Paclitaxel-Ebeve Concentrate for infusion solution 6mg/ml 50ml vial, 1pc

Composition

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1 ml contains:

Active ingredients:

paclitaxel 6 mg.

Auxiliary substances:

macrogol glycerylricinoleate (polyoxyethylated castor oil) – 522.396 mg,

ethanol – 401.664 mg.

The bottle contains 50 ml of concentrate.

In a cardboard box 1 bottle.

Pharmacological action

Pharmacodynamics

Antitumor drug of natural origin, obtained semi-synthetically from the Taxus baccata plant.

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 dose-dependent suppression of bone marrow hematopoiesis.

Pharmacokinetics

Distribution

When administered intravenously for 3 hours at a dose of 135 mg/m2, Cmax is 2170 ng / ml, AUC is 7952 ng / h / ml; when the same dose is administered for 24 hours, it is 195 ng / ml and 6300 ng / h/ml, respectively. The values of Cmax and AUC are dose-dependent: when infused for 3 hours, an increase in the dose to 175 mg / m2 leads to an increase in these parameters by 68% and 89%; within 24 hours-by 87% and 26%, respectively.

Binding to plasma proteins is 88-98%. The average Vd is 198-688 l / m2.

The half-life from blood to tissue is 30 minutes. It easily penetrates the body’s tissues, mainly in the liver, spleen, pancreas, stomach, intestines, heart, and muscles. With repeated infusions in the body does not accumulate.

Metabolism

It is metabolized in the liver by hydroxylation with the participation of cytochrome P 450 isoenzymes CYP2D8 (with the formation of the metabolite 6-alpha-hydroxypactaxel) and CYP3CA4 (with the formation of the metabolites 3-para-hydroxypactaxel and 6-alpha,3-para-dihydroxypactaxel).

Deduction

It is mainly excreted in bile-90%. T1 / 2 and total clearance are variable and depend on the dose and duration of intravenous use: 13.1-52.7 hours and 12.2-23.8 l/h / m2, respectively. After intravenous infusion (1-24 h), total renal excretion 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 / m2.

Indications

• Ovarian cancer (first-line therapy in combination with platinum drugs and second-line therapy of metastasis after standard therapy, did not give a positive result);
• breast cancer (as a therapy of first and second line and adjuvant treatment);
• non-small cell lung cancer (first-line therapy of patients who have not planned for surgery and/or radiotherapy /in combination with cisplatin/);
• Kaposi’s sarcoma in AIDS patients (second-line therapy after ineffective treatment with liposomal anthracyclines).

Use during pregnancy and lactation

No controlled studies have been conducted on the use of paclitaxel in pregnant women. Animal studies have shown embryotoxic, teratogenic and mutagenic effects of paclitaxel. Therefore, paclitaxel should not be used during pregnancy.

It is not known whether paclitaxel is excreted in breast milk, so in order to avoid toxic effects of the drug on the baby, breastfeeding should be discontinued during treatment

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

Contraindications

• Hypersensitivity to the components of the drug;
• hypersensitivity to other drugs, dosage form which includes polyoxyethylene castor oil;
• the original contents of neutrophils less than 1500/µl for patients with solid tumors;
• the source (or was in the process of treatment) content of neutrophils less than 1000/µl when Kaposi’s sarcoma in AIDS patients;
• pregnancy;
• lactation (breastfeeding);
• children’s age (safety and efficacy not established).

With caution: used in patients with inhibition of bone marrow hematopoiesis (including after chemotherapy or radiation therapy), liver failure, acute infectious diseases (including shingles, chickenpox, herpes), severe coronary heart disease, with a history of myocardial infarction, with arrhythmia.

Side effects

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

Determining the frequency of side effects:

• very often – > 10%;>
• often – from 1 to 10%;
• infrequently-from 0.1% to 1%;
• rarely-from 0.01 to 0.1%;
• very rarely-less than 0.01%.

From the hematopoietic system: very often-myelosuppression, neutropenia, thrombocytopenia, anemia, leukopenia, bleeding; rarely-febrile neutropenia; very rarely-acute myeloid leukemia, myelodysplastic syndrome.

From the nervous system: very often – neurotoxic effects (mainly peripheral neuropathy), paresthesia; rarely-motor neuropathy (moderate weakness of the distal muscles, difficulty performing precise movements); very rarely-vegetative neuropathy (leading to paralytic intestinal obstruction and orthostatic hypotension), large epileptic seizures (grand mal), convulsions, encephalopathy, dizziness, headache, confusion, ataxia.

From the cardiovascular system: often-bradycardia, decreased blood pressure; infrequently-cardiomyopathy, asymptomatic ventricular tachycardia, AV block, syncope, increased blood pressure, myocardial infarction, vascular thrombosis, thrombophlebitis; very rare-atrial fibrillation, supraventricular tachycardia, shock.

From the sensory organs: very rarely-optic nerve damage and / or visual disturbances (atrial fibrillation), hearing loss, tinnitus, dizziness.

From the respiratory system: rarely – shortness of breath, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure, radiation pneumonitis in patients undergoing radiation therapy at the same time; very rare-cough.

From the digestive system: very frequent-nausea, vomiting, diarrhea, inflammation of the mucous membranes; rarely-pancreatitis, intestinal perforation, ischemic colitis; very rarely – anorexia, constipation, mesenteric thrombosis, pseudomembranous colitis, esophagitis, ascites, neutropenic colitis, liver necrosis, hepatic encephalopathy (there are isolated reports of death).

From the skin and skin appendages: very often – alopecia; often – transient small changes in the nails and skin (pigmentation disorders, discoloration of the nail bed); rarely – itching of the skin, rashes, erythema; very rarely – Stevens-Johnson syndrome (ulceration of the mucous membrane of the mouth, throat, eyes, genitals, other areas of the skin and mucous membranes), epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis.

Musculoskeletal disorders: very common – arthralgia, myalgia.

From the immune system: very frequent-infections (mainly of the urinary tract and upper respiratory tract); infrequently-serious hypersensitivity reactions that require therapeutic measures (namely, a decrease in blood pressure, angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in the extremities, severe sweating, increased blood pressure); rarely-anaphylatoid reactions.

From the side of laboratory parameters: often-an increase in the activity of hepatic transaminases, an increase in the concentration of alkaline phosphatase, bilirubin, and creatinine in the blood serum.

Local reactions: often-pain, localized edema, erythema, induration and pigmentation of the skin at the injection site; extravasation can cause inflammation and necrosis of the subcutaneous tissue.

Other: rarely-asthenia, fever, dehydration, general weakness.

Interaction

Cisplatin reduces the total clearance of paclitaxel by 20%, so when combined chemotherapy paclitaxel should be administered before cisplatin. More pronounced myelosuppression is observed when paclitaxel is administered after cisplatin. With combined chemotherapy (paclitaxel and cisplatin), the risk of developing renal failure is higher than with cisplatin monotherapy.

Concomitant use with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to plasma proteins.

Since elimination of doxorubicin and its active metabolites can be reduced by shortening the time interval between paclitaxel and doxorubicin use, paclitaxel should be administered 24 hours after doxorubicin.

Information on the potential interaction of paclitaxel with inhibitors and inducers of cytochrome P450 isoenzymes (in particular, the CYP3A4 isoenzyme) is limited, so caution should be exercised when using inhibitors (for example, erythromycin, fluoxetine, gemfibrozil) or inducers (for example, rifampicin, carbamazepine, phenytoin, phenobarbital) of cytochrome P450 isoenzymes at the same time.

Microsomal oxidation inhibitors (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine) inhibit paclitaxel metabolism. However, it is known that with simultaneous use of ketoconazole and paclitaxel, the elimination of the latter does not slow down, so both drugs can be used without dose adjustment.

Concomitant use of paclitaxel with nelfinavir or ritonavir (but not indinavir) significantly reduces the systemic clearance of paclitaxel. There is insufficient information on the interaction of paclitaxel and other protease inhibitors when used concomitantly.

Polyoxyethylated castor oil, which is part of paclitaxel, can cause the extraction of di-(2-hexyl)phthalate (DEHP) from plasticized PVC containers, and the degree of leaching of DEHP increases with increasing solution concentration and time. Therefore, when preparing, storing and administering Paclitaxel-Ebeve, you should use equipment that does not contain PVC parts.

How to take, course of use and dosage

Enter iv.

Paclitaxel can be used both as monotherapy and in combination with other antitumor drugs. The dose and regimen of the drug are selected individually.

To prevent severe hypersensitivity reactions, all patients should be premedicated using corticosteroids, histamine H1 – and H2-receptor blockers. The recommended premedication regimen is 20 mg dexamethasone (or its equivalent) orally approximately 12 hours and 6 hours before use of Paclitaxel-Ebeve,50 mg diphenhydramine (or its equivalent) IV and 300 mg cimetidine or 50 mg ranitidine IV 30-60 minutes before use of Paclitaxel-Ebeve.

First-line chemotherapy for ovarian cancer

A combined treatment regimen with paclitaxel and cisplatin is recommended. Paclitaxel is administered at a dose of 175 mg / m2 of body surface area for a 3-hour intravenous infusion or at a dose of 135 mg/m2 for a 24-hour intravenous infusion, followed by cisplatin at a dose of 75 mg/m2. The intervals between courses are 3 weeks.

Second-line chemotherapy for ovarian cancer

Paclitaxel is recommended to be administered at a dose of 175 mg / m2 of body surface area by 3-hour intravenous infusion. The intervals between courses are 3 weeks.

Adjuvant chemotherapy for breast cancer

Paclitaxel is prescribed after chemotherapy with anthracyclines and cyclophosphamide. Paclitaxel is recommended to be administered at a dose of 175 mg/m2 IV for 3 h. 4 courses with intervals between courses-3 weeks.

First-line chemotherapy for breast cancer

In the case of combined use with doxorubicin (at a dose of 50 mg/m2 of body surface area), paclitaxel should be administered 24 hours after doxorubicin.

The recommended dose of paclitaxel is 220 mg / m2 of body surface area when administered by a 3-hour intravenous infusion. The intervals between courses are 3 weeks.

In the case of combined use with trastuzumab, paclitaxel is recommended to be administered at a dose of 175 mg/m2 of body surface area by 3-hour intravenous infusion with an interval between courses of 3 weeks. Paclitaxel can be administered the day after the first dose of trastuzumab or immediately after subsequent doses, if the previous doses of trastuzumab were well tolerated.

Second-line chemotherapy for breast cancer

Paclitaxel is recommended to be administered at a dose of 175 mg / m2 by 3-hour intravenous infusion. The intervals between courses are 3 weeks.

Chemotherapy for advanced non-small cell lung cancer

A combined treatment regimen with paclitaxel and cisplatin is recommended. Paclitaxel is administered at a dose of 175 mg / m2 of body surface area by a 3-hour intravenous infusion, followed by cisplatin at a dose of 80 mg/m2. The intervals between courses are 3 weeks.

Chemotherapy for Kaposi’s sarcoma on the background of AIDS

Paclitaxel is recommended to be administered at a dose of 100 mg / m2 by 3-hour intravenous infusions. The intervals between courses are 2 weeks.

Subsequent doses of paclitaxel are set individually depending on the tolerability of therapy. The next dose of paclitaxel can be administered only after increasing the number of neutrophils to ≥1500 cells/µl (≥1000 cells/µl in the case of Kaposi’s sarcoma), and platelets to > 100,000 cells/mm3 (>> 75,000 cells/mm3 in the case of Kaposi’s sarcoma). Patients who have experienced severe neutropenia (neutrophil count less than 500 cells/µl for 7 days or more) or severe peripheral neuropathy, the following doses are reduced by 20% (25% in the case of Kaposi’s sarcoma).

Currently, there is insufficient data to provide recommendations for dose adjustment in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment should not be prescribed paclitaxel.

Rules for preparing the solution for infusions

When preparing, storing, and administering Paclitaxel-Ebeve, use equipment that does not contain PVC, such as glass, polypropylene, or polyolefin.

The drug solution is prepared by diluting the concentrate to the final concentration of paclitaxel from 0.3 to 1.2 mg / ml. As a diluent solution can be used: 0.9% sodium chloride solution,5% dextrose solution,5% dextrose solution in 0.9% sodium chloride solution,5% dextrose solution in Ringer’s solution. The prepared solutions may opalescent due to the carrier base present in the dosage form. When the drug is administered, a system with a membrane filter (pore size not exceeding 0.22 microns) should be used.

Infusion solutions prepared by diluting Paclitaxel-Ebeve with 0.9% sodium chloride solution or 5% dextrose solution are physically and chemically stable for 51 hours when stored at 25°C and 14 days when stored at 5°C. From a microbiological point of view, the infusion solution should be administered immediately after preparation. If the solution is not used immediately after preparation, the storage time should not exceed 24 hours at a temperature of 2° to 8°C, unless the solution was prepared under controlled aseptic conditions.

To reduce the risk of sediment formation, the infusion solution should be administered immediately after dilution and avoid excessive shaking, vibration and agitation.

The infusion system should be thoroughly flushed before use. During use, it is necessary to regularly monitor the appearance of the solution and stop the infusion if a sediment is detected.

Overdose

Symptoms: bone marrow suppression, peripheral neuropathy, inflammation and ulceration of the mucous membranes.

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

Special instructions

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

If severe hypersensitivity reactions develop, Paclitaxel-Ebeve should be discontinued immediately and symptomatic therapy should be initiated, and repeated use of the drug should not be carried out.

If Paclitaxel-Ebeve is used in combination with cisplatin, Paclitaxel-Ebeve should be administered first, followed by cisplatin.

When working with Paclitaxel-Ebeve, care should be taken (as when working with other cytotoxic substances), wear gloves and avoid contact with the skin or mucous membranes. In case of contact with the skin, it should be thoroughly washed with soap and water; in case of contact with the eyes – with plenty of water.

Monitoring of laboratory parameters

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 monitoring should be performed before starting therapy and regularly during treatment.

If AV conduction disorders develop during repeated injections, continuous ECG monitoring should be performed.

Use in pediatrics

The safety and efficacy of Paclitaxel-Ebeve in children has not been established. Use in pediatrics is contraindicated.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Due to the likelihood of side effects, such as headache, dizziness, drowsiness, during treatment, patients should refrain from engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Precautions for handling and disposal of unused product

Caution should be exercised when using Paclitaxel-Ebeve. Dilute the drug should be in aseptic conditions in a specially designated room. This should be handled by trained personnel. It is necessary to take all measures to prevent the paclitaxel solution from getting on the skin and mucous membranes, in particular, use protective clothing (robe, cap, mask, glasses and disposable gloves). Shortness of breath, chest pain, burning sensation in the throat, and nausea have been reported when inhaling paclitaxel vapors or sprayed solutions.

If paclitaxel gets on the skin or mucous membranes, wash thoroughly with soap and water or (eyes) with plenty of water.

The drug should not be frozen, as it can form a precipitate. This precipitate usually dissolves when the vial is heated to room temperature (25°C). If the solution in the previously frozen bottle remains cloudy or there is an insoluble precipitate, the drug cannot be used and such a bottle must be destroyed. The prepared infusion solution does not need to be protected from light.

Drug residues and all tools and materials that were used to prepare the solution for infusion and use of Paclitaxel-Ebeve should be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substance waste, taking into account the current regulations for the disposal of hazardous waste.

Form of production

Concentrate for preparation of solution for infusions

Storage conditions

Keep out of the reach of children, protected from light at a temperature not exceeding 25°C.

Shelf

life is 3 years.

Active ingredient

Paclitaxel

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Breast Cancer