Taxol^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb S.r.L. (Italy)

ATC Code

L01CD01 (Paclitaxel)

Active Substance

Paclitaxel (Rec.INN registered by WHO)

Dosage Forms

	Taxol®	Concentrate for solution for infusion 6 mg/1 ml: 30 mg vial, 1 pc.
		Concentrate for solution for infusion 6 mg/1 ml: 100 mg vial, 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear, colorless or slightly yellowish, viscous solution.

Excipients: macrogolglycerol ricinoleate (Cremophor^® EL), ethanol, nitrogen.

5 ml – 5 ml vials (1) – cardboard packs.

Concentrate for solution for infusion is a clear, colorless or slightly yellowish, viscous solution.

Excipients: macrogolglycerol ricinoleate (Cremophor^® EL), ethanol, nitrogen.

16.7 ml – 20 ml vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic drug obtained by biosynthetic means. The mechanism of action is associated with the ability to stimulate the “assembly” of microtubules from dimeric tubulin molecules, stabilize their structure by suppressing depolymerization and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.

In addition, Paclitaxel induces the formation of abnormal clusters or “bundles” of microtubules throughout the cell cycle and causes the formation of multiple microtubule stars during mitosis.

Causes dose-dependent suppression of bone marrow hematopoiesis.

Experimental studies have shown that Paclitaxel has mutagenic and embryotoxic properties and causes a decrease in reproductive function.

Pharmacokinetics

The pharmacokinetics of paclitaxel were studied after IV infusion of the drug at doses of 135 mg/m² and 175 mg/m² over 3 and 24 hours.

Distribution

After IV administration, the concentration of paclitaxel in blood plasma decreases in accordance with biphasic kinetics.

The mean V_d ranges from 198 to 688 L/m².

The pharmacokinetics of paclitaxel becomes nonlinear with increasing dose. When the drug dose was increased by 30% (from 135 mg/m² to 175 mg/m²), the C_max and AUC_0-∞ values increased by 75% and 81%, respectively.

No evidence of paclitaxel accumulation was obtained during repeated courses of therapy.

Protein binding averages 89%.

Metabolism

In vitro studies have shown that Paclitaxel is metabolized in the liver with the participation of the isoenzyme CYP2C8 to form the metabolite 6-alpha-hydroxypaclitaxel and with the participation of the isoenzyme CYP3A4 to form the metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxypaclitaxel.

Excretion

T_1/2 and total clearance of paclitaxel are variable, depend on the dose and duration of administration and are 13-52.7 hours and 12.2-23.8 L/h/m², respectively.

From 1.3% to 12.6% of the administered dose (15-275 mg/m² as a 1-, 6-, or 24-hour infusion) of the drug is excreted unchanged in the urine, indicating the presence of intense extrarenal clearance.

Pharmacokinetics in special clinical cases

The effect of renal impairment on the metabolism of paclitaxel has not been studied.

Dialysis does not affect the rate of drug elimination from the body.

Indications

Ovarian cancer

• First-line therapy in combination with cisplatin in patients with advanced metastatic disease or residual tumor (more than 1 cm) after initial laparotomy;
• Second-line therapy in patients with advanced metastatic ovarian cancer after standard therapy that did not yield a positive result.

Breast cancer

• Adjuvant therapy in patients with lymph node metastases after standard combination treatment;
• First-line therapy for metastatic cancer and for disease progression after adjuvant therapy with anthracycline drugs;
• Second-line therapy for disease progression after combination chemotherapy with anthracycline antitumor antibiotics in the absence of contraindications to their use;
• Adjuvant therapy for the treatment of patients after therapy with anthracycline drugs and cyclophosphamide;
• First-line therapy for metastatic breast cancer in combination with trastuzumab in patients with HER-2 expression level 3+ according to immunohistochemical study and in the presence of contraindications to therapy with anthracycline drugs.

Non-small cell lung cancer

• As first-line therapy in combination with cisplatin or for monotherapy of non-small cell lung cancer in patients for whom surgical treatment and/or radiation therapy is not planned.

Kaposi’s sarcoma in AIDS patients

• As second-line therapy.

ICD codes

Dosage Regimen

To prevent severe hypersensitivity reactions, premedication with corticosteroids, histamine H₁-receptor blockers and histamine H₂-receptor blockers should be administered prior to Taxol^® administration. For example, dexamethasone (or its equivalent) at a dose of 20 mg orally approximately 12 hours and 6 hours before Taxol^® administration or dexamethasone at a dose of 20 mg IV approximately 30-60 minutes before Taxol^® administration, diphenhydramine (or equivalent) at a dose of 50 mg IV and cimetidine at a dose of 300 mg or ranitidine at a dose of 50 mg IV 30-60 minutes before Taxol^® administration.

Ovarian cancer

First-line therapy: the recommended dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion or 135 mg/m² as a 24-hour IV infusion followed by cisplatin at a dose of 75 mg/m²; the interval between treatment courses should be 3 weeks.

Second-line therapy: in monotherapy mode, the dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion every 3 weeks.

Breast cancer

Adjuvant therapy is carried out after standard combination therapy. The dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion. A total of 4 courses of therapy are recommended at 3-week intervals.

First-line therapy

In monotherapy mode: the dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion every 3 weeks.

In combination therapy mode

• In combination with trastuzumab, the recommended dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion every 3 weeks. Administration of Taxol^® can be started the day after the first dose of trastuzumab or, if well tolerated, on the day of trastuzumab administration.
• In combination with doxorubicin (50 mg/m²), Taxol^® is prescribed at a dose of 220 mg/m² as a 3-hour IV infusion every 3 weeks. Administration of Taxol^® should be started 24 hours after doxorubicin administration.

Second-line therapy

For the treatment of patients with disseminated disease after combination chemotherapy that did not yield a positive result – 175 mg/m² as a 3-hour IV infusion every 3 weeks.

Non-small cell lung cancer

• In combination therapy mode, the recommended dose of Taxol^® is 175 mg/m² as a 3-hour IV infusion or 135 mg/m² as a 24-hour IV infusion followed by cisplatin, the interval between courses is 3 weeks;
• In monotherapy mode, the recommended dose of Taxol^® ranges from 175 mg/m² to 225 mg/m² as a 3-hour IV infusion every 3 weeks.

Kaposi’s sarcoma in AIDS patients

For second-line therapy, the recommended dose of Taxol^® is 135 mg/m² as a 3-hour IV infusion every 3 weeks or 100 mg/m² IV drip over 3 hours every 2 weeks.

Depending on the immunosuppression observed in patients with developing AIDS, it is recommended

1. to reduce the dose of oral dexamethasone (one of the three components of premedication) to 10 mg;

2. to administer Taxol^® only when the neutrophil count is at least 1000/µl;

3. for patients with severe neutropenia (less than 500/µl for a week or more) to reduce the dose of Taxol^® by 20% in subsequent courses;

4. to use G-CSF concomitantly according to clinical indications.

Rules for preparation of infusion solution

Before administration, the concentrate is diluted to a concentration of 0.3-1.2 mg/ml with 0.9% sodium chloride solution, 5% dextrose solution, 5% dextrose in 0.9% sodium chloride solution or 5% dextrose in Ringer’s solution.

Taxol^® should be administered through a system with an in-line membrane filter with a pore size of no more than 0.22 µm.

The prepared solutions may appear opalescent due to the carrier base present in the dosage form, and the opalescence of the solution persists after filtration.

When preparing, storing and administering Taxol^®, equipment that does not contain polyvinyl chloride parts should be used.

Adverse Reactions

When using the combination of Taxol^® with platinum drugs, no clinically significant changes in the drug’s safety profile were noted compared to its use as monotherapy.

In patients with Kaposi’s sarcoma developing against the background of AIDS, suppression of hematopoiesis, infections (including opportunistic infections) and febrile neutropenia occur more often and are more severe. In these patients, dose reduction of the drug and supportive therapy are required.

Definition of frequency of adverse effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

From the hematopoietic system very common – myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, fever, bleeding; rare – febrile neutropenia; very rare – acute myeloid leukemia, myelodysplastic syndrome.

Neutropenia (90%), less dependent on the drug dose and more dependent on the duration of infusion; severe neutropenia (less than 500/µl) is more often observed with 24-hour infusions than with 3-hour infusions in approximately half of the patients, with 1/3 of them accompanied by fever; development of infectious complications (30%); fatal outcome was registered in 1% of patients with diagnoses of sepsis, pneumonia, peritonitis.

Thrombocytopenia (20%) with platelet count less than 100,000/µl; severe thrombocytopenia with minimal platelet count below 50,000/µl (7%); anemia (78%); severe anemia with hemoglobin less than 8 g/dL (16%).

The frequency and severity of anemia depended on the baseline hemoglobin level and did not depend on the dose and regimen of Taxol^® administration.

Allergic reactions very common – minor manifestations, mainly in the form of hot flashes, skin rash; uncommon – severe hypersensitivity reactions (decreased BP, angioedema, tachycardia, respiratory dysfunction, generalized urticaria), back pain, chills; rare – anaphylactic reactions (including fatal); very rare – anaphylactic shock.

From the cardiovascular system very common – ECG changes, decreased BP; common – bradycardia; uncommon – cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, AV block and syncope, myocardial infarction, increased BP, thrombosis, thrombophlebitis; very rare – atrial fibrillation, supraventricular tachycardia, shock.

From the respiratory system rare – dyspnea, pleural effusion, respiratory failure, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism; very rare – cough. More frequent development of radiation pneumonitis was noted in patients simultaneously undergoing a course of radiation therapy.

From the central and peripheral nervous system very common – peripheral sensory neuropathy; rare – motor neuropathy (limb weakness); very rare – autonomic neuropathy, manifested by paralytic ileus and orthostatic hypotension, grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia.

From the musculoskeletal system: very common – arthralgia, myalgia.

From the digestive system: very common – nausea, vomiting, diarrhea, mucositis; common – significant increase in AST level, ALP; uncommon – significant increase in bilirubin level; rare – intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis; very rare – mesenteric artery thrombosis, pseudomembranous colitis, esophagitis, constipation, ascites, fatal hepatic necrosis, fatal hepatic encephalopathy.

From the urinary system: cases of renal dysfunction with reversible increases in serum creatinine levels have been described in patients with Kaposi’s sarcoma and AIDS.

Dermatological reactions: very common – alopecia; rare – itching, rash, erythema, fibrosis, very rare – Stevens-Johnson syndrome, epidermal necrolysis, exudative multiforme erythema, exfoliative dermatitis, urticaria, onycholysis.

Local reactions: common – pain, swelling, erythema, induration and skin pigmentation at the injection site, rare – phlebitis, skin desquamation; extravasation can cause inflammation and necrosis of the subcutaneous tissue.

Other: anorexia, confusion, asthenia and general malaise.

Contraindications

• Baseline neutrophil count less than 1500/µl in patients with solid tumors;
• Baseline (or recorded during treatment) neutrophil count less than 1000/µl in patients with Kaposi’s sarcoma in AIDS patients;
• Concomitant, serious, uncontrolled infections in patients with Kaposi’s sarcoma;
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to the components of the drug (including polyoxylated castor oil).

With caution the drug should be used for thrombocytopenia (less than 100,000/µl), hepatic insufficiency, acute infectious diseases (including herpes zoster, chickenpox, herpes), severe coronary artery disease, myocardial infarction (in history), arrhythmia.

Use in Pregnancy and Lactation

Taxol^® is contraindicated for use during pregnancy and during lactation (breastfeeding).

Patients of childbearing potential should use reliable methods of contraception during treatment with Taxol^® and for at least 3 months after the end of therapy.

Use in Hepatic Impairment

Changes in paclitaxel metabolism in hepatic impairment with three-hour infusion have not been formally studied.

Use in Renal Impairment

Changes in paclitaxel metabolism in renal impairment with three-hour infusion have not been formally studied.

Pediatric Use

The safety and efficacy of Taxol^® in children have not been established.

Special Precautions

Treatment with Taxol^® should be carried out by a physician experienced in the use of antineoplastic chemotherapeutic drugs.

When using Taxol^® in combination with cisplatin, Taxol^® should be administered first, followed by cisplatin.

During treatment, it is necessary to regularly monitor the peripheral blood picture, BP, heart rate and respiratory rate (especially during the first hour of infusion), ECG monitoring (also before starting treatment).

If severe hypersensitivity reactions develop, the infusion of Taxol^® should be stopped immediately and symptomatic treatment should be started, and the drug should not be readministered.

In cases of development of AV conduction disorders, continuous cardiac monitoring should be performed during repeated administrations.

Taxol^® is a cytotoxic substance, and caution should be exercised when handling it, gloves should be worn and contact with skin or mucous membranes should be avoided; in such cases, they should be thoroughly washed with soap and water, or (eyes) with plenty of water.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should refrain from engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Use in pediatrics

The safety and efficacy of Taxol^® in children have not been established.

Overdose

Symptoms bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment symptomatic therapy is carried out. A specific antidote for paclitaxel is unknown.

Drug Interactions

Cisplatin reduces the total clearance of paclitaxel by 33% (with more pronounced myelosuppression observed when Paclitaxel is administered after cisplatin).

When using Taxol^® in combination with doxorubicin, an increase in the plasma concentration of doxorubicin (and its active metabolite doxorubicinol) is possible. When administering Taxol^® (24-hour infusion) prior to doxorubicin (48-hour infusion), more pronounced neutropenia and cases of stomatitis were observed. However, when doxorubicin was administered by bolus injection and Taxol^® was administered over 3 hours, no changes in the nature of toxic effects related to the sequence of drug administration were noted.

Concomitant use with cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect the binding of paclitaxel to plasma proteins.

The metabolism of paclitaxel is catalyzed by the CYP2C8 and CYP3A4 isoenzymes; therefore, caution is required when using Taxol^® during treatment with substrates, inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) or inhibitors (e.g., erythromycin, fluoxetine, gemfibrozil) of the CYP2C8 and CYP3A4 isoenzymes.

In vitro, microsomal oxidation inhibitors (including ketoconazole, verapamil, diazepam, quinidine, cyclosporine) at concentrations exceeding those achieved with therapeutic doses in vivo, as well as testosterone, 17α-ethinylestradiol, retinoic acid, and quercetin, inhibit the metabolism of paclitaxel.

Macrogol glycerol ricinoleate, which is part of the Taxol^® drug, can cause the extraction of DEHP [di-(2-ethylhexyl) phthalate] from plasticized polyvinyl chloride containers, and the degree of DEHP leaching increases with increasing solution concentration and over time.

Storage Conditions

List B. The drug should be stored out of the reach of children, in a light-protected place at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 2 years.

If unopened vials are stored in the refrigerator, the drug may precipitate; the precipitate dissolves again when the vial is warmed to room temperature with slight agitation (or without it). The quality of the drug is not impaired in this case. If the drug in the vial remains cloudy or an insoluble precipitate is observed, the drug should be discarded. Freezing does not affect the quality of the drug.

Diluted solutions are stable for 27 hours when stored at a temperature not exceeding 25°C (77°F) and under room lighting (including the infusion time).

Solutions obtained by diluting the drug with a 5% dextrose solution are stable for 7 days; solutions obtained by diluting with a 0.9% sodium chloride solution are stable for 14 days when stored at a temperature between 5°C (41°F) and 25°C (77°F).

Diluted solutions should not be stored in the refrigerator.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.