Antimicrotubule Anti Cancer Medicines Paclitaxel Concentrate For Infusion 30mg / 5ml

Paclitaxel Concentrate for Infusion 30mg/5ml Anticancer medicine 

COMPOSITION:

Each 5 mL vial contains 30 mg paclitaxel and 49,7% v/v of dehydrated alcohol.

PHARMACOLOGICAL ACTION:

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The initial rapid decline represents distribution to the peripheral compartment and elimination; the later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. In patients treated with doses of 135 and 175 mg/m² given as 3 and 24 hour infusions, mean terminal half-life has ranged from 3,0 to 52,7 hours. Mean values for total body clearance ranged from 11.6 to 24 L/h/m². Mean steady state volume of distribution has ranged from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding.
The pharmacokinetics of paclitaxel are non-linear. There is a disproportionately large increase in Cmax and AUC with increasing dose, accompanied by an apparent dose-related decrease in total body clearance. These findings are most readily observed in patients in whom, high plasma concentrations of paclitaxel are achieved. Saturable processes in distribution and elimination/metabolism may account for these findings. 
There was no evidence of accumulation of paclitaxel with multiple treatment course.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0,1 to 50 micrograms/mL, indicate that, on average, 89% of drug is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. After intravenous administration of paclitaxel, mean values of cumulative urinary recovery of unchanged drug ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. 
Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel is metabolized primarily by cytochrome P450 enzymes. Hydroxylated metabolites have been demonstrated to be the principal metabolites. The formation of 6 alpha-hydroxypaclitaxel ,3’-p-hydroxypaclitaxel and 6 alpha,3’-p-dihydroxypaclitaxel is catalysed by CYP2C8, 3A4 and both 2C8 and 3A4 respectively. The effect of the renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated. The clearance of paclitaxel was not affected by cimetidine pre-treatment. Ketoconazole may inhibit the metabolism of paclitaxel. Plasma levels of doxorubicin and doxorubicinol may be increased when paclitaxel and doxorubicin are used in combination.

INDICATIONS:

1.The palliative treatment of stage 3 or 4 advanced local carcinoma of the ovary after surgical resection, in combination with cisplatin.

2.The palliative management of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.

3.The treatment of metastatic carcinoma of the breast after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contra-indicated.4.    Palliative treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

DOSAGE AND DIRECTIONS FOR USE
Dosage
Indication 1:
Primary treatment of ovarian carcinoma: a combination regimen consisting of Paclitaxel 135 mg/m² administered over 24 hours, followed by cisplatin 75 mg/m², every 3 weeks. Paclitaxel should be administered before cisplatin.
Indication 2 and 3:
Secondary treatment of ovarian carcinoma: Paclitaxel at a dose of 175 mg/m² administered intravenously over 3 hours every 3 weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast after the failure of first line or subsequent chemotherapy.
Indication 4
Palliative treatment of advanced non-small cell lung carcinoma: the recommended dose of Paclitaxel is 175 mg/m²administered over a period of 3 hours; followed by a platinum compound , with a 3 week interval between courses.
Paclitaxel should not be readministered until the neutrophil count is at least 1 500/mm³ and the platelet count is at least 100 000/mm³. Patients who experience severe neutropenia (neutrophil count <500/mm³) or moderate to severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS). The incidence and severity of neurotoxicity and haematologic toxicity increases with dose.
All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to Paclitaxel administration, e.g. dexamethasone 20 mg orally approximately 12 and 6 hours before Paclitaxel, promethazine 25 mg IV 30 to 60 minutes prior to Paclitaxel, and cimetidine 300 mg or ranitidine 50 mg, IV 30 to 60 minutes before Paclitaxel.
Paclitaxel should be administered through an in-line filter with a microporous membrane not greater that 0,22 microm.
Directions for Use/Handling
Handling: Caution should be exercised when handling Paclitaxel. Dilution should be carried out by trained personnel in a designated area. Adequate protective gloves should be worn. Precautions should be taken to avoid contact with the skin, and mucous membranes. Following topical exposure, tingling, burning and redness have been observed. In the event of contact with the skin, the area should be washed with soap and water. In the event of contact with the mucous membranes, these should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning eyes, sore throat and nausea have been reported.
Preparation for IV Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0,9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0,9% Sodium Chloride Injection, or 5% Dextrose in Ringer's Injection to a final concentration of 0,3 to 1,2 mg/mL. The prepared solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting condition