erythema, incl. Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, onycholysis.

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 adverse reactions: 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).Simultaneous administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to plasma proteins. Inhibitors of microsomal oxidation (incl. ketoconazole, cimetidine, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel. Polyoxyethylated castor oil, which is a part of paclitaxel, can cause extraction of DEHP [di- (2-hexyl) phthalate] from plasticized polyvinylchloride (PVC) containers, 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.

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

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

Patients should be treated with safe contraceptive methods during treatment with Paclitera and at least 3 months after the end of therapy. During the treatment period, care must be taken when driving vehicles to engage in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Pacitera 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 rinsed with soap and water or (eyes) with plenty of water.

After diluting the concentrate, the physico-chemical stability of the preparation is maintained for 96 hours at a temperature below 25 ° C.

After dilution, the solution should not be frozen.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 6 mg / ml.

Packaging:

At 30 mg / 5 ml, 100 mg / 16.7 ml, 150 mg / 25 ml and 300 mg / 50 ml in colorless glass bottles capped with a rubber lid, rolled up with an aluminum cap and covered with a plastic lid "Flip off". For 1 bottle in a cardboard box with the attached instructions for use.

Storage conditions:

At a temperature of 15 to 25 ° C in a dark place.

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:LSR-003329/09

Date of registration:30.04.2009

The owner of the registration certificate:PROTERA, LTD. PROTERA, LTD. Russia

Manufacturer: & nbsp

HAUPT PHARMA WOLFRATSHAUSEN, GmbH Germany

Information update date: & nbsp15.10.2015

Illustrated instructions

Instructions

Pacifier (Paclitera)