Sindaxel (Concentrate) Instructions for Use

Marketing Authorization Holder

Actavis Group hf. (Iceland)

Manufactured By

S.C. Sindan-Pharma S.R.L. (Romania)

Or

Actavis Italy, S.p.A. (Italy)

Contact Information

ACTAVIS GROUP AO (Iceland)

ATC Code

L01CD01 (Paclitaxel)

Active Substance

Paclitaxel (Rec.INN registered by WHO)

Dosage Forms

	Sindaxel	Concentrate for solution for infusion 6 mg/1 ml: 5 ml vial, 1 pc.
		Concentrate for solution for infusion 6 mg/1 ml: 16.67 ml vial, 1 pc.
		Concentrate for solution for infusion 6 mg/1 ml: 25 ml vial, 1 pc.
		Concentrate for solution for infusion 6 mg/1 ml: 43.33 ml vial, 1 pc.
		Concentrate for solution for infusion 6 mg/1 ml: 50 ml vial, 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion slightly viscous, clear, colorless to pale yellow.

Excipients: anhydrous citric acid – 2 mg, macrogolglycerol ricinoleate (Cremophor^® EL) – 527 mg, absolute ethanol – up to 920 mg (equiv. 1 ml).

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

Concentrate for solution for infusion slightly viscous, clear, colorless to pale yellow.

Excipients: anhydrous citric acid – 2 mg, macrogolglycerol ricinoleate (Cremophor^® EL) – 527 mg, absolute ethanol – up to 920 mg (equiv. 1 ml).

16.67 ml – glass vials (1) – cardboard packs.

Concentrate for solution for infusion slightly viscous, clear, colorless to pale yellow.

Excipients: anhydrous citric acid – 2 mg, macrogolglycerol ricinoleate (Cremophor^® EL) – 527 mg, absolute ethanol – up to 920 mg (equiv. 1 ml).

25 ml – glass vials (1) – cardboard packs.

Concentrate for solution for infusion slightly viscous, clear, colorless to pale yellow.

Excipients: anhydrous citric acid – 2 mg, macrogolglycerol ricinoleate (Cremophor^® EL) – 527 mg, absolute ethanol – up to 920 mg (equiv. 1 ml).

43.33 ml – glass vials (1) – cardboard packs.

Concentrate for solution for infusion slightly viscous, clear, colorless to pale yellow.

Excipients: anhydrous citric acid – 2 mg, macrogolglycerol ricinoleate (Cremophor^® EL) – 527 mg, absolute ethanol – up to 920 mg (equiv. 1 ml).

50 ml – glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Sindaxel (Paclitaxel) is an antineoplastic drug of natural origin, obtained semi-synthetically from the plant Taxus Baccata.

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

It causes dose-dependent suppression of bone marrow hematopoiesis. According to experimental data, it has mutagenic and embryotoxic properties, and causes a decrease in reproductive function.

Pharmacokinetics

When administered IV over 3 hours at a dose of 135 mg/m², C_max is 2170 ng/ml, AUC is 7952 ng/h/ml; when the same dose is administered over 24 hours – 195 ng/ml and 6300 ng/h/ml, respectively. C_max and AUC are dose-dependent: with a 3-hour infusion, an increase in dose to 175 mg/m² leads to an increase in these parameters by 68% and 89%, respectively, with a 24-hour infusion – by 87% and 26%, respectively.

Does not accumulate with repeated infusions.

Plasma protein binding – 88-98%. Half-life of distribution from blood to tissues – 30 min. Easily penetrates and is adsorbed by tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles.

Metabolized in the liver by hydroxylation involving cytochrome P450 isoenzymes CYP2D8 (forming the metabolite 6-alpha-hydroxypaclitaxel) and CYP3CA4 (forming metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxypaclitaxel). T_1/2 and total clearance are variable and depend on the dose and duration of IV administration: 13.1-52.7 h and 12.2-23.8 l/h/m², respectively. 90% of the drug is excreted in bile as metabolites. A small amount (from 1.3 to 12.6%, depending on the administered dose level) is excreted unchanged in the urine.

Indications

• Ovarian cancer (first-line therapy for patients with advanced disease or residual tumor (more than 1 cm) after laparotomy (in combination with cisplatin) and second-line therapy for metastases after standard therapy that did not yield a positive result);
• Breast cancer (presence of affected lymph nodes after standard combination therapy (adjuvant treatment); after disease recurrence, within 6 months of starting adjuvant therapy – first-line therapy;
  Metastatic breast cancer after ineffective standard therapy – second-line therapy);
• Non-small cell lung cancer (first-line therapy for patients not planned for surgical treatment and/or radiation therapy (in combination with cisplatin).
• Kaposi’s sarcoma in AIDS patients (second-line therapy, after ineffective therapy with liposomal anthracyclines)

ICD codes

Dosage Regimen

To prevent severe hypersensitivity reactions, all patients should receive premedication with glucocorticosteroids, antihistamines, and H₂-histamine receptor antagonists: 20 mg dexamethasone (or its equivalent) orally approximately 12 and 6 hours before paclitaxel administration, 50 mg diphenhydramine (or its equivalent) intravenously and 300 mg cimetidine or 50 mg ranitidine intravenously 30-60 minutes before Sindaxel administration. When choosing the regimen and doses in each individual case, one should be guided by data from specialized literature.

Sindaxel is administered IV as a 3-hour or 24-hour infusion at a dose of 135-175 mg/m² with an interval between courses of 3 weeks. The drug is used as monotherapy or in combination with cisplatin (ovarian cancer and non-small cell lung cancer) or doxorubicin (breast cancer).

The recommended dose of Sindaxel for the treatment of Kaposi’s sarcoma in AIDS patients is 100 mg/m² as a 3-hour infusion every 2 weeks. Administration of Sindaxel should not be repeated until the neutrophil count is at least 1500/µl of blood and the platelet count is at least 100,000/µl of blood. In patients who experienced severe neutropenia (neutrophil count <500/µl of blood for 7 days or longer) or severe peripheral neuropathy after Sindaxel administration, the dose of Sindaxel should be reduced by 20% in subsequent courses of treatment. The drug solution is prepared immediately before administration by diluting the concentrate with 0.9% sodium chloride solution, or 5% dextrose solution, or 5% dextrose in 0.9% sodium chloride solution for injection, or 5% dextrose in Ringer's solution to a final concentration of 0.3 to 1.2 mg/ml. The prepared solutions may be opalescent due to the carrier base present in the drug formulation, and the opalescence of the solution persists after filtration.

When preparing, storing, and administering Paclitaxel, equipment that does not contain PVC parts should be used.

Paclitaxel should be administered through a system with an in-line membrane filter (pore size not more than 0.22 microns).

Adverse Reactions

The frequency and severity of side effects are dose-dependent.

From the hematopoietic organs: neutropenia, thrombocytopenia, anemia. Suppression of bone marrow function, mainly the granulocytic lineage, was the main toxic effect limiting the dose of the drug. The maximum decrease in neutrophil levels is usually observed on days 8-11, normalization occurs on day 22.

Allergic reactions: in the first hours after Sindaxel administration, hypersensitivity reactions may occur, manifested by bronchospasm, decreased blood pressure, chest pain, facial flushing, skin rashes, generalized urticaria, angioedema. Isolated cases of chills and back pain have been described.

From the cardiovascular system: decreased BP, less commonly increased BP, bradycardia, tachycardia, atrioventricular block, ECG changes, vascular thrombosis and thrombophlebitis are possible.

From the respiratory system: interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, as well as more frequent development of radiation pneumonitis in patients simultaneously undergoing a course of radiation therapy.

From the nervous system: mainly paresthesia. Rarely – grand mal seizures, visual disturbances, ataxia, encephalopathy, autonomic neuropathy, manifested by paralytic ileus and orthostatic hypotension.

From the musculoskeletal system: arthralgia, myalgia.

From the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation. Isolated reports of acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis.

From liver function: increased activity of “hepatic” transaminases (more often AST), alkaline phosphatase and bilirubin in blood serum. Cases of hepatonecrosis and hepatic encephalopathy have been described.

From the skin and skin appendages: alopecia, rarely pigmentation disorder or discoloration of the nail bed.

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

Other: asthenia and general malaise.

Contraindications

• Pregnancy and breastfeeding period;
• 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;
• Hypersensitivity to the drug, as well as to other drugs whose dosage form includes polyoxyl castor oil.

With caution thrombocytopenia (less than 100,000/µl), hepatic insufficiency, acute infectious diseases (including herpes zoster, chickenpox, herpes), severe coronary artery disease, myocardial infarction (in history), arrhythmias.

Pediatric Use

Use in pediatrics. The safety and efficacy of Sindaxel in children have not been established.

Special Precautions

Administration of Sindaxel should be carried out under the supervision of a physician experienced in the use of antineoplastic chemotherapeutic drugs.

If Sindaxel is used in combination with cisplatin, Sindaxel 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 (before the start and during treatment).

If severe hypersensitivity reactions occur, the infusion of Sindaxel should be stopped immediately and symptomatic treatment started, and the drug should not be readministered.

In cases of atrioventricular conduction disturbances, continuous cardiac monitoring should be performed during repeated administrations.

Patients should use reliable methods of contraception during treatment with Sindaxel and for at least 3 months after the end of therapy.

During the treatment period, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Sindaxel is a cytotoxic substance, and caution must be exercised when handling it, using gloves and avoiding contact with skin or mucous membranes, which in case of contact with the drug should be thoroughly washed with soap and water or (eyes) with plenty of water.

Overdose

Symptoms bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment symptomatic. No antidote for paclitaxel is known.

Drug Interactions

Cisplatin reduces the total clearance of Sindaxel by 20% (with more pronounced myelosuppression observed when Sindaxel is administered after cisplatin). Concurrent use with cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect the binding of Sindaxel to plasma proteins.

Inhibitors of microsomal oxidation (including ketoconazole, verapamil, diazepam, quinidine, cyclosporine, etc.) inhibit the metabolism of Sindaxel.

Polyoxyl castor oil, which is part of the Sindaxel drug, can cause extraction of DEHP [di-(2-ethylhexyl) phthalate] from plasticized PVC containers, and the degree of DEHP leaching increases with increasing solution concentration and over time.

Storage Conditions

Store in a light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

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.