Nanoxel

Each vial contains paclitaxel 100 mg and 5 mL of dehydrated alcohol added until sufficient as active ingredients. It also contains polymer PNP 50 mg, sodium deoxycholate 33.35 mg, sodium citrate 50 mg and 5 mL of water for injection added until sufficient, as inactive ingredients.
Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via a semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel is a white to off-white crystalline powder with the empirical formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.9. It is highly lipophilic, insoluble in water and melts at around 216-217°C.
Nanoxel nanoparticle injection is a cremophor-free, clear, colorless solution, water soluble, nanoparticle formulation of paclitaxel based on polymeric carrier for drug delivery. The polymer being an amphiphilic molecule eg, having both hydrophilic and hydrophobic groups, forms nano-size micelles when exposed to an aqueous environment. Core region of the micelles consists of hydrophobic groups that serve as a reservoir where paclitaxel, a highly hydrophobic drug, is entrapped by physical incorporation and is thus shielded from the aqueous environment. The mean particle size of nanoparticles is approximately 80 nanometers.

Pharmacology: Mechanism of Action: Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of 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.
Pharmacokinetics: Pharmacokinetic parameters of paclitaxel nanoparticle injection were evaluated in 29 patients after the 1st cycle and 23 patients after the 2nd cycle during the 1st two courses of therapy to account for intra-patients variations if any. The studied doses ranged from 135-375 mg/m². No significant difference was noted in AUC and C_max values between the 2 cycles, thus indicating absence of cumulative effect.
It was observed that pharmacokinetic parameters best fitted into a 2-compartment model. Pharmacokinetic analysis has shown a linear correlation between the mean AUC and dose up to 375 mg/m². Paclitaxel pharmacokinetics per se follows 2 compartmental model and paclitaxel nanoparticle injection does not alter the basis pharmacokinetic characteristics of paclitaxel. The drug exposure (AUCs) was dose proportional over 135-375 mg/m². At 200 and 300 mg/m² dose level of paclitaxel nanoparticle injection, the mean maximum concentration of paclitaxel (C_max) at the end of infusion, was 5859.36 ng/mL and 11682.72 ng/mL, respectively.
The mean total clearance at 200 mg/m² dose level was 32.4 L/hr and the volume of disturbance was 76.8 L. No significant interindividual variation was observed in PK profile of the formulation. PK behavior was consistent showing that reconstitution did not introduce any significant variability.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1-50 mcg/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.
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 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 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.
The effect of renal or hepatic dysfunction on the disposition of paclitaxel nanoparticle injection has not been investigated. Clinical Studies: The safety and efficacy of paclitaxel nanoparticle injection was evaluated as monotherapy in patients with metastatic breast cancer who relapsed on 1st line therapy with anthracyclines or locally advanced or recurrent breast cancer that relapsed after adjuvant therapy with anthracyclines, in an open label, randomized, multicenter study.
Patients were randomized to receive either paclitaxel nanoparticle injection or conventional paclitaxel. Paclitaxel nanoparticle injection infusion was given over a period of 1-hr every 3 weeks at two different doses of 300 mg/m² (Arm B) and 220 mg/m² (Arm C). Conventional paclitaxel was administered to patients in Arm A at the therapeutically approved dose of 175 mg/m² (3-hr infusion, every 3 weeks).
At the time of interim report submission, out of 193 patients, 168 were analyzed for efficacy. Objective response (OR) was observed in 38.2% of patients receiving paclitaxel nanoparticle injection at 220 mg/m² dose as compared with 32.3% in patients receiving conventional paclitaxel. There were more percentage of patients who progressed while on therapy with conventional paclitaxel as compared to those on paclitaxel nanoparticle injection 220 mg/m² (35.5% vs 27.3% respectively).
A higher clinical benefit (CR+PR+SD) was observed with paclitaxel nanoparticle injections 220 mg/m² (85.4%) as compared to conventional paclitaxel (74.2%).

Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Breast Cancer: After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, Nanoxel at a dose of 220 mg/m² administered IV over 1 hour every 3 weeks.
For the therapy of patients with breast cancer, courses of Nanoxel should not be repeated until the neutrophil count is ≥1500 cells/mm³ and the platelet count is ≥ 100,000 cells/mm³. Patients who experience severe neutropenia (neutrophil <500 cells/mm³ for a week or longer) or severe peripheral neuropathy during Nanoxel therapy should have dosage reduced by 25% for subsequent courses of Nanoxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.
Hepatic Impairment: The appropriate dose of Nanoxel for patients with bilirubin >1.5 mg/dL is not known.
No premedication to prevent hypersensitivity reactions is required prior to administration of Nanoxel.

There is no known antidote for Nanoxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

Paclitaxel nanoparticle injections should not be used in breast cancer patients with baseline neutrophil count of <1500 cells/mm³.

Bone marrow suppression (primarily neutropenia) is dose dependent and is dose-limiting toxicity. Nanoxel should not be administered to patients with baseline neutrophil counts of < 1500 cells/mm³. Frequent monitoring of blood counts should be instituted during Nanoxel treatment. Patients should not be retreated with subsequent cycles of Nanoxel until neutrophils recover to a level of >1500 cells/mm³ and platelet recover to a level >100,000 cells/mm³.
The use of Nanoxel has not been studied in patients with hepatic or renal dysfunction.

Hematology: Nanoxel therapy should not be administered to patients with baseline neutrophil counts of <1500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Nanoxel. Patients should not be retreated with subsequent cycles of Nanoxel until neutrophils recover to a level >1500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ ≥7 days) during a course of Nanoxel therapy, a 25% reduction in dose for subsequent courses of therapy is recommended. (See Dosage & Administration).
Nervous System: Sensory neuropathy occurs frequently with Nanoxel. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be witheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of Nanoxel (see Dosage & Administration).
Injection Site Reaction: Injection site reactions occur infrequently with Nanoxel and were mild in severity. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Carcinogenicity, Mutagenicity & Impairment of Fertility: The carcinogenic potential of Nanoxel has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice) paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Use in pregnancy: Pregnancy Category D: There are no adequate and well-controlled studies in pregnanct women. If Nanoxel is used during pregnancy or if the patient becomes pregnant while receiving Nanoxel, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Use in lactation: It is not known whether paclitaxel is excreted in human milk. Following IV administration of carbon-14 labeled paclitaxel injection to rats on days 9-10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma conentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving Nanoxel therapy.
Use in children: The safety and effectiveness of Nanoxel in pediatric patients have not been established.

Use in pregnancy: Pregnancy Category D: There are no adequate and well-controlled studies in pregnanct women. If Nanoxel is used during pregnancy or if the patient becomes pregnant while receiving Nanoxel, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Use in lactation: It is not known whether paclitaxel is excreted in human milk. Following IV administration of carbon-14 labeled paclitaxel injection to rats on days 9-10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma conentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving Nanoxel therapy.

The distribution of adverse events as per each body system involved is given in the table.

Click on icon to see table/diagram/image

Hematologic: Hematological toxicities were modest throughout the duration of therapy. Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. The incidence of neutropenia (all grades) with Nanoxel 220 mg/m² was 38.5% as compared to conventional paclitaxel (48.4%). Patients receiving Nanoxel 220 mg/m² had lower incidence of grade 4 neutropenia (12.3%) as compared to conventional paclitaxel (14%). The number of patients requiring G-CSF therapy was found to be comparable ie, 10.9% with conventional paclitaxel and 9.2% with Nanoxel 220 mg/m². Febrile neutropenia was reported in 1 patient in the Nanoxel 220 mg/m² arm. The median ANC nadirs were higher in Nanoxel 220 mg/m² arm as compared to patients treated with conventional paclitaxel (2.2 versus 1.9 cells x 10³/mm³).
Grade 3-4 leucopenia was observed in 7.7% of patients treated with Nanoxel (220 mg/m²) as compared to patients treated with conventional paclitaxel (12.5%). The severity of leucopenia was mild (grade 1 & 2) in majority of patients receiving Nanoxel at 220 mg/m² dose.
Thrombocytopenia was uncommon, which was observed in 4.6% of patients in Nanoxel 220 mg/m² arm.
Anemia was observed in lesser number of patients in the Nanoxel 220 mg/m² arm (13.8%) as compared to conventional paclitaxel arm (25%). None of the patient in Nanoxel 220 mg/m² arm had grade 4 anemia.
Hypersensitivity Reactions (HSRs): In the present study no hypersensitivity reaction was seen in patients who had received Nanoxel despite absence of premedication.
Neurologic: There was no incidence of grade 4 neuropathy in any arm. Sensory neuropathy was the common type of neuropathy observed. In Nanoxel 220 mg/m² arm, patients who had neuropathy was 46.1%. However, majority of them had grade 1 neuropathy (35.4%). Only 1 patient in this arm suffered from grade 3 neuropathy. In conventional paclitaxel arm, patients who had grade 3 neuropathy was 4.7% compared to 1.5% in the Nanoxel 220 mg/m² arm.
Musculoskeletal: Myalgia was observed in 7.7% of patients in Nanoxel 220 mg/m² arm compared to 6.3% in patients receiving conventional paclitaxel. All the events were grade 1/2 in severity, which rsolved without sequelae.
Gastrointestinal: The majority of these GI events were nausea, vomiting, diarrhea and oral mucositis. Nausea/vomiting, diarrhea and mucositis were reported by 40, 10.8 and 12.3% of Nanoxel (220 mg/m²) treated patients. The majority of GI adverse events were of grade 1 & 2 severity and resolved without sequelae.
Dermatologic: The incidence of events related to skin and subcutaneous tissues showed a similar trend in conventional paclitaxel arm and Nanoxel 220 mg/m² arm (56.4% versus 52.1%, respectively). Most of the events were grade 1-2 in severity.
Hepatic: There was minimal elevation in bilirubin, SGOT and SGPT levels after administration of Nanoxel. All events were of mild to moderate severity. Among patients treated with Nanoxel 220 mg/m² 6.2, 1.5, 3 and 3.1% had elevations in bilirubin, alkaline phosphatase, SGOT and SGPT, respectively.
Accidental Exposure: No reports of accidental exposure to Nanoxel have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat and nausea have been reported. Following topical exposure, events have included tingling, burning and redness.

No drug interaction studies have been conducted with Nanoxel. The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering Nanoxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. (See Pharmacology under Actions).
Potential interactions between paclitaxel, a substrate of CYP3A4 and protease inhibitors (ritonavir, saquinavir, indinavir and nelfinavir) which are substrates and/or inhibitors of CYP3A4 have not been evaluated in clinical trials.

Instructions for Reconstitution: The components of Nanoxel should be reconstituted at the bedside prior to the IV infusion. Depending on the required dosage (calculated as per body surface area) the required volume of Nanoxel should be calculated. Based upon the calculated dose the required number of vials should be taken out of the refigerator and brought to room temperature prior to reconstitution. Nanoxel should be reconstituted only in 10% w/v dextrose injection in glass bottle (do not use dextrose injection available in plastic containers) and not in other solutions like sodium chloride injection or dextrose and sodium chloride injection. Nanoxel is reconstituted in following 3 steps:
Step 1: "Concentrate of excipients for Nanoxel" in volume equal to the calculated volume of Nanoxel should be drawn in a suitable sterile disposable syringe and added to the 10% w/v dextrose injection bottle. The bottle should then be shaken gently to mix the contents. Vigorous shaking should be avoided to prevent foaming of the solution.
Step 2: The bottle should then be placed in an inverted position on the IV stand and another fresh sterile disposable suitable size syringe should be used to draw the required amount of Nanoxel using a 22G 1-inch needle. Precautions should be taken to avoid air bubbles in the solution if any. The drug solution should then be rapidly injected in the 10% w/v dextrose injection bottle containing the concentrate of excipients (in the inverted position only) such that the contents of the syringe flow out in a continuous stream without any interruption. Precautions should be taken that the contents are injected rapidly in 1 go. Both hands, if required, may be used to push the piston/plunger.
Step 3: Nanoxel solution is now ready to be infused in the patient.
Reconstituted solutions will be slightly opalescent, which is attributed to the formation of nanoparticles. Nanoxel should be administered through an IV set with an in-line filter with a microporous membrane of 0.2 microns. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.2 microns) filter. No drug or any other substance should be added to the Nanoxel infusion as addition may affect the stability of nanoparticles.
Note: Ten percent dextrose injection should only be used for flushing of the IV set. Other liquids like saline etc, should not be used.
Handling and Disposal: Paclitaxel is a cytotoxic agent and as with other cytotoxic drugs caution should be exercised in handling Nanoxel. The use of gloves and safety goggles is recommended. If Nanoxel or the reconstituted solution comes in contact with the skin it should be washed thoroughly with soap and water. If Nanoxel comes in contact with the mucous membranes, it should be flushed thoroughly with water.
Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Store Nanoxel and the concentrate of excipients for Nanoxel under refrigeration at 2-8°C. Protect from light. Do not freeze. The reconstituted infusion should be infused within 6 hours of reconstitution.
Stability: Nanoxel and concentrate of excipients of Nanoxel are stable for at least 24 months at recommended storage conditions (2-8°C).

Cytotoxic Chemotherapy

L01CD01 - paclitaxel ; Belongs to the class of taxanes from plant alkaloids and other natural products. Used in the treatment of cancer.

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