Paxene (Concentrate) Instructions for Use

Marketing Authorization Holder

Ivax-CR, A.S. (Czech Republic)

ATC Code

L01CD01 (Paclitaxel)

Active Substance

Paclitaxel (Rec.INN registered by WHO)

Dosage Forms

	Paxene	Concentrate for solution for infusion 30 mg/5 ml: vial 1 pc.
		Concentrate for solution for infusion 100 mg/16.7 ml: vial 1 pc.
		Concentrate for solution for infusion 150 mg/25 ml: vial 1 pc.
		Concentrate for solution for infusion 300 mg/50 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, yellowish solution, free from visible mechanical inclusions.

Excipients: anhydrous citric acid, ethanol, polyoxylated castor oil.

5 ml – vials (1) – cardboard packs.

Concentrate for solution for infusion as a clear, yellowish solution, free from visible mechanical inclusions.

Excipients: anhydrous citric acid, ethanol, polyoxylated castor oil.

16.7 ml – vials (1) – cardboard packs.

Concentrate for solution for infusion as a clear, yellowish solution, free from visible mechanical inclusions.

Excipients: anhydrous citric acid, ethanol, polyoxylated castor oil.

25 ml – vials (1) – cardboard packs.

Concentrate for solution for infusion as a clear, yellowish solution, free from visible mechanical inclusions.

Excipients: anhydrous citric acid, ethanol, polyoxylated castor oil.

50 ml – vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

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.

Causes dose-dependent suppression of bone marrow hematopoiesis.

Experimental studies have shown that Paclitaxel has mutagenic and embryotoxic properties and impairs reproductive function.

Pharmacokinetics

Absorption

After IV administration of Paxene at a dose of 135 mg/m² over 3 hours, the C_max of paclitaxel in blood plasma is 2170 ng/ml, AUC – 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, increasing the 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.

Distribution

Binding to plasma proteins – 88-98%. Mean V_d – 198-688 l/m². The half-life of distribution from blood to tissues is 30 min. It easily penetrates tissues, accumulating mainly in the liver, spleen, pancreas, stomach, intestines, heart, and muscles.

Metabolism

Metabolized in the liver by hydroxylation involving cytochrome P₄₅₀ isoenzymes CYP2D8 (forming the metabolite 6-alpha-hydroxypaclitaxel) and CYP3A4 (forming metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxypaclitaxel).

Excretion

Excreted mainly with bile – 90%. Does not accumulate with repeated infusions.

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. After IV infusion (1-24 h), total renal excretion is 1.3-12.6% of the dose (15-275 mg/m²), indicating intensive extrarenal clearance. Total clearance – 11-24 l/m².

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 the start of 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);
• 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 corticosteroids, antihistamines, and histamine H₂ receptor blockers. For example, 20 mg of dexamethasone (or its equivalent) orally approximately 12 hours and 6 hours before Paxene administration, 50 mg of diphenhydramine (or its equivalent) IV and 300 mg of cimetidine or 50 mg of ranitidine IV 30-60 minutes before Paxene administration.

Paxene is administered IV at a dose of 135-175 mg/m² as a 3-hour or 24-hour infusion, 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 Paxene for treatment of Kaposi’s sarcoma in AIDS patients is 100 mg/m² as a 3-hour infusion every 2 weeks.

When choosing the regimen and doses in each individual case, one should be guided by data from specialized literature.

Administration of Paxene should not be repeated until the neutrophil count in the peripheral blood is at least 1500/µl, and the platelet count is at least 100,000/µl. In patients who experienced severe neutropenia (neutrophil count <500/µl for 7 days or longer) or severe peripheral neuropathy after Paxene administration, the dose of Paxene should be reduced by 20% during 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 presence of the carrier base in the drug formulation, and the opalescence of the solution persists after filtration.

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

Adverse Reactions

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

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

Allergic reactions in the first hours after Paxene administration, bronchospasm, decreased blood pressure, chest pain, facial flushing, skin rashes, generalized urticaria, angioedema are possible. Isolated cases of chills, back pain have been described.

From the cardiovascular system decreased blood pressure, tachycardia, AV block, ECG changes, vascular thrombosis and thrombophlebitis are possible; rarely – increased blood pressure, bradycardia.

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 are possible.

From the central and peripheral nervous system paresthesias are possible; rarely – grand mal seizures, visual disturbances, ataxia, encephalopathy, autonomic neuropathy manifested by paralytic ileus and orthostatic hypotension.

From the musculoskeletal system arthralgia, myalgia are possible.

From the digestive system nausea, vomiting, diarrhea, mucositis, anorexia, constipation are possible; increased activity of liver transaminases (more often AST), alkaline phosphatase and bilirubin in blood serum; in isolated cases – acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis, hepatonecrosis, hepatic encephalopathy.

Dermatological reactions 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

• 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;
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to the drug, as well as to other drugs whose dosage form includes polyoxylated castor oil.

With caution in 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.

The safety and efficacy of Paxene in children have not been established.

Use in Pregnancy and Lactation

Paxene is contraindicated during pregnancy and lactation (breastfeeding).

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

Use in Hepatic Impairment

With caution in hepatic insufficiency.

Pediatric Use

The safety and efficacy of Paxene in children have not been established.

Special Precautions

Treatment with Paxene should be carried out under the supervision of a physician experienced in the use of antineoplastic chemotherapeutic drugs.

To prevent severe hypersensitivity reactions, all patients should receive premedication with corticosteroids, antihistamines, and histamine H₂ receptor blockers: 20 mg of dexamethasone (or its equivalent) orally approximately 12 hours and 6 hours before Paxene administration, 50 mg of diphenhydramine (or its equivalent) IV and 300 mg of cimetidine or 50 mg of ranitidine IV 30-60 minutes before Paxene administration.

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

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

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

When used in combination with cisplatin, Paxene should be administered first, followed by cisplatin.

The polyoxylated castor oil included in the composition of Paxene may cause extraction of DEHP /di-(2-ethylhexyl) phthalate/ from plastic polyvinyl chloride (PVC) containers, and the degree of DEHP leaching increases with increasing solution concentration and over time. Therefore, when preparing, storing, and administering the Paxene solution, equipment that does not contain PVC parts should be used.

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

Overdose

Symptoms bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment symptomatic therapy. Antidote is unknown.

Drug Interactions

Cisplatin reduces the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when Paclitaxel is administered after cisplatin).

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

Inhibitors of microsomal oxidation (including ketoconazole, cimetidine, dexamethasone, verapamil, diazepam, quinidine, cyclosporine) suppress the metabolism of paclitaxel. This interaction when prescribing drugs in therapeutic doses has no clinical significance.

Storage Conditions

The drug should be stored in a light-protected place, out of the reach of children, at a temperature from 10°C (50°F) to 25°C (77°F).

Shelf Life

Shelf life – 3 years.

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.