Paclitaxel-Ebeve, 6 mg/ml 16.7 ml

• Ovarian cancer (first-line therapy in combination with platinum drugs and second-line therapy for metastases after standard therapy with no positive result);
• Breast cancer (as first- and second-line therapy as well as adjuvant treatment);
non-small cell lung cancer (first-line therapy in patients who are not scheduled for surgery and/or radiation therapy /in combination with cisplatin/);
• Kaposi’soma in AIDS patients (second-line therapy, after ineffective therapy with liposomal anthracyclines).

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Active ingredient

Composition

1 ml contains:

Active substances:

Paclitaxel 6 mg.

Associates:

macrogoal glycerylicinoleate (polyoxyethylated castor oil) – 522.396 mg,

ethanol – 401.664 mg.

The bottle contains 16.7 ml of concentrate.

There is 1 vial in the carton pack.

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How to take, the dosage

It is administered intravenously.

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

In order to prevent severe hypersensitivity reactions, all patients should be premedicated with corticosteroids, histamine H1- and H2-receptor blockers. The recommended premedication regimen is 20 mg dexamethasone (or equivalent) orally approximately 12 h and 6 h before administration of Paclitaxel-Ebeve, 50 mg diphenhydramine (or equivalent) IV and 300 mg cimetidine or 50 mg ranitidine IV 30-60 min before administration of Paclitaxel-Ebeve.

First-line chemotherapy for ovarian cancer

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

Adjuvant chemotherapy for breast cancer

Paclitaxel is administered after chemotherapy with anthracyclines and cyclophosphamide. Paclitaxel is recommended at a dose of 175 mg/m2 by IV for 3 hours. Four courses with 3 weeks intervals between courses.

First-line chemotherapy for breast cancer

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

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

In case of combined use with trastuzumab, paclitaxel is recommended at a dose of 175 mg/m2 of body surface by 3-hour IV 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 previous doses of trastuzumab have been well tolerated.

Second-line chemotherapy for breast cancer

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

The chemotherapy of advanced non-small cell lung cancer

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

The chemotherapy of Kaposi’s sarcoma with AIDS

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

The subsequent doses of paclitaxel are set individually depending on the tolerability of therapy. Next dose of paclitaxel can be administered only after increase of neutrophil number up to ≥1500 cells/μl level (≥1000 cells/μl in Kaposi sarcoma) and platelets up to 100000 cells/mm3 level (> 75000 cells/mm3 in Kaposi sarcoma). In patients with 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 sarcoma).

There are currently insufficient data to recommend dose adjustments for patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment should not be prescribed paclitaxel.

Regulations for preparing the infusion solution

Paclitaxel-Ebeve should be prepared, stored and administered using PVC-free equipment such as glass, polypropylene or polyolefin.

The drug solution is prepared by diluting the concentrate to a final paclitaxel concentration of 0.3 to 1.2 mg/ml. As a diluting 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. Prepared solutions may become opalescent due to the carrier base present in the drug form. When administering the drug, a membrane filter system should be used (pore size max. 0.22 µm).

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 in case of storage at 25 °С and 14 days in case of storage at 5 °С. 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 2° to 8°C unless the solution was prepared under controlled aseptic conditions.

In order to reduce the risk of sedimentation, the infusion solution should be administered immediately after dilution and excessive shaking, vibration and agitation should be avoided.

The infusion system should be thoroughly rinsed prior to use. The appearance of the solution should be monitored regularly during administration and the infusion should be stopped if precipitate is detected.

Interaction

Cisplatin decreases total clearance of paclitaxel by 20%, therefore in combination chemotherapy paclitaxel should be administered before cisplatin. More pronounced myelosuppression is observed when paclitaxel is administered after cisplatin. When combined chemotherapy (paclitaxel and cisplatin) the risk of renal failure is higher than with cisplatin monotherapy.

Concomitant administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the plasma protein binding of paclitaxel.

Because elimination of doxorubicin and its active metabolites may decrease when the time interval between paclitaxel and doxorubicin is shortened, paclitaxel should be administered 24 hours after doxorubicin.

. Information about potential interaction of paclitaxel with inhibitors and inducers of cytochrome P450 system isoenzymes (in particular CYP3A4 isoenzyme) is limited, therefore caution is required when using simultaneously inhibitors (e.g. erythromycin, fluoxetine, gemfibrozil) or inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital) of cytochrome P450 system isoenzymes.

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

The simultaneous use of paclitaxel and 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, a component of paclitaxel, can cause extraction of di-(2-hexyl)phthalate (DEHP) from plasticized PVC containers, and the degree of DEHP washout increases with increasing solution concentration and time. Therefore, when preparing, storing and administering Paclitaxel-Ebeve, equipment that does not contain PVC parts should be used.

Special Instructions

The use of Paclitaxel-Ebeve should be supervised by a physician experienced in the use of antitumor chemotherapeutic agents.

In case of severe hypersensitivity reactions, administration of Paclitaxel-Ebeve should be stopped immediately and symptomatic therapy should be initiated, and the drug should not be re-injected.

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

Paclitaxel-Ebeve should be handled with caution (as with other cytotoxic agents), use gloves and avoid contact with the skin or mucous membranes. If skin contact occurs, it should be washed thoroughly with soap and water; if it gets into the eyes, wash with plenty of water.

Control of laboratory parameters

The peripheral blood count, BP, HR and number of breaths should be monitored regularly during treatment (especially during the first hour of infusion).

The ECG should be monitored before therapy and regularly during treatment.

If AV conduction abnormalities develop during repeated infusions, continuous ECG monitoring should be performed.

Pediatric use

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

Impact on ability to drive vehicles and other mechanisms requiring high concentration

Because of the possibility of side effects such as headache, dizziness, somnolence, during treatment patients should refrain from potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Precautions for handling and disposal of unused drug

Precautions must be taken when working with the drug Paclitaxel-Ebeve. The drug must be dispensed under aseptic conditions in a designated area. This should be done by trained personnel. All measures should be taken to prevent contact of paclitaxel solution with skin and mucous membranes, in particular protective clothing (gown, cap, mask, goggles and disposable gloves). When inhaling paclitaxel vapors or sprayed solutions, dyspnea, chest pain, a burning sensation in the throat, and nausea have been reported.

If paclitaxel comes into contact with the skin or mucous membranes, you should wash thoroughly with soap and water or (eyes) with plenty of water.

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

The remains of the drug and all instruments and materials that have been used to prepare the solution for infusion and administration of Paclitaxel-Ebeve should be disposed of in accordance with standard hospital procedures for the disposal of cytotoxic waste, in compliance with current regulations on the disposal of hazardous waste.

Contraindications

Side effects

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

Determining the frequency of side effects:

Blood system disorders: very common – myelosuppression, neutropenia, thrombocytopenia, anemia, leukopenia, bleeding; rare – febrile neutropenia; very rare – acute myeloid leukemia, myelodysplastic syndrome.

Nervous system disorders: very common – neurotoxic effects (mainly peripheral neuropathy), paresthesias; rare – motor neuropathy (moderately pronounced weakness of distal muscles, difficulty in performing precise movements); very rare – autonomic neuropathy (leading to paralytic bowel obstruction and orthostatic hypotension), grand mal epileptic seizures (grand mal), seizures, encephalopathy, dizziness, headache, confusion, ataxia.

Cardiovascular system: frequently – bradycardia, decreased BP; infrequently – cardiomyopathy, asymptomatic ventricular tachycardia, AV-blockade, syncope, increased BP, myocardial infarction, vascular thrombosis, thrombophlebitis; very rarely – atrial fibrillation, supraventricular tachycardia, shock.

Sensory system disorders: very rare – damage of the optic nerve and/or visual disturbances (scotoma), hearing loss, tinnitus, dizziness.

Respiratory system: rarely – shortness of breath, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure, radiation pneumonitis in patients receiving radiation therapy; very rare – cough.

Digestive system disorders: very frequent – nausea, vomiting, diarrhea, mucous membrane inflammation; rare – pancreatitis, bowel perforation, ischemic colitis; very rare – anorexia, constipation, mesenteric thrombosis, pseudomembranous colitis, esophagitis, ascites, neutropenic colitis, liver necrosis, hepatic encephalopathy (there are single reports of fatal outcome).

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

Muscular system disorders: very common – arthralgia, myalgia.

Intrinsic system disorders: very frequent – infections (mainly of the urinary tract and upper respiratory tract); infrequent – serious hypersensitivity reactions requiring therapeutic measures (namely, decreased BP, angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremities, marked sweating, increased BP); rare – anaphylatoid reactions.

Laboratory measures: often – increased activity of liver transaminases, increased concentration of alkaline phosphate, bilirubin, creatinine in serum.

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

Others: rare – asthenia, increased body temperature, dehydration, general weakness.

Overdose

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

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

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