Vexel-30/Vexel-100

Vexel-30/Vexel-100

paclitaxel

Manufacturer:

Vexxa Lifesciences

Distributor:

VE Pharma
Full Prescribing Info
Contents
Paclitaxel.
Description
Paclitaxel 30 mg/5 mL (Vexel-30): Each mL contains: Paclitaxel USP 6 mg.
Paclitaxel 100 mg/16.7 mL (Vexel-100): Each mL contains: Paclitaxel USP 6 mg.
Paclitaxel is a white to off-white powder. It is insoluble in water, soluble in alcohol. The molecular formula is C47H51NO14 and the molecular weight is 853.91. Paclitaxel is described chemically as Benzenepropanoic acid,-(benzoylamino)-hydroxy-,6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester, [2aR- [2a,4,4a,6,9(R*,S*),11,12,12a,12b]]-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)1,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca[3,4]-benz[1,2-b]oxet-5-one 6, 12b-diacetate, 12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Action
Pharmacotherapeutic group: Antineoplastic agent/taxanes. ATC Code: L01C D01.
Pharmacology: Pharmacodynamics: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability inhibits normal dynamic reorganization of the microtubule network, which 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.
Pharmacokinetics: Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The pharmacokinetics of paclitaxel determined following 3 and 24 hour infusions at doses levels of 135 and 175 mg/m2 were determined in an ovarian cancer patients. The mean half-life was between 3 and 52.7 hours, and the mean non-compartmentally derived value for total body clearance was between 11.6 and 24 L/hr. /m2. The total body clearance appeared to decrease with higher plasma concentrations. The mean steady-state volume of distribution was between 198 and 688 L/m2, indicating extensive extravascular distribution and/or tissue binding. Dose increases associated with the 3 hour infusion resulted in non-linear pharmacokinetics. When the dose increased by 30% from 135 mg/m2 to 175 mg/m2, the maximum plasma concentration (Cmax) increased by 75% and the area under the plasma concentration time curve (AUC0-∞) by 81%. The variation of systemic paclitaxel exposure in the same patients was found to be minimal. No signs of cumulative effects were found for paclitaxel in association with multiple treatment courses.
In vitro studies of serum protein binding indicate that 89-98% of paclitaxel is bound to proteins. Cimetidine, ranitidine, dexamethasone, or diphenhydramine were not found to affect the protein binding of paclitaxel.
The distribution and metabolism of paclitaxel in humans has not been fully investigated. The cumulative excretion of unchanged paclitaxel in the urine has been between 1.3% and 12.6% of the dose on average, which is an indication of extensive non-renal clearance. Hepatic metabolism and biliary clearance are possibly the principal mechanisms for elimination of paclitaxel. Paclitaxel is primarily metabolized by the action of CYP450 enzyme. An average of 26% of the radioactively marked dose of paclitaxel was eliminated in the faeces as 6α-hydroxypaclitaxel, 2% as 3'p-dihydroxypaclitaxel and 6% as 6α-3'p-dihydroxypaclitaxel. 6α-hydroxypaclitaxel is formed by the effect of CYP2C8, 3'p-hydroxypaclitaxel by CYP3A4 and 6α-3'p-dihydroxypaclitaxel by CYP2C8 and CYP3A4. The effect of renal or hepatic insufficiency on the elimination of paclitaxel after 3 hour infusions has not been studied. The pharmacokinetic parameters of a patient on haemodialysis were of values similar to those of nondialysis patients when the administration rate was 135mg/m2 of paclitaxel as a 3 hour infusion. Following an intravenous dose of 100 mg/m2 given as a 3 hour infusion to 19 Kaposi's Sarcoma patients; the mean Cmax was 1530 ng/mL (range 761-2860 ng/mL) and the mean AUC 5619 ng·hr/mL (range 2609-9428 ng.hr/mL). Clearance was 20.6 L/h/m2 (range 11-38) and the volume of distribution was 291 L/m2 (range 121-638). The terminal elimination half-life averaged 23.7 hours (range 12-33).
In clinical trials where paclitaxel and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites were prolonged. Total plasma exposure to doxorubicin was 30% higher when paclitaxel immediately followed doxorubicin than when there was a 24-hour interval between drugs.
Toxicology: Preclinical safety data: Administration prior to or during mating produced impairment of fertility in male and female rats. Additionally, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. The carcinogenic potential of paclitaxel has not been studied. However, paclitaxel is a potential carcinogenic and genotoxic agent based on its pharmacodynamic mechanisms of action. Paclitaxel has been shown to be mutagenic in both in vitro and in vivo mammalian test systems.
Indications/Uses
Ovarian Cancer: In first line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of patients with advanced disease or a residual disease >1 cm after initial laparotomy, in combination with cisplatin. In second line chemotherapy of ovarian cancer, paclitaxel is indicated in the treatment of metastatic carcinoma of the ovary after failure of standard platinum based therapy.
Breast Cancer: In the adjuvant setting, paclitaxel is indicated for the treatment of patients with node-positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with paclitaxel should be regarded as an alternative to extended AC therapy. Paclitaxel is indicated for the initial treatment of locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is suitable, or in combination with trastuzumab, in patients who over-express human epidermal growth factor 2 (HER-2) at a 3+level as determined by immunohistochemistry and for whom an anthracycline is not suitable. As a single agent, treatment of metastatic carcinoma of the breast in patients who have failed to respond adequately to standard treatment with anthracyclines or in whom anthracycline therapy has not been appropriate.
Advanced non-small cell lung cancer (NSCLC): Paclitaxel, in combination with cisplatin, is indicated for the treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgical intervention and/or radiation therapy.
Dosage/Direction for Use
See table.

Click on icon to see table/diagram/image

First-line treatment of ovarian cancer: Although alternative medication regimens for paclitaxel are under investigation at present, a combination therapy of paclitaxel and cisplatin is recommended.
Depending on the duration of infusion, two different dosages are recommended for paclitaxel treatment: 175 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of three hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals, or 135 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of 24 hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals.
Second-line treatment of ovarian cancer: The recommended dose of paclitaxel is 175mg/m2 administered over 3 hours, with a 3-week interval between courses.
Adjuvant chemotherapy in breast carcinoma: The recommended dose of paclitaxel is 175 mg/m2 administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.
First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m2), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses.
When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses. Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.
Second-line chemotherapy of breast carcinoma: The recommended dose of paclitaxel is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3- week interval between courses.
Advanced non-small cell lung cancer: The recommended dose of paclitaxel is 175 mg/m2 administered over 3 hours followed by 80 mg/m2 of cisplatin, with a 3-week interval between courses.
Treatment of AIDS-related KS: The recommended dose of paclitaxel is 100 mg/m2 administered as a 3 hour intravenous infusion every two weeks.
Dose adjustment: Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Paclitaxel should not be re-administered until the neutrophil count is ≥1.5 x 109/L (≥1 x 109/L for KS patients) and the platelet count is ≥100 x 109/L (≥75 x 109/L for KS patients).
Patients, who experience severe neutropenia (neutrophil count <0.5 x 109/L for a minimum of 7 days) or severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (25% for KS patients).
Patients with hepatic impairment: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairment. Paclitaxel is not recommended in patients with severely impaired hepatic function.
Caution For Usage
Special precautions for disposal and other handling: Handling: Paclitaxel is a cytotoxic anticancer medicinal product and caution should be exercised in handling paclitaxel. Dilution should be carried out under aseptic conditions, by trained personnel in a designated area. Appropriate gloves should be used. Contact of paclitaxel with skin and mucous membranes should be avoided. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning throat, and nausea have been reported.
Preparation for IV administration: During dilution of the concentrate for infusion, cytostatic dispensing needles or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the solution. Prior to infusion, paclitaxel must be diluted to a ready-to-use solution for infusion (0.3 to 1.2 mg/mL) using aseptic techniques with one of the following solutions: 9 mg/mL (0.9%) sodium chloride solution for infusion; 50 mg/mL (5%) glucose solution for infusion; 50 mg/mL glucose and 9 mg/mL sodium chloride solution for infusion; or Ringer's solution containing 50 mg/mL glucose. Once diluted, the ready-to-use infusions are for single use only.
The ready-to-use infusion should be visually inspected for particulate matter and discoloration. Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. However haziness does not affect the potency of the product. The solution for infusion should be administered through an in-line filter with microporous membrane not greater than 0.22 microns. No significant losses in potency have been noted following simulated delivery of the solution through I.V tubing containing an in-line (0.22 micron) filter.
There have been some reports of precipitation during paclitaxel infusions, with precipitation usually taking place towards the end of a 24-hour infusion period. To reduce the risk of precipitation, paclitaxel should be used as soon as possible after dilution and excessive shaking or agitation should be avoided. The infusion solution should be regularly inspected during infusion and the infusion should be discontinued if precipitation occurs. To minimize patient exposure to di-2-ethylhexyl phthalate (DEHP) which may be leached from plasticized PVC infusion bags, sets, or other medical instruments, diluted paclitaxel solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices which incorporate short inlet and/or outlet plasticized PVC tubing has not resulted in significant leaching of DEHP. The solutions are physically and chemically stable up to 27 hours at ambient temperature 25°C.
Storage
Store at temperatures not exceeding 30°C. Protect from light.
Shelf Life: 24 months from manufacturing date.
ATC Classification
L01CD01 - paclitaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Presentation/Packing
Vexel-30: Infusion concentrate (vial) 30 mg/5 mL (clear colourless to pale yellow viscous solution free from visible extraneous particulate matter) x 1's.
Vexel-100: Infusion concentrate (vial) 100 mg/16.7 mL (clear colourless to pale yellow viscous solution free from visible extraneous particulate matter) x 1's.
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