Claxel

Paclitaxel.

Each mL contains: Paclitaxel 6 mg.

Pharmacology: Pharmacodynamics: 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 function. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations.
The pharmacokinetics of paclitaxel was determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m². Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m²; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m², indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m² to 175 mg/m², the Cmax and AUC→∞ values increased 75% and 81%, respectively.
Following an intravenous dose of 100 mg/ m² given as a 3-hour infusion to19 KS patients, the mean Cmax was 1,530 ng/ml (range 761 - 2,860 ng/ml) and the mean AUC 5,619 ng·h/ml (range 2,609- 9,428 ng·hr/ml). Clearance was 20.6 l/h/m² (range 11-38) and the volume of distribution was 291 l/m² (range 121- 638). The terminal elimination half-life averaged 23.7 hours (range 12 - 33).

Ovarian carcinoma: In the first-line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of patients with advanced carcinoma of the ovary or with residual disease (> 1 cm) after initial laparotomy, in combination with cisplatin.
In the second-line chemotherapy of ovarian cancer, Paclitaxel is indicated for the treatment of metastatic carcinoma of the ovary after failure of standard, platinum containing therapy.
Breast carcinoma: In the adjuvant setting, Paclitaxel is indicated for the treatment of patients with node-positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with Paclitaxel should be regarded as an alternative to extended AC therapy.
Paclitaxel is indicated for the initial treatment of locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is suitable or in combination with trastuzumab, in patients who over-express HER-2 at a 3+ level as determined by immunohistcohemistry and for whom an anthracycline is not suitable.
As a single agent, Paclitaxel is indicated for the treatment of metastatic carcinoma of the breast in patients who have failed, or are not candidates for standard, anthracycline containing therapy.
Advanced non-small cell lung carcinoma: Paclitaxel, in combination with cisplatin, is indicated for the treatment of non-small cell lung carcinoma (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy.
AIDS-related Kaposi's sarcoma: Pacilitaxel is indicated for the treatment of patients with advanced AIDS-related Kaposi's sarcoma (KS) who have failed prior liposomal anthracycline therapy.

Paclitaxel must be diluted before use in 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection, to a final concentration of 0.3 to 1.2 mg/ml and should only be administered intravenously.
All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to paclitaxel, e.g. (see table.)

Click on icon to see table/diagram/image

First-line chemotherapy of ovarian carcinoma: Although other dosage regimens are under investigation, a combination regimen of paclitaxel and cisplatin is recommended. According to duration of infusion, two doses of paclitaxel are recommended: Paclitaxel 175 mg/m² administered intravenously over 3 hours, followed by cisplatin at a dose of 75 mg/m² every three weeks or paclitaxel 135 mg/m², in a 24-hour infusion followed by cisplatin 75 mg/m², with a 3 week interval between courses.
Second-line chemotherapy of ovarian carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 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 doxorubcin. The recommended dose of paclitaxel is 220 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses (see Interactions and Pharmacology: Pharmacodynamics under Actions). 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 (see Pharmacology: Pharmacodynamics under Actions). 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 (for detailed trastuzumab posology see the Summary of Product Characteristics of trastuzumab).
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.
Treatment of advanced non-small cell lung cancer: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, followed by cisplatin 80 mg/m², 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.
Subsequent doses of paclitaxel should be administered according to individual patient tolerance.
Dose adjustments during treatment: Paclitaxel should not be readministered until the neutrophil count is ≥1,500/mm³ (≥1,000/mm³ for KS patients) and the platelet count is ≥100,000/mm³ (≥75,000/mm³ for KS patients). Patients who experience severe neutropenia (neutrophil count <500/mm³ for ≥7 days) or severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (25% for KS patients and patients with metastatic disease).
Patients who experience mucositis (grade 2 or worse) during paclitaxel therapy should have their dosage reduced by 25% for subsequent courses of paclitaxel.
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 should not be treated with paclitaxel.
Patients with impaired renal function: Studies in patients with impaired renal function have not been performed and there are insufficient data to permit dosage recommendations.
Pediatric population: Paclitaxel is not recommended for use in children less than 18 years due to lack of data on safety and efficacy. Or as prescribed by the physician.

There is no known antidote for paclitaxel overdosage.
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.

Paclitaxel is contraindicated in patients who have a history of hypersensitivity to the active substance or to any of the excipients, especially Polyoxyethylated 35 castor oil (Macrogolglycerol ricinoleate 35). Lactation and patients with baseline neutrophils < 1,500/mm³ (<1,000/mm³ for KS patients) is also contraindicated.
In KS, Paclitaxel is contraindicated in patients with concurrent, serious, uncontrolled infections.

Since paclitaxel concentrate for solution for infusion contains ethanol (392 mg/ml), consideration should be given to possible CNS and other effects.
Paclitaxel concentrate for solution for infusion contains Polyoxyl Castor oil, which may cause severe allergic reactions.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Paclitaxel should be given before cisplatin when used in combination.

Pregnancy: There is no adequate information on the use of paclitaxel in pregnant women. Paclitaxel has been shown to be embryotoxic and foetotoxic in rabbits, and to decrease fertility in rats.
As with other cytotoxic drugs, paclitaxel may cause fetal harm, and is therefore contraindicated during pregnancy. Women should be advised to avoid becoming pregnant during therapy with paclitaxel, and to inform the treating physician immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraception for at least 6 months after treatment with paclitaxel.
Breast-feeding: Paclitaxel is contraindicated during lactation. It is not known whether paclitaxel is excreted in human milk. Breastfeeding should be discontinued for the duration of therapy.

Infections and infestations: Infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome, flu syndrome, septic shock, pneumonia peritonitis, sepsis.
Blood and lymphatic system disorders: Myelosuppression, neutropenia, anemia, thrombocytopenia, leucopenia, bleeding, neutropenic fever, severe anemia, febrile neutropenia, acute myeloid leukemia, myelodysplastic syndrome.
Immune system disorders: Minor hypersensitivity reactions (mainly flushing and rash), significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremities, diaphoresis and hypertension), anaphylactic reactions, anaphylactic shock.
Metabolism and nutrition disorders: Weight gain, weight loss, anorexia, tumor lysis syndrome.
Psychiatric disorders: Confusional stage.
Nervous system disorders: Neurotoxicity (mainly: peripheral neuropathy), paresthesia, somnolence, depression, severe neuropathy, nervousness, insomnia, hypokinesia, abnormal gait, abnormal thinking, hypoesthesia, taste change, motor neuropathy (with resultant minor distal weakness), autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia.
Eye disorders: Dry eyes, amblyopia, visual field defect, optic nerve and/or visual disturbances (scintillating scotoma), particularly in patients who have received higher doses than recommended, macular oedema, photopsia, vitreous floaters.
Ear and labyrinth disorders: Ototoxicity, hearing loss, tinnitus, vertigo.
Cardiac disorders: Bradycardia, tachycardia, palpitation, syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, AV block and syncope, myocardial infarction, congestive heart failure, cardiac failure, atrial fibrillation, supraventricular tachycardia.
Vascular disorders: Hypotension, vasodilation (flushing), hypertension, thrombosis, thrombophlebitis, shock, phlebitis.
Respiratory, thoracic and mediastinal disorders: Epistaxis, dyspnea, pleural effusion, interstitial pneumonia, lung fibrosis, pulmonary embolism, respiratory failure, cough, pulmonary hypertension.
Gastrointestinal disorders: Nausea, vomiting, diarrhea, mucosal inflammation, stomatitis, abdominal pain, dry mouth, mouth ulceration, melena, dyspepsia, bowel obstruction, bowel perforation, ischemic colitis, pancreatitis, mesenteric thrombosis, pseudomembranous colitis, esophagitis, constipation, ascites, neutropenic colitis.
Hepato-biliary disorders: Hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome).
Skin and subcutaneous tissue disorders: Alopecia, transient and mild nail and skin changes, changes in nail pigmentation or discoloration of nail bed, pruritus, rash, erythema, Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet), folliculitis, scleroderma.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, bone pain, leg cramps, myasthenia, back pain, systemic lupus erythematosus.
Renal and urinary disorders: Dysuria.
General disorders and administration site conditions: Asthenia, pain, oedema including peripheral and face, injection site reactions (including localized oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis, skin fibrosis and skin necrosis), chest pain, chills, asthenia, pyrexia, dehydration, oedema, malaise.

The recommended regimen of paclitaxel administration for the first-line chemotherapy of ovarian carcinoma is for paclitaxel to be given before cisplatin. When paclitaxel is given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single-agent use. When paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.
Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin.
The metabolism of paclitaxel is catalyzed, in part, by cytochrome P450 isoenzymes CYP2C8 and 3A4. Clinical studies have demonstrated that CYP2C8- mediated metabolism of paclitaxel, to 6α- hydroxypaclitaxel, is the major metabolic pathway in humans. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of drug interactions between paclitaxel and other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or CYP3A4.
Paclitaxel clearance is not affected by cimetidine premedication.
Studies in KS patients, who were taking multiple concomitant medications, suggest that the systemic clearance of paclitaxel was significantly lower in the presence of nelfinavir and ritonavir, but not with indinavir. Insufficient information is available on interactions with other protease inhibitors. Consequently, paclitaxel should be administered with caution in patients receiving protease inhibitors as concomitant therapy.

Special Precautions for Handling and Disposal: Upon preparations, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. Paclitaxel should be administered through an in-line filter with a microporous membrane ≤0.22 µm. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line filter.
Dilution should be carried out under aseptic conditions by trained personnel in a designated area. Adequate protective gloves should be worn. Precautions should be taken to avoid contact with the skin and mucous membranes.

Store at temperatures not exceeding 30°C.
After opening before dilution: Chemical and physical in-use stability has been demonstrated for 28 days at 25°C following multiple needle entries and product withdrawals. From a microbiological point of view, once opened the product may be stored for a maximum of 28 days at 25°C.
After dilution: Chemical and physical in-use stability of the solution prepared for infusion has been demonstrated at 2°C to 8°C and at 25°C for 7 days when diluted in 5% dextrose solution, 5% dextrose and 0.9% sodium chloride solution and for 14 days when diluted in 0.9% sodium chloride injection.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

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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