Ontaxel IV Infusion

Paclitaxel is a novel anti-microtubule 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.

All patients should be premedicated prior to Paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel.

First-line treatment of ovarian cancer: Although alternative medication regimens for paclitaxel are under investigation at present, a combination therapy of paclitaxel and cisplatin is recommended. Depending on the duration of infusion, two different dosages are recommended for paclitaxel treatment: 175 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of three hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals, or 135 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of 24 hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals.

Second-line treatment of ovarian cancer: The recommended dose of paclitaxel is 175 mg/m2 administered over 3 hours, with a 3-week interval between courses.

Adjuvant chemotherapy in breast carcinoma: The recommended dose of paclitaxel is 175 mg/m2 administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.

First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m2), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses. When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses. Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Second-line chemotherapy of breast carcinoma: The recommended dose of paclitaxel is 175 mg/m2 administered over a period of 3 hours, with a 3-week interval between courses.

Advanced non-small-cell lung cancer: The recommended dose of paclitaxel is 175 mg/m2 administered over 3 hours followed by 80 mg/m2 of cisplatin, with a 3-week interval between courses.

Treatment of AIDS-related KS: The recommended dose of paclitaxel is 100 mg/m2 administered as a 3-hour intravenous infusion every two weeks.

Dose adjustment: Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Paclitaxel should not be re-administered until the neutrophil count is >1.5 x 109/1 (>1 x 109/1 for KS patients) and the platelet count is >100 x 109/1 (>75 x 109/1 for KS patients).

Ontaxel clearance is not affected by cimetidine premedication.

Cisplatin: Administration of Ontaxel after cisplatin treatment leads to greater myelosuppression and about a 20% decrease in Ontaxel clearance. Patients treated with Ontaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.

Doxorubicin: Since the elimination of doxorubicin and its active metabolites can be reduced when Ontaxel and doxorubicin are given closer in time, Ontaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin. Sequence effects characterized by more profound neutropenic and stomatitis episodes have been observed with combination use of Ontaxel and doxorubicin when Ontaxel was administered before doxorubicin and using longer than recommended infusion times (Ontaxel administered over 24 hours; doxorubicin over 48 hours).

Active substances metabolized in the liver: The metabolism of Ontaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Therefore, in the absence of a PK drug-drug interaction study, caution should be exercised when administering Ontaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of Ontaxel may be increased due to higher Ontaxel exposure. Administering Ontaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower Ontaxel exposures.

• Paclitaxel is contraindicated in patients with severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil.)
• Paclitaxel is contraindicated during lactation.
• Paclitaxel should not be used in patients with baseline neutrophils <1.5x10⁹/I (<1x10⁹/I for KS patients) or platelets <100x10⁹/I (<75x10⁹/I for KS patients).
• In KS, paclitaxel is also contraindicated in patients with concurrent, serious, uncontrolled infections.
• Patients with severe hepatic impairment must not be treated with paclitaxel.

Common: Low blood counts leading to increased risk for infection, anemia and/or bleeding, hair loss, arthralgias and myalgias, pain in the joints and muscles, peripheral neuropathy, nausea, vomiting (usually mild), diarrhea, Mouth sores, hypersensitivity reaction, fever, facial flushing, chills, shortness of breath, or hives after Ontaxel is given.

Rare: swelling of the feet or ankles (edema), liver problems, low blood pressure, darkening of the skin where previous radiation treatment has been given.

Pregnancy Category D. There is no adequate data from the use of paclitaxel in pregnant women, however as with other cytotoxic medicinal products, paclitaxel may cause foetal harm when administered to pregnant women. Paclitaxel is contraindicated during lactation.

Ontaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Ontaxel should be given before cisplatin when used in combination.

Significant hypersensitivity reactions, as characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in <1% of patients receiving Ontaxel after adequate premedication. Fatal hypersensitivity reactions have occurred in patients despite premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, Ontaxel infusion should be discontinued immediately.

Bone marrow suppression, primarily neutropenia, is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until the neutrophil count is ≥1.5 x 109/1 (≥1 x 109/1 for KS patients) and the platelets recover to ≥100 x 109/1 (≥75 x 109/1 for KS patients).

Severe cardiac conduction abnormalities have been reported rarely with single agent Ontaxel. If patients develop significant conduction abnormalities during Ontaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with Ontaxel.

Patients who experience severe neutropenia: (neutrophil count <0.5 x 109/1 for a minimum of 7 days) or severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (25% for KS patients).

Patients with hepatic impairment: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments. Patients with severe hepatic impairment must not be treated with Ontaxel.

Pediatric use: Ontaxel is not recommended for use in children below 18 years due to lack of data on safety and efficacy

There is no known antidote for Ontaxel overdose. In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities, which consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Overdoses in paediatric patients may be associated with acute ethanol toxicity.

Preparation for Intravenous Infusion: Ontaxel Injection must be diluted prior to infusion. Ontaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/ml. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (below 30°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Keep in a dry place and store below 30°C. Protect from light and keep out of the reach of children. Use only freshly prepared solution.