Rx Prescription information

PACLITAXEL - BELMED

(Information for experts)

Trade Name: Paclitaxel - Belmed

International nonproprietary name: Paclitaxel

Appearance: oily clear colorless or yellowish liquid

Composition: 1 ml contains:

active ingredients: semisynthetic paclitaxel – 6.00 mg;

excipients:citric acid anhydrous, ethanol anhydrous, macrogolglycerol ricinoleate.

Pharmaceutical form: concentrate for infusion, 100 mg per 16.7 ml

Pharmaceutical group: Antitumor agent. Plant origin alkaloids. Taxanes.

ATC code: L01CD01

 

Pharmacological characteristics

Pharmacodynamics

Plant origin antitumor agent. It is extracted by the semisynthetic method from yew tree leaves (Taxus brevifolia). Interferes with the process of cell division, modifies the process of mitotic spindle microtubules formation and stabilization and prevents depolymerization. As a result, the dynamic microtubular reticulum reorganization gets suppressed in mitosis interphase, causes the abnormal bundles of microtubules formation throughout the cell cycle and multiple star-like condensations (asters) during mitosis.

Pharmacokinetics

Maximum concentration of 2170 mg/ml is observed after 3 hours i/v infusion at the dose 135 mg/m2, the area under pharmacokinetic curve (AUC) is 7952 mg/ml/h, when administered within 24 hours of that dose – 195 mg/ml/h and 6300 ng/mL/h respectively. Maximum concentration and AUC are the dose-related parameters: during 3 hour infusion the increase in dose to 175 mg/m2 leads to these parameters raise by 68 and 89%; after 24 hours administration – by 87 and 26% respectfully. An average volume of distribution is 198-688 l/m2. Plasma proteins binding capacity is – 88 - 98%. Half distribution period from blood into tissues is 30 min. It is easily absorbed and passes through the tissues, accumulating primarily in the liver, spleen, pancreas, stomach, intestines, heart and muscles. It is metabolized in the liver by hydroxylation involving cytochrome CYP2D8 (with the metabolite – 6-alpha-hydroxypaclitaxel formation) and CYP3A4 (with the metabolites – 3 para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxyipaclitaxel formation). It is excreted mainly into bile – 90%. It does not accumulate at the repeated infusions. Half-distribution period and the total clearance vary and depend on the dose and i/v infusion duration: 13.1 – 52.7 hours and 12.2 – 23.8 l/h/m2 respectively. Following i/v infusion (1-24 hours) the total kidneys elimination is 1.3 – 12.6% of the dose, which indicates the intensive extrarenal clearance. Total clearance – 11-24 l/h/m2.

Indications

- Ovarian Cancer (the 1st line therapy (in combination with cisplatin) in patients with advanced metastatic or residual tumor (more than 1 cm) after laparotomy and the 2nd line therapy in patients with advanced metastatic ovarian cancer after unsuccessful standard therapy).

- Breast cancer (adjuvant therapy in patients with lymph nodes metastasis after standard combination therapy, the 1st line therapy in metastatic cancer and the disease aggravation after adjuvant therapy with anthracyclines, the 2nd line therapy with the disease aggravation after combination chemotherapy with anthracycline antitumor antibiotics).

- Non-small cell lung cancer (the 1st line therapy in combination with cisplatin or monotherapy in patients who haven’t been planned for surgery and/or radiation therapy with the chance to be cured).

- Kaposi's sarcoma in AIDS patients: the 2nd line therapy.

- Squamous cell carcinoma of head and neck.

- Transitional cell carcinoma of the bladder.

Dosage and mode administration

I/v drip during 3 hours once in 3 weeks. The solution has to be diluted before the injection to the concentration 0.3-1.2 mg/ml in 0.9% NaCl or 5% dextrose solution.

In case of ovarian cancer – 135-175 mg/m2. In breast cancer, non-small cell lung cancer – 175 mg/m2 (prolonged infusions may last for 24 hours at the dose 135 mg/m2 every 3 weeks). In Kaposi's sarcoma – 135 mg/m2 or 100 mg/m2 over 3 hours once in 2 weeks. The second course should be carried out when the peripheral blood neutrophil count is more than 1.5 thousand/l and platelet count – more than 100 thousand/ml. For the patients with profound neutropenia (less than 500/µl) or severe peripheral neuropathy, developed during the treatment, the dose should be reduced by 20% for the next courses.

In case of head and neck squamous cell carcinoma (as a part of polychemotherapy courses) – 175 mg/m2 intravenous 3 hours infusion should be done on the 1st day with premedication. Intervals between the courses are 4 weeks.

In case of bladder transitional cell carcinoma (as a part of polychemotherapy courses) – 150-225 mg/m2 intravenous 3-hours infusion should be done on the first day.

All the patients are given premedication to prevent the allergic reactions development. Glucocorticoids are given prior to administration (i/m dexamethasone 20 mg or its equivalent – 12 and 6 hrs. before infusion), antihistamines (bolus i/v diphenhydramine 50 mg administration 30 min before infusion), H2-receptors inhibitors (cimetidine 300 mg or ranitidine 50 mg 30 min before infusion).

Side effects

Hemopoietic system: bone marrow hemopoiesis arrest (neutropenia, thrombocytopenia, anaemia).

Cardiovascular system: drop in blood pressure, rare – blood pressure rise, bradycardia and/or tachycardia, AV block, ventricular tachycardia, tachycardia coupled with bigeminy, atrial fibrillation, shock, cardiomyopathy, mesenteric thrombosis, syncope, heart attack, congestive heart failure (in case of combination chemotherapy with an anthracycline), thrombophlebitis, ECG changes.

Nervous system: dizziness, headache, grand mal type seizures, cramps, encephalopathy, neuropathy (peripheral, sensory, motor, autonomic), ataxia, paresthesias.

Sensory organs: decrement in visual acuity, visual field loss (scintillating scotoma).

Digestive system: nausea, vomiting, diarrhea, esophagitis, mucositis, loss of appetite, constipation, intestine obstruction and perforation, ischemic colitis, pseudomembranous colitis, liver necrosis and hepatic encephalopathy (including fatalities), pancreatitis, ascites, mesenteric artery thrombosis.

Muskulo-skeletal system: arthralgia, myalgia, peripheral edema.

Skin and subcutaneous tissue: pruritus, rash, erythema multiforme, Stevens-Jones syndrome, toxic epidermal necrolysis, exfoliative dermatitis, urticaria, onycholysis, alopecia (reversible), nail infections.

Allergic reactions: skin rash, flushes to the face and upper chest, drop of blood pressure, tachycardia, angioedema, bronchospasm, generalized urticaria, back pain, fever, anaphylactic shock, anaphylactic reactions (including fatalities).

Others: anorexia, confusion, fatigue, malaise, immunosuppression, decreased resistance to infection (any etiology).

Laboratory parameters: aspartate aminotransferase (ACT) and alkaline phosphatase activity increase, hyperbilirubinemia.

Local reactions: pain, edema, erythema, injection site skin induration and pigmentation, phlebitis, desquamation, subcutaneous tissue inflammation and necrosis in case of extravasation.

Contraindications

Hypersensitivity (including polyoxyethylated castor oil), neutropenia (less than 1.5 thousand/ml), thrombocytopenia (less than 100 thousand/ml), pregnancy, lactation, severe uncontrolled concomitant infections (including herpes zoster, chickenpox, herpes).

With caution: hepatic failure, arrhythmias, heart attack (in anamnesis), ischemic heart disease, bone marrow hematopoiesis suppression after chemotherapy or radiation therapy.

Overdose

Symptoms: aplasia of the bone marrow, peripheral neuropathy, mucositis.

Treatment: symptomatic. No specific antidote.

Interaction with other drug products

Cisplatin reduces by 20% the total paclitaxel body clearance (with a more prominent myelosuppression observed when paclitaxel is followed by cisplatin). Microsomal oxidation Inhibitors (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine, etc.) suppress paclitaxel metabolism.

The concentration of doxorubicin and its active metabolite in plasma doxorubicinol can be significantly increased by the first administration of paclitaxel followed by doxorubicin.

Special indications

It is not recommended to use polyvinyl chloride infusion sets for the administration. Solutions should be prepared and stored in glass, polypropylene, or polyolefin systems, and administered through infusion systems with the polyethylene inner surface and also through connected to the system a membrane filter with a pore size not greater than 0.22 microns.

Medical personnel should wear protective gloves while dealing with paclitaxel. In case of contact with paclitaxel solution the skin or mucous membranes should be washed immediately with plenty of water. At the local contact with paclitaxel one may experience tingling, burning, and flushing sensation on the skin.

Safety precautions: in case of severe hypersensitivity reactions, paclitaxel administration should be stopped immediately and not to be ordered again.

Peripheral blood composition, blood pressure, heart rate and the number of breaths (especially during the first hour of infusion) should be regularly monitored across the treatment. In cases of myocardial conduction disturbances, it is necessary to carry out continuous ECG monitoring on the re-administration. It possesses an embryo and fetotoxicity. It is necessary to use reliable contraceptives during the treatment. Paclitaxel should be administered under the outpatient clinic supervision or the hospital physician experienced in anticancer drugs administration and under available conditions required for the complications relief.

Ability to drive and operate potentially dangerous machinery: during the treatment one should refrain from driving and attending other potentially hazardous activities required high concentration and psychomotor reactions rate.

Storage conditions

Store in protected from light place at temperature below 30°C.

Keep out of reach of children.

Shelf life

2 years.

Do not use after expiry of shelf life indicated on the package.

Package

16.7 ml in a glass vial closed with rubber stopper and rolled with aluminum cap. Vial together with leaflet is placed into carton box.

Pharmacy purchasing terms

On prescription.

Manufacturer

Belmedpreparaty RUE

Republic of Belarus, Minsk, 220007,

30, Fabritsius str.,

Tel./fax (+ 375 17) 220 37 16

e-mail: medic@belmedpreparaty.com

http://www.belmedpreparaty.com