ONXOL® (paclitaxel) Injection is a clear colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. ONXOL is available in 30 mg (5mL), 150 mg (25mL) and 300 mg (50mL) multiple dose vials. Each mL of sterile non-pyrogenic solution contains 6 mg paclitaxel, 527 mg of polyoxyl 35 castor oil, NF, 2 mg citric acid anhydrous and 49.7% (v/v) dehydrated alcohol, USP.
Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via an extractive process from Taxus brevifolia or Taxus yunnanensis. The chemical name for paclitaxel is (2а R,4S,4а S,6 R,9 S,11 S,12 S,12а R,12b S)-1,2а,3,4,4а,6,9,10,11,12,12а,12b-Dodecahydro-4,6,9,11,12,-12b-hexahydroxy-4а,8,13,13-tetramethyl-7,11-methano-5 H -cyclodeca [3,4] benz [1,2- b ] oxet-5-one 6,12b-diacetate, 12-benzoate, 9-ester with (2 R,3 S)- N -benzoyl-3-phenylisoserine. Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.93. It is highly lipophilic, insoluble in water, and melts at around 216˚ - 217˚C.
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, 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
| DOSE || INFUSION || N || C MAX || AUC (0-∞)|| T-HALF || CL T |
| (mg/m 2 ) || DURATION (h) || (patients) || (ng/mL) || (ng•h/ml) || (h) || (L/h/m 2 ) |
|CMAX = 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 CMAX by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3 hour infusion, for a 30% increase in dose, the CMAX and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at 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 to 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 a 24 hour infusions (n=54) in Phase 1 & 2 studies. Values for CL T 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 μg/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 to 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 5 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 ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’- p -hydroxypaclitaxel and 6-α, 3’-p-dihydroxypaclitaxel by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-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, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See “ PRECAUTIONS: Drug Interactions ” section.) The effect of ranal 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.
Second-Line Data: 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 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% Cl = 11% to 37%) and 30% (95% Cl = 18% to 46%) with a total of six 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 to 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 responses, 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 SECOND-LINE OVARIAN CARCINOMA STUDY
| 175/3 || 175/24 || 135/3 || 135/24 |
| (n=96) || (n=106) || (n=99) || (n=106) |
| Response |
|- rate (percent)||14.6||21.7||15.2||13.2|
|- 95% Confidence Interval||(8.5-23.6)||(14.5-31.0)||(9.0-24.1)||(7.7-21.5)|
| Time to Progression |
|- median (months)||4.4||4.2||3.4||2.8|
|- 95% Confidence Interval||(3.0-5.6)||(3.5-5.1)||(2.8-4.2)||(1.9-4.0)|
| Survival |
|- median (months)||11.5||11.8||13.1||10.7|
|- 95% Confidence Interval||(8.4-14.4)||(8.9-14.6)||(9.1-14.6)||(8.1-13.6)|
Analyses were performed as planned by the bifactorial study design described in the 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 had a response rate similar to that of 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 paclitaxel had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months (p=0.03). The median time to progression for patients receiving the 3 hours vs. the 24 hour infusion was 4.0 months vs. 3.7 months respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of paclitaxel and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of paclitaxel and 11.2 months for patients receiving the 24-hour infusion (p=0.91). 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, a platinum containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.
The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in ten clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 4 & 5) and narrative form.
The results of the randomized study support the use of paclitaxel injection at doses of 135 to 175 mg/m2, administered by a 3 hour intravenous infusion. The same doses administered by 24 hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.
After Failure of Initial Chemotherapy: Data from 83 patients accrued in three Phase 2 open label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of paclitaxel in patients with metastatic breast carcinoma.
Phase 2 Open Label Studies: Two studies were conducted in 53 patients previously treated with a maximum of one prior chemotherapeutic regimen. Paclitaxel was administered in these 2 trials as a 24 hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% Cl: 37% - 75%) and 52% (95% Cl: 32% - 72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of metastatic disease. The dose of paclitaxel was 200 mg/m2 as a 24 hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% Cl: 15% - 50%).
Phase 3 Randomized Study: This multicenter trial was conducted in patients previously treated with one or two regimens of chemotherapy. Patients were randomized to receive paclitaxel at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3 hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.
The overall response rate for the 454 evaluable patients was 26% (95% Cl: 22% - 30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4 – 18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range: 0.03 – 17.1 months). Median survival was 11.7 months (range: 0-18.9 months).
Response rates, median survival and median time to progression for the 2 arms are given in the following table:
TABLE 3: EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
| 175/3 || 135/3 |
| (n=235) || (n=236) |
| Response |
|- rate (percent)||28||22|
| Time to Progression |
|- median (months)||4.2||3.0|
| Survival |
|- median (months)||11.7||10.5|
The adverse event profile of the patients who received single-agent paclitaxel in the phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 4 & 6) and narrative form.
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