Source: Health Products Regulatory Authority (IE) Revision Year: 2012 Publisher: Ebewe Pharma Ges.mb.H Nfg.KG, Mondseestrasse 11, 4866 Unterach, Austria
Pharmacotherapeutic group: antineoplastic agents (taxanes)
ATC code: L01CD01
Paclitaxel is a antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. 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.
In the first-line chemotherapy of ovarian carcinoma, the safety and efficacy of paclitaxel were evaluated in two major, randomised, controlled (vs. cyclophosphamide 750 mg/m² / cisplatin 75 mg/m²) trials. In the Intergroup trial (BMS CA139-209), over 650 patients with stage II b-c , III or IV primary ovarian cancer received a maximum of 9 treatment courses of paclitaxel (175 mg/m² over 3 hr) followed by cisplatin (75 mg/m²) or control. The second major trial (GOG-111/BMS CA139-022) evaluated a maximum of 6 courses of either paclitaxel (135 mg/m² over 24 hrs) followed by cisplatin (75 mg/m²) or control in over 400 patients with stage III/IV primary ovarian cancer, with a >1 cm residual disease after staging laparotomy, or with distant metastases. While the two different paclitaxel posologies were not compared with each other directly, in both trials patients treated with paclitaxel in combination with cisplatin had a significantly higher response rate, longer time to progression, and longer survival time when compared with standard therapy. Increased neurotoxicity, arthralgia/myalgia but reduced myelosuppression were observed in advanced ovarian cancer patients administered 3-hour infusion paclitaxel/cisplatin as compared to patients who received cyclophosphamide/cisplatin.
In the adjuvant treatment of breast carcinoma, 3121 patients with node positive breast carcinoma were treated with adjuvant paclitaxel therapy or no chemotherapy following four courses of doxorubicin and cyclophosphamide (CALGB 9344, BMS CA 139-223). Median follow-up was 69 months. Overall, paclitaxel patients had a significant reduction of 18% in the risk of disease recurrence relative to patients receiving AC alone (p = 0.0014), and a significant reduction of 19% in the risk of death (p = 0.0044) relative to patients receiving AC alone.
Retrospective analyses show benefit in all patient subsets. In patients with hormone receptor negative/ unknown tumors, reduction in risk of disease recurrence was 28% (95%CI: 0.59-0.86). In the patient subgroup with hormone receptor positive tumors, the risk reduction of disease recurrence was 9% (95%CI: 0.78-1.07). However, the design of the study did not investigate the effect of extended AC therapy beyond 4 cycles. It cannot be excluded on the basis of this study alone that the observed effects could be partly due to the difference in duration of chemotherapy between the two arms (AC 4 cycles; AC + paclitaxel 8 cycles). Therefore, adjuvant treatment with paclitaxel should be regarded as an alternative to extended AC therapy.
In a second large clinical study in adjuvant node positive breast cancer with a similar design, 3060 patients were randomized to receive or not four courses of paclitaxel at a higher dose of 225 mg/m² following four courses of AC (NSABP B-28, BMS CA139-270). At a median follow-up of 64 months, paclitaxel patients had a significant reduction of 17% in the risk of disease recurrence relative to patients who received AC alone (p = 0.006); paclitaxel treatment was associated with a reduction in the risk of death of 7% (95%CI: 0.78-1.12). All subset analyses favored the paclitaxel arm. In this study patients with hormone receptor positive tumor had a reduction in the risk of disease recurrence of 23% (95%CI: 0.6-0.92); in the patient subgroup with hormone receptor negative tumor the risk reduction of disease recurrence was 10% (95%CI: 0.7-1.11).
In the first-line treatment of metastatic breast cancer, the efficacy and safety of paclitaxel were evaluated in two pivotal, phase III, randomised, and controlled open-label trials.
In the first study (BMS CA139-278), the combination of bolus doxorubicin (50 mg/m²) followed after 24 hours by paclitaxel (220 mg/m² by 3-hour infusion) (AT), was compared versus standard FAC regimen (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²), both administered every three weeks for eight courses. In this randomised study, 267 patients with metastatic breast cancer, who had either received no prior chemotherapy or only non-anthracycline chemotherapy in the adjuvant setting, were enrolled. Results showed a significant difference in time to progression for patients receiving AT compared to those receiving FAC (8.2 vs. 6.2 months; p = 0.029). The median survival was in favour of paclitaxel/doxorubicin vs. FAC (23.0 vs. 18.3 months; p = 0.004). In the AT and FAC treatment arm 44% and 48% respectively received follow-up chemotherapy which included taxanes in 7% and 50% respectively. The overall response rate was also significantly higher in the AT arm compared to the FAC arm (68% vs. 55%). Complete responses were seen in 19% of the paclitaxel/doxorubicin arm patients vs. 8% of the FAC arm patients. All efficacy results have been subsequently confirmed by a blinded independent review.
In the second pivotal study, the efficacy and safety of the paclitaxel and Herceptin combination was evaluated in a planned subgroup analysis (metastatic breast cancer patients who formerly received adjuvant anthracyclines) of the study HO648g. The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been proven. The combination of trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) and paclitaxel (175 mg/m²) 3-hour infusion, every three weeks was compared to single-agent paclitaxel (175 mg/m²) 3-hour infusion, every three weeks in 188 patients with metastatic breast cancer overexpressing HER2 (2+ or 3+ as measured by immunohistochemistry), who had previously been treated with anthracyclines. Paclitaxel was administered every three weeks for at least six courses while trastuzumab was given weekly until disease progression. The study showed a significant benefit for the paclitaxel/trastuzumab combination in terms of time to progression (6.9 vs. 3.0 months), response rate (41% vs. 17%), and duration of response (10.5 vs. 4.5 months) when compared to paclitaxel alone. The most significant toxicity observed with the paclitaxel/trastuzumab combination was cardiac dysfunction (see section 4.8).
In the treatment of advanced NSCLC, paclitaxel 175 mg/m² followed by cisplatin 80 mg/m² has been evaluated in two phase III trials (367 patients on paclitaxel containing regimens). Both were randomised trials, one compared to treatment with cisplatin 100 mg/m², the other used teniposide 100 mg/m² followed by cisplatin 80 mg/m² as comparator (367 patients on comparator). Results in each trial were similar. For the primary outcome of mortality, there was no significant difference between the paclitaxel containing regimen and the comparator (median survival times 8.1 and 9.5 months on paclitaxel containing regimens, 8.6 and 9.9 months on comparators). Similarly, for progression-free survival there was no significant difference between treatments. There was a significant benefit in terms of clinical response rate. Quality of life results are suggestive of a benefit on paclitaxel containing regimens in terms of appetite loss and provide clear evidence of the inferiority of paclitaxel containing regimens in terms of peripheral neuropathy (p <0.008).
In the treatment of AIDS-related KS, the efficacy and safety of paclitaxel were investigated in a non-comparative study in patients with advanced KS, previously treated with systemic chemotherapy. The primary end-point was best tumour response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the core efficacy population. The overall success rate (complete/partial response) after 15 cycles of treatment was 57% (CI 44-70%) in liposomal anthracycline-resistant patients. Over 50% of the responses were apparent after the first 3 cycles. In liposomal anthracycline-resistant patients, the response rates were comparable for patients who had never received a protease inhibitor (55.6%) and those who received one at least 2 months prior to treatment with paclitaxel (60.9%). The median time to progression in the core population was 468 days (95% CI 257-NE). Median survival could not be computed, but the lower 95% bound was 617 days in core patients.
Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations.
The pharmacokinetics of paclitaxel were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m². Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m²; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m², indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m² to 175 mg/m², the Cmax and AUC0→∞ values increased 75% and 81%, respectively.
Following an intravenous dose of 100 mg/m² given as a 3-hour infusion to 19 KS patients, the mean Cmax was 1,530 ng/ml (range 761-2,860 ng/ml) and the mean AUC 5,619 ng.hr/ml (range 2,609-9,428 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).
Intrapatient variability in systemic paclitaxel exposure was minimal. There was no evidence for accumulation of paclitaxel with multiple treatment courses.
In vitro studies of binding to human serum proteins indicate that 89-98% 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. Mean values for cumulative urinary recovery of unchanged drug have 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 appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6-3'-p-dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, -3A4, and both -2C8 and -3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of paclitaxel 135 mg/m² were within the range of those defined in non-dialysis patients.
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.
For use of paclitaxel in combination with other therapies, please consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.
The carcinogenic potential of paclitaxel has not been studied. However, paclitaxel may be a potential carcinogenic and genotoxic agent, due to its pharmacodynamic mechanism of action.
Paclitaxel has demonstrated to be mutagenic in both in vitro and in vivo mammalian test systems.
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