POXOL^TM (Paclitaxel Injection) - EU generic Paclitaxel Injection is produced in European GMP manufacturer. It conforms the USP26 Specification for Paclitaxel Injection which is official valid from 1 Arpil 2003.
Two dosages will be available:
30mg /5mL vials.
100mg/16.7mL vials.
The Exclusive Global Marketing Agent - 21CEC (UK & USA) , Contact: <21cec@21cep.com>

POXOL^TM 
(Paclitaxel Injection)

DESCRIPTION

POXOL^{TM (}Paclitaxel Injection) is a clear colorless to slightly yellow viscous solution intended for intravenous administration. It is supplied as a sterile nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel Injection is available in 30 mg (5mL) and 100 mg (16.7 mL) multidose vials.  Each ml of sterile nonpyrogenic solution contains 6 mg of paclitaxel, 527 mg of polyoxyethylated castor oil and 49.7% (v/v) dehydrated alcohol, USP.

Paclitaxel is a natural product with antitumor activity. Paclitaxel is extracted from Taxus yunnanensis without any semi-synthesis process. The chemical name for paclitaxel is (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. It has a molecular weight of 853.93 and a molecular formula C₄₇H₅₁NO₁₄ . Paclitaxel has the following structural formula:  

Paclitaxel is a white to off-white crystalline powder and is highly lipophilic, insoluble in water, and melts at around 216-217°C.

                           CLINICAL PHARMACOLOGY

Paclitaxel is a novel 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 reorganization 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 of paclitaxel injection, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3 and 24 hour infusions of paclitaxel at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:

TABLE 1: SUMMARY OF PHARMACOKINETIC PARAMETERS - MEAN VALUES

C_max = Maximum plasma concentration
AUC(0-¥) = Area under the plasma concentration-time curve from time 0 to infinity
CL_T = Total body clearance

It appeared that with the 24 hour infusion of paclitaxel, a 30% increase in dose (135 mg/m² versus 175 mg/m²) increased the C_max by 87% whereas the AUC(0- ¥) remained proportional. However, with a 3 hour infusion, for a 30% increase in dose, the C_maxand AUC(0- ¥) were increased by 68% and 89%, respectively. The mean apparent volume of distribution in steady state, with the 24 hour infusion of paclitaxel ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15-135 mg/m² given by 1 hour infusions (n=15), 30 to 275 mg/m² given by 6 hour infusions (n=36), and 200 to 275 mg/m² given by 24 hour infusions (n=54) in Phase 1 & 2 studies. Values for total body clearance and volume of distribution were consistent with the findings in the Phase 3 study.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mg/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15-275 mg/m² doses of paclitaxel as 1, 6, or 24 hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radio-labeled paclitaxel as a 3 hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity range from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6a-hydroxypaclitaxel accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6a-3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6a- hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17a-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor od CYP2CB, also inhibited the formation of 6a-hydroxypaclitaxel in vitro. The pahrmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2CB and/or CYP3A4. (See PRECAUTIONS - Drug Interactions Section.) The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Clinical Studies:
Ovarian Carcinoma: Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter, randomized Phase 3 study (407 patients) as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel injection in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m² in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these two studies were 22% (95% CI = 11-37%) and 30% (95% CI = 18-46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5 to 15.8 months) and 7.5 months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2 to 36.7 months) and 15.9 months (range: 1.8 to 34.5+ months). 

The Phase 3 study had a bifactorial design and compared the efficacy and safety of paclitaxel, administered at two different doses (135 or 175 mg/m²) and schedules (3 or 24 hour infusion). The overall response rate for the 407 patients was 16.2% (95% Cl = 12.8 to 20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2 to 21.6 months). Median time to progression was 3.7 months (range: 0.1+ to 25.1+ months). Median survival was 11.5 months (range: 0.2 to 26.3+ months). Response rates, median survival and median time to progression for the 4 arms are given in the following table.

TABLE 2: EFFICACY IN THE PHASE 3 STUDY

Analysis were performed as planned by the study protocol, by comparing the two doses ( 135 or 175 mg/m²) irrespective of the schedule (3 or 24 hours) and the two schedules irrespective of dose. Patients receiving the 175 mg/m² dose achieved a higher response rate than those receiving the 135 mg/m² dose; 18% vs. 14% (p=0.28). No difference in response rate was detected when comparing the 3 hour with the 24 hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m² dose of pacliraxel had a longer time to progression than those receiving 135 mg/m² dose: median 4.2 vs. 3.1 months (p=0.03). Time to progression was longer for patients receiving the 3 hour vs. the 24 hour infusion: 4.0 months vs. 3.7 months (p=0.08). No difference in survival according to dose or schedule was observed. These statistical analyses should be viewed with caution because of the multiple comparisons made.

Paclitaxel remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, platinum containing regimen) with response rate of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.

The adverse event profile in the Phase 3 study was consistent with that seen for a pooled analysis performed on 812 patients treated in ten clinical studies (See ADVERSE REACTIONS Section). For the 403 patients who received paclitaxel injection in the Phase 3 study, the following table shows the incidence of several important adverse events.

TABLE 3: FREQUENCY OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY