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

Pharmacodynamics:PACLITAXEL is an antitumor preparation of natural 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 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:

At intravenous (iv) introduction within 3 hours in a dose of 135 mg / ml the maximum concentration (Сmах) 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.

Communication with plasma proteins is 88-98%. The average volume of distribution is 198-688 l / m². 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 CYP2C8 (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-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 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.

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 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.

- Child age (safety and efficacy not established).

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 .

Dosing and Administration:

To prevent severe reactions of hypersensitivity, all patients should be

premedication with glucocorticosteroids, antihistamines. For example, 20 mg of dexamethasone (or its equivalent) orally for about 12 and 6 hours before the administration of the drug PACLITAXEL, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes before the administration of the drug PACLITAXEL. When choosing the regimen and doses in each individual case, one should be guided by the literature data.

PAKLITAXEL 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 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 PACLITAXEL for the treatment of Kalosha sarcoma in AIDS patients is 100 mg / m² in the form of a 3-hour infusion every 2 weeks.

Administration of the drug PACLITAXEL not should 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 had severe neutropenia (neutrophil count <500 / μL blood for 7 days or longer) or severe peripheral neuropathy after the administration of PAKLITAXEL during subsequent courses of treatment should be reduced by a dose of PACLITAXEL by 20 %.

Rules for the preparation of a solution for infusions.

Solution for infusion is prepared immediately before the introduction,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 of from 03 to 13 mg / ml . The prepared solutions may be opalescent due to the carrier-form present in the formulation, after filtration, the opalescence of the solution is retained.

With multiple selection of the drug from the vial of the concentrate and the "preparation of a solution for infusions remains microbiologically, physically and chemically stable for 28 days at a temperature of 25 ° C.

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

PACLITAXEL should be administered through a system with an integrated membrane filter (pore diameter not more than 0.22 microns).

If unopened vials are placed in the refrigerator, a precipitate may form which dissolves again with little stirring (or without stirring) when room temperature is reached. The quality of the product does not deteriorate.If the solution remains cloudy, or if there is an insoluble deposit, the vial should be destroyed.

Side effects:

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

The following undesirable phenomena noted with the use of the drug are distributed according to the frequency of occurrence in accordance with the following gradation: very often (≥1/10), often (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100), rarely (from ≥1/10000 to <1/1000), very rarely (<1/10000).

On the part of the organs of hematopoiesis

Often: severe neutropenia, severe leukopenia, thrombocytopenia, anemia;

Often: febrile neutropenia;

Infrequently: severe anemia;

Rarely: acute myeloblastic leukemia, myelodysplastic syndrome. Suppression of bone marrow function, mainly of 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

Often: reactions of hypersensitivity, manifested mainly by skin rashes and "tides" of blood to the face;

Infrequently: hypersensitivity of delayed type, expressed reactions hypersensitivity, requiring additional treatment (eg, lowering blood pressure, angioedema, respiratory distress syndrome, generalized urticaria);

Rarely: anaphylactic reactions;

Rarely: anaphylactic shock, including lethal cases;

Single cases of chills and pains in the back are described.

From the nervous system

Often: peripheral neuropathy (mainly paresthesia), drowsiness;

Often: severe neuropathy (mainly peripheral), dizziness, increased excitability, insomnia, impaired thinking, depression, hypokinesia, gait disturbance, hypoesthesia, taste change, headache;

Rarely: peripheral motor neuropathy (leading to distal weakness);

Rarely: convulsive seizures of the type grand mal, ataxia, acute encephalopathy, confusion, optic nerve damage, vegetative neuropathy, manifested by paralytic intestinal obstruction and orthostatic hypotension.

From the sense organs

Often: tinnitus;

Infrequently: dry eye, amblyopia, visual field defects;

Rarely: visual disturbances (flickering scotoma), in particular, in patients receiving doses exceeding recommended, reduced visual acuity, conjunctivitis, increased lacrimation, hearing loss by neurosensory type, vertigo.

From the side of the cardiovascular system

Often: lowering of blood pressure (BP);

Often: tachycardia, palpitation, bradycardia, syncope, vasodilation (hot flashes);

Infrequently: cardiomyopathy, asymptomatic ventricular tachycardia, ventricular bigeminy, atrioventricular blockade, myocardial infarction, thrombophlebitis, increased blood pressure, thrombosis of venous vessels;

Rarely: rhythm disturbance, changes in ECG;

Rarely: shock.

From the respiratory system

Often: shortness of breath, nosebleed;

Rarely: interstitial pneumonia, pulmonary fibrosis;

Rarely: cough, pulmonary hypertension, pulmonary embolism, and a more frequent development of radiation pneumonitis in patients undergoing radiotherapy.

From the digestive system

Often: nausea, vomiting, diarrhea, mucositis, constipation, stomatitis, abdominal pain;

Often: dry mouth, ulceration of the oral mucosa, melena, indigestion;

Rarely: anorexia, acute pancreatitis, esophagitis, ascites, increased activity of "hepatic" transaminases (more often aspartate aminotransferase), alkaline phosphatase and bilirubin in serum.

There are isolated reports of acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis.

The cases of development of hepatonecrosis and hepatic encephalopathy are described.

From the skin and skin appendages

Often: alopecia;

Often: reversible skin changes, dry skin, exfoliative dermatitis, psoriasis, rash, acne, moderately severe disorders of the nail plate;

Infrequently: violation of pigmentation or discoloration of the nail bed;

Rarely: erythema;

Rarely: multiforme exudative erythema, incl. Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, onycholysis.

From the musculoskeletal system

Often: arthralgia, myalgia;

Often: pain in the bones, cramps in the legs, myasthenia gravis, back pain.

Local Reactions

Often: moderately expressed phenomena at the injection site (pain, swelling, erythema, induration and skin pigmentation, extravasation can cause inflammation and necrosis of subcutaneous tissue).

Other

Often: asthenia, edema (including peripheral and edema of the face), a decrease in tolerance to infections (any etiology);

Often: flu-like syndrome, malaise, chest pain, chills, fever;

Infrequently: dehydration, decreased or increased body weight, severe infections, septic shock.

Overdose:

Symptoms: bone marrow aplasia, peripheral neuropathy, mucositis.

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

Interaction:

Interaction with other drugs and other forms of interaction

With the administration of paclitaxel after cisplatin, clearance of paclitaxel is reduced by approximately 20%, with more pronounced myelosuppression, and, therefore, cisplatin it is recommended to administer after paclitaxel.

Simultaneous administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the association of paclitaxel with plasma proteins.

With the use of paclitaxel in combination with doxorubicin, an increase in the content of doxorubicin and its active metabolite of doxorubicin in blood plasma can be observed.

Polyoxyethylated castor oil, which is part of paclitaxel, can cause the extraction of DEHP [di- (2-diethylhexyl) phthalate] from plasticized polyvinylchloride (PVC) containersand the leaching rate DEHP increases with increasing solution concentration and with time.

Special instructions:Treatment with drug PACLITAXEL should be carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs.

If the drug PACLITAXEL is used in combination with cisplatin, PACLITAXEL, and then cisplatin.

In the case of severe hypersensitivity reactions, infusion preparation PACLITAXEL should immediately stop and start symptomatic treatment, 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 during drug treatment PACLITAXEL and at least 3 months after the end of therapy, reliable methods of contraception should be used.

PACLITAXEL is an cytotoxic agent, use caution when handling, 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.

During the treatment period, care must be taken when driving motor vehicles, employment by potentially dangerous kinds of activity demanding the raised concentration of attention and speed of psychomotor reactions.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 30 mg / 5 ml, 100 mg / 16.7 ml, 140 mg / 23.3 ml, 150 mg / 25 ml, 210 mg / 35 ml, 250 mg / 41.7 ml, 260 mg / 43.4 ml, 276 mg / 46 ml, 300 mg / 50 ml, 600 mg / 100 ml (6 mg / ml).

Packaging:Manufacturer PJSC "PHARMSTANDART-BIO LEK ".

5 ml in bottles of glass tube or 5 ml, 16.7 ml, 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml in a flaskStones made of glass, ukuporennyh stoppersnew with aluminum caps or with caps made of aluminum and plastics.

For 1 vial of 5 ml or 16.7 ml, 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml with instructions for use put in a pack of cardboard.

It is allowed to pack in a film of 10 packs with one bottle of 5 ml or 16.7 ml, or 1 pack with one bottle of 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml.

Manufacturer of ONKO JENERICS.

5 ml, 16.7 ml, 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml each into bottles of glass, sealed with rubber stoppers with aluminum caps or with caps combined of aluminum and plastic.

1 bottle of 5 ml, 16.7 ml, 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml together with the instructions for use are placed in a pack of cardboard.

It is allowed to pack in a film of 10 packs with one bottle of 5 ml or 16.7 ml, or 1 pack with one bottle of 23.3 ml, 25 ml, 35 ml, 41.7 ml, 43.4 ml, 46 ml, 50 ml, 100 ml.

Storage conditions:In the dark place at a temperature of 15 ° C to 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000464

Date of registration:01.03.2011 / 23.09.2014

Expiration Date:01.03.2016

The owner of the registration certificate:FARM STANDART, OJSC FARM STANDART, OJSC Russia

Manufacturer: & nbsp

PHARMSTANDART-BIOOLEK, PAO Ukraine

Information update date: & nbsp11.10.2015

Illustrated instructions

Instructions

Paclitaxel (Paclitaxel)