Napro-Tax

Napro-Tax

paclitaxel

Manufacturer:

Naprod

Distributor:

Multicare

Marketer:

Multicare
Full Prescribing Info
Contents
Paclitaxel.
Description
Each mL contains Paclitaxel 6 mg.
Action
Pharmacology: Mechanism of Action: Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers. It stabilizes microtubules by preventing depolymerization resulting in the inhibition of the normal dynamic reorganization of the microtubule network essential for cellular functions. Paclitaxel also induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: The pharmacokinetics of Paclitaxel have been evaluated over a wide range of doses up to 300 mg/m2 and infusion schedules ranging from 3 to 24 hours and have been shown to be non-linear and saturable with a disproportionately large increase in Cmax and AUC with increasing dose accompanied by an apparent dose-related decrease in total body clearance.
Following intravenous administration, Paclitaxel exhibits a biphasic decline in plasma concentrations. The initial rapid decline represents distribution to the peripheral compartment and elimination of paclitaxel. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. In patients treated with doses of 135 mg/m2 and 175 mg/m2 given as 3- and 24-hour infusions. Mean terminal half life has ranged from 13.1-52.7 hours and total body clearance has ranged from 12.2-23.8 L/hr/m2. Mean steady-state volume of distribution has ranged from 198-688 L/m2, indicating extensive extravascular distribution and/or tissue binding.
Distribution: On average, 89% of paclitaxel is bound to serum proteins, the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect protein binding of paclitaxel.
Metabolism: In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P-450 isozyme CYP2C8 and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel by CYP3A4.
Elimination: 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 paclitaxel ranged from 1.3-12.6% of the dose.
Indications/Uses
PACLITAXEL is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary As first-line therapy, is indicated in combination with cisplatin. PACLITAXEL is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. PACLITAXEL is indicated for the 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.
PACLITAXEL in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.
PACLITAXEL is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.
Dosage/Direction for Use
All patients should be premedicated prior to paclitaxel injection administration in order to minimize severe hypersensitivity reaction. Such premedication may consist of dexamethasone 20 mg orally approximately 12 and 6 hours before paclitaxel injection, diphenhydramine (or its equivalent) 50 mg IV 30-60 minutes prior to paclitaxel injection and cimetidine (300 mg) or ranitidine (60 mg) IV 30-60 minutes before paclitaxel injection.
Paclitaxel injection at a dose of 175 mg/m2 administered IV over 3 hours every 3 weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast who have failed standard therapy.
For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel 175 mg/m2 IV over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy.
After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, at a dose of 175 mg/m2 administered IV over 3 hours every 3 weeks has been shown to be effective.
Alternatively, a more myelosuppressive regimen of paclitaxel may be administered IV 135 mg/m2 over 24 hours followed by a platinum compound with a week interval between courses.
For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is administered IV over 24 hours at a dose of 135 mg/m2, followed by cisplatin 75 mg/m2.
For patients with AIDS-related Kaposi's sarcoma, administered at a dose of 135 mg/m2 given IV over 3 hours every 3 weeks or at a dose of 100 mg/m2 given IV over 3 hours every 2 weeks is recommended (dose intensity 45-50 mg/m2/week).
Single courses of paclitaxel injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3) or severe peripheral neuropathy during paclitaxel injection therapy should have the dosage reduced by 20% for subsequent courses of paclitaxel injection.
Concomitant hematopoietic growth factor (G-CSF) should be initiated as clinically indicated.
Overdosage
There is no known antidote for paclitaxel injection overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.
Contraindications
Paclitaxel injection is contraindicated in patients who have a history of severe hypersensitivity reactions to paclitaxel injection or other drugs formulated in cremophor EL (polyethoxylated castor oil). Paclitaxel injection should not be used in patients with severe baseline neutropenia (<1500 cells/mm3).
Special Precautions
The drug should be administered with caution in the following patients.
Paclitaxel injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
Patients receiving paclitaxel injection should be pre-treated with corticosteroids, antihistamines and H-antagonist (such as dexamethasone, diphenhydramine and cimetidine or ranitidine) to minimize hypersensitivity reactions. Severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema and generalized urticaria have occurred in patients receiving paclitaxel injection. These reactions are probably histamine-mediated. One of these reactions was fatal in a patient treated without premedication in a phase I study. Patients who experience severe hypersensitivity reactions to paclitaxel injection should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Frequent monitoring of blood counts should be instituted during paclitaxel injection treatment. Patients should not be treated with subsequent cycles of paclitaxel injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
General: Hematology: Paclitaxel injection should be administered to patients with baseline neutrophil counts of less than 1,500 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 paclitaxel injection.
Patients should not be retreated with subsequent cycles of Paclitaxel injection until neutrophils recover to a level of >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3) during a course of Paclitaxel injection therapy, a 20% reduction in dose for a subsequent courses of therapy is recommended.
Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reaction to products containing cremophor EL should not be treated with paclitaxel injection. Minor symptoms eg, flushing, skin reactions, dyspnea, hypotension or tachycardia do not require interruption of therapy. However, severe reactions such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria require immediate discontinuation of paclitaxel injection and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel injection.
Cardiovascular: Hypotension and bradycardia observed during administration of paclitaxel injection but generally do not require treatment. Frequent vital sign monitoring particularly during the first hour of paclitaxel injection infusion is recommended. Continuous cardiac monitoring is not required except for patients who develop serious conduction abnormalities.
Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel injection.
Hepatic: There is no evidence that the toxicity of paclitaxel injection is enhanced in patients with abnormal liver function, but no data are available for patients with severe baseline cholestasis.
Use In Pregnancy & Lactation
Use in pregnancy: There are no studies in pregnant women. Paclitaxel injection has been shown to be embryo and feto-toxic in rabbits and to decrease fertility in rats.
Use in lactation: Paclitaxel injection should not be administered to nursing mothers.
Adverse Reactions
A dose of 175 mg/m2 and a 3 hours infusion schedule. All patients were premedicated to minimize hypersensitivity reactions. Data from these clinical trials demonstrate that Paclitaxel Injection given at this dose and schedule is well tolerated. Myelosuppression. in particular, is less frequent and less severe than with 24 hour infusion schedule. Moreover, as compared to a 24 hour infusion schedule, the incidence of hypersensitivity reaction, peripheral neuropathy or other significant undesirable effects was not increased when Paclitaxel Injection was administered at this dose and schedule.
None of the observed toxicities were influenced by age.
Hematologic: The most frequent significant undesirable effect of Paclitaxel Injection was bone marrow suppression. Severe neutropenia (<500 cells/mm3) occurred in 27% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for 7 days or more Eighteen percent of patients had an infectious episode. Although severe septic episodes associated with severe neutropenia attributable to Paclitaxel Injection were reported in early clinical trials, no severe infections or septic episodes were seen at the recommended dose and infusion schedule.
Thrombocytopenia was reported in 6% of patients. One percent of patients had a platelet low 3 count 50.000/mm3 at least once while on study.
Anemia was observed in 62% of patients, but was severe (Hb<8g/dL) in only 6% of patients. Incidence and severity of anemia are related to baseline hemoglobin status. Hypersensitivity Reactions: A significant Hypersensitivity reaction (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy or generalized urticaria) occurred in 2 patients. Thirty-nine percent of patients (20% of all courses) experienced minor hypersensitivity reaction. These minor reaction, mainly flushing and rash did not require therapeutic intervention nor did they prevent continuation of Paclitaxel Injection therapy.
Cardiovascular: Hypotension and bradycardia were experienced by 22% and 3% of patients, respectively, and were asymptomatic in all cases.
Neurologic: Peripheral neuropathy, mainly manifested by paresthesia, affected 64% of patients, but was severe in only 4% of patients. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to Paclitaxel Injection Sensory symptoms have usually improved or resolved within several months of Paclitaxel Injection discontinuation Preexisting neuropathies resulting from prior therapies are not a contraindication for Paclitaxel Injection therapy.
Arthralgia/Myalgia: Arthralgia or myalgia affected 54% of patients and was severe in 12% of patients.
Alopecia: Alopecia was observed in almost all patients.
Gastrointestinal: Gastrointestinal side effects were usually mild to moderate: nausea/vomiting, diarrhoea and mucositis were reported by 44%, 25% and 20% of patients respectively. Other gastrointestinal events included anorexia (25% of patients) constipation (18%) and intestinal obstruction (4%).
Hepatic: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression. Dose adjustment is recommended. Severe elevation (>5 x normal values) in AST (SGOT), alkaline phosphate or bilirubin were seen in 5%, 5% and 1% of patients.
Drug Interactions
In a phase 1 trial using escalating doses of paclitaxel injection (110-220 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound when paclitaxel injection was given after cisplatin than with the alternate sequence (ie, paclitaxel injection before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel injection was administered following cisplatin.
Doxorubicin: Sequence effects characterized by more profound neutropenic stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
Caution For Usage
Preparation for Intravenous Administration: Paclitaxel injection must be diluted prior to infusion. Paclitaxel injection should be diluted in 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection or 5% dextrose in Ringer's injection to a final concentration of 0.3-1.2 mg/mL.
The solutions are physically and chemically stable for up to 27 hours at ambient temperature (<25°C).
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle.
Data collected for the presence of the extractable plasticizer di-(2-ethylhexyl) phthalate (DEHP) show that levels increase with time and concentration when dilutions are prepared in polyvinyl chloride (PVC) containers. Consequently, the use of plasticized PVC, containers and administration sets is not recommended. Paclitaxel injection solutions should be prepared and stored in glass, polypropylene or polyolefin containers. Non-PVC containing administration sets eg, those which are polyethylene-lined, should be used.
No significant loss in potency has been noted following stimulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.
Use of filter devices eg, IVEX-2 filter which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.
Paclitaxel injection is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling paclitaxel injection. The use of gloves is recommended. If paclitaxel injection solution comes in contact with the skin, wash the skin immediately and thoroughly with soap and water. If paclitaxel injection comes in contact with mucous membranes, flush it thoroughly with water.
Storage
Store at temperatures not exceeding 25°C. Protect from light.
ATC Classification
L01CD01 - paclitaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 6 mg/mL (clear, colorless to slightly yellow viscous) x 5 mL, 16.67 mL, 43.34 mL.
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