Taxol

Uses

Taxol Injection is used for first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first- line therapy, paclitaxel is used for combination with cisplatin.

Taxol Injection is used for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor negative tumors.

Taxol Injection is used 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 anthracyclineunless clinically contraused. Taxol Injection, in combination with cisplatin, is used 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. Taxol Injection is used for the second-line treatment of AIDS-related Kaposi's sarcoma.

Taxol is also used to associated treatment for these conditions: Advanced Cervical Cancer, Advanced Head and Neck Cancer, Advanced Ovarian Cancer, Advanced Soft Tissue Sarcoma, Esophageal Cancers, Fallopian Tube Cancer, Kaposi’s sarcoma, Locally Advanced Non-Small Cell Lung Cancer, Malignant Neoplasm of Stomach, Malignant Peritoneal Neoplasm, Metastatic Bladder Cancer, Metastatic Breast Cancer, Metastatic Melanoma, Metastatic Non-Small Cell Lung Cancer, Non-Small Cell Lung Carcinoma (NSCLC), Ovarian Cancer, Pancreatic Adenocarcinoma Metastatic, Advanced Bladder cancer, Advanced Thymoma, Metastatic Penile cancer, Refractory Small cell lung cancer, Refractory Testicular germ cell cancer

How Taxol works

Taxol interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.

Dosage

Taxol dosage

Advanced non-small cell lung cancer: 135 mg/m2 over 24 hr or 175 mg/m2 over 3 hr, followed by cisplatin and repeated at 3 wk intervals.

Ovarian carcinoma: Primary treatment (in combination with cisplatin or carboplatin): 135 mg/m2 infused over 24 hr followed by cisplatin and repeated at 3 wk intervals. Secondary treatment (as a single agent): 135 or 175 mg/m2 infused over 3 hr once every 3 weeks.

Breast cancer: Adjuvant therapy; 2nd line monotherapy or 1st line treatment with trastuzumab: 175 mg/m2 infused over 3 hr once every 3 wk for 4 courses; when used with trastuzumab, the dose should be given the day after the 1st dose of trastuzumab or immediately after subsequent doses if well-tolerated. 1st line with doxorubicin: 220 mg/m2over 3 hr every 3 wk, the dose to be administered 24 hr after doxorubicin.

AIDS-related Kaposi's sarcoma: 135 mg/m2 over 3 hr every 3 weeks. Alternatively, 100 mg/m2 over 3 hr every 2 wk especially in patients with poor performance status.

Taxol must be diluted before infusion. It can be diluted in 0.9% sodium chloride inj, 5% dextrose inj, 5% dextrose and 0.9% sodium chloride inj or 5% dextrose in lactated Ringer's inj to a concentration of 0.3-1.2 mg/ml.

Side Effects

Neutropenia, leukopenia, thrombocytopenia, anaemia, bleeding; hypersensitivity reactions (dyspnoea, flushing, chest pain, tachycardia, rash, hypotension, hypertension); bradycardia, abnormal ECG; neurotoxicity (mainly peripheral neuropathy), myalgia, arthralgia; nausea, vomiting, diarrhoea; severe mucositis, alopecia; rarely hepatic necrosis and encephalopathy, inj site reactions e.g. erythema, tenderness, skin discolouration, swelling; interstitial pneumonitis; infections (mainly UTIs and upper respiratory tract); mucosal inflammation, severe elevation in LFTs (aspartate aminotransferase and alkaline phosphatase).

Toxicity

Rat (ipr) LD₅₀=32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity.

Precaution

Bone marrow suppression during therapy. Monitor cardiac function if conduction abnormalities result. Premedicaton (with corticosteroid, antihistamine and histamine H2-receptor antagonist) may be required to reduce risk of hypersensitivity reaction. Discontinue, if severe reactions e.g. hypotension, dyspnoea, angioedema or urticaria occur. Caution in patients with moderate hepatic impairment. Monitor for reactions of admin. Safety and efficacy in paediatric patients have not been established. Administer before platinum derivatives (cisplatin, carboplatin) if used in combination. Hazardous agent; use appropriate precautions for handling and disposal.

Interaction

Myelosuppression was more profound when given after cisplatin than with the alternate sequence (e.g., paclitaxel before cisplatin). CYP2C8 inducers e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifapentine, and secobarbital may reduce levels or effects. CYP2C8 inhibitors e.g. gemfibrozil, ketoconazole, montelukast, and ritonavir may increase levels or effects. CYP3A4 inducers e.g. aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins may decrease the levels or effects. CYP3A4 inhibitors e.g. azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil may increase levels or effects. May increase anthracycline (eg doxorubicin, epirubicin) levels or toxicity; admin of anthracycline at least 24 hr prior to paclitaxel may reduce interaction. May decrease the absorption of cardiac glycosides (may only affect digoxin tablets); levels should be monitored.

Food Interaction

• Avoid echinacea. Co-administration may decrease the effectiveness of immunosuppressants, and echinacea may induce CYP3A4 increasing paclitaxel metabolism.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of paclitaxel.
• Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of paclitaxel and may reduce its serum concentration.

[Moderate] MONITOR: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may increase the plasma concentrations of paclitaxel, which is a substrate of the isoenzyme.

Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit.

Specific data for paclitaxel are lacking; however, in a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg

In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months.

Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%.

In addition, in a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel AUC increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg
MANAGEMENT: Caution is recommended if paclitaxel is to be used in combination with grapefruit and grapefruit juice.

Patients should be closely monitored for the development of paclitaxel toxicity, including diarrhea, mucositis, myelosuppression, and peripheral neuropathy and dose adjustment considered per local treatment protocols.

Taxol Drug Interaction

Moderate: paclitaxel protein-bound, doxorubicin, aprepitant, pegfilgrastimMinor: ascorbic acidUnknown: aspirin, fluticasone / salmeterol, palonosetron, lorazepam, diphenhydramine, loratadine, ubiquinone, cyclophosphamide, apixaban, omega-3 polyunsaturated fatty acids, acetaminophen, albuterol, cyanocobalamin, cholecalciferol, ondansetron

Taxol Disease Interaction

Major: infections, conduction disorders, hepatic dysfunction, myelosuppression, peripheral neuropathyModerate: anaphylaxis

Volume of Distribution

• 227 to 688 L/m^2 [apparent volume of distribution at steady-state, 24 hour infusion]

Elimination Route

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL.

Half Life

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.

Clearance

• 21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h]
• 23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h]
• 7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h]
• 12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h]

Elimination Route

In 5 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.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

History of hypersensitivity (especially macrogol glycerol ricinolate). Patients with baseline neutropenia of <1500 cells/mm3 (<1000 cells/mm3 for kaposi's sarcoma). Pregnancy and lactation. In kaposi's sarcoma, contraindicated in patients with concurrent, serious, uncontrolled infections.

Special Warning

Hepatic Impairment:

Advanced non-small cell lung cancer: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

Ovarian carcinoma: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendations, consult local protocol.

Breast cancer: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

AIDS-related Kaposi's sarcoma: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

Acute Overdose

Complications: bone marrow suppression, peripheral neurotoxicity and mucositis. There is no known antidote. Treatment is symptom specific and supportive.

Innovators Monograph

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