Paclitaxel: Package Insert and Label Information

PACLITAXEL- paclitaxel injection, solution
Athenex Pharmaceutical Division, LLC.

(Patient Information Included)

novaplusTM + Rx ONLY

WARNING

Paclitaxel Injection, USP should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists (see DOSAGE AND ADMINISTRATION section). Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm3 and should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline neutrophil count is less than 1,000 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.

DESCRIPTION

Paclitaxel Injection, USP 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. Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multi-dose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of Polyoxyl 35 Castor Oil, NF, 49.7% (v/v) Dehydrated Alcohol, USP and 2 mg Citric Acid, USP.

Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via an extraction process from Taxus X media ‘ Hicksii’. 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.

Paclitaxel has the following structural formula:

Structural Formula
(click image for full-size original)

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47 H51 NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216° to 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, 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

Cmax = Maximum plasma concentration

AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity

CLT = Total body clearance

Dose (mg/m 2 ) Infusion Duration (h) N (patients) C max (ng/mL) AUC (0-∞) (ng•h/mL) T-HALF (h) CL T (L/h/m 2 )
135 24 2 195 6300 52.7 21.7
175 24 4 365 7993 15.7 23.8
135 3 7 2170 7952 13.1 17.7
175 3 5 3650 15007 20.2 12.2

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 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi’s sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mcg/mL, indicate that between 89% to 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 Injection, USP 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 radiolabeled 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 -hydroxy-paclitaxel and 6α, 3′-p -dihydroxy-paclitaxel, 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 disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m2), but no observed increase in plasma exposure (see PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION). 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

First-Line Data

The safety and efficacy of paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB-C, III, or IV disease (optimally or non-optimally debulked) received either paclitaxel 175 mg/m2 infused over 3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either paclitaxel 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 for 6 courses.

In both studies, patients treated with paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (Tables 2A and 2B). Kaplan-Meier survival curves for each study are shown in Figures 1 and 2.

Table 2A. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Studies

a Paclitaxel dose in mg/m2 /infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b Among patients with measurable disease only.

c Unstratified for the Intergroup Study, Stratified for Study GOG-111.

Intergroup (non-optimally debulked subset) GOG-111
T175/3 a c75 (n=218) C750 a c75 (n=227) T135/24 a c75 (n=196) C750 a c75 (n=214)
• Clinical Response b (n=153)(n=153)(n=113)(n=127)
— rate (percent) 58 43 62 48
— p-valuec 0.016 0.04
• Time to Progression
— median (months)13.2 9.9 16.6 13.0
— p-valuec 0.00600.0008
— hazard ratio (HR)c 0.760.70
— 95% CIc 0.62-0.92 0.56-0.86
• Survival
— median (months) 29.5 21.9 35.5 24.2
— p-valuec 0.0057 0.0002
— hazard ratio (HR)c 73 0.64
— 95% CIc 0.58-0.91 0.50-0.81
Table 2B. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Intergroup Study

a Paclitaxel dose in mg/m2 /infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b Among patients with measurable disease only.

c Unstratified.

T175/3 a c75 (n=342) C750 a c75 (n=338)
• Clinical Response b (n=162) (n=161)
— rate (percent) 59 45
— p-valuec 0.014
• Time to Progression
— median (months) 15.3 11.5
— p-valuec 0.0005
— hazard ratio (HR)c 0.74
— 95% CIc 0.63–0.88
• Survival
— median (months) 35.6 25.9
— p-valuec 0.0016
— hazard ratio (HR)c 0.73
— 95% CIc 0.60–0.89

Figure 1. Survival: Cc Versus Tc (Intergroup)

Figure 1
(click image for full-size original)

Figure 2. Survival: Cc Versus Tc (GOG-111)

Figure 2
(click image for full-size original)

The adverse event profile for patients receiving paclitaxel in combination with cisplatin in these studies was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 11) and narrative form.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.