Paract (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

L01XA02 (Carboplatin)

Active Substance

Carboplatin (Rec.INN registered by WHO)

Dosage Forms

	Paract	Concentrate for solution for infusion 10 mg/1 ml: 5 ml vial, 1 pc.
		Concentrate for solution for infusion 10 mg/1 ml: 15 ml vial, 1 pc.
		Concentrate for solution for infusion 10 mg/1 ml: 45 ml vial, 1 pc.
		Concentrate for solution for infusion 10 mg/1 ml: 60 ml vial, 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

15 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

45 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

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

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

60 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

15 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

45 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless or pale yellow solution.

Excipients : water for injections – up to 1 ml.

60 ml – glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Carboplatin is an inorganic complex compound containing a heavy metal – platinum.

The primary mechanism of action of this drug is presumed to be due to binding with DNA, resulting mainly in intrastrand cross-links, which alter the DNA structure and suppress its synthesis. This effect is manifested regardless of the cell cycle phase. The hydration of carboplatin, which produces the active form(s) of the drug, occurs more slowly than the hydration of cisplatin.

Pharmacokinetics

The pharmacokinetics of carboplatin is a complex process and includes the transformations of the original carboplatin, total platinum, and ultrafilterable platinum.

Total platinum consists of protein-bound and non-protein-bound platinum, while ultrafilterable platinum consists of carboplatin and non-protein-bound metabolites of carboplatin. In pharmacokinetic studies of carboplatin, the level of ultrafilterable platinum is usually measured, as only non-protein-bound platinum or its platinum-containing metabolites are typically cytotoxic.

After a single intravenous infusion of carboplatin, the C_max of carboplatin, total platinum, and ultrafilterable platinum is reached almost immediately.

Platinum is distributed in all tissues and body fluids, with the highest concentrations observed in the kidneys, liver, skin, and tumor tissues. The initial T_1/2 of carboplatin, total platinum, and ultrafilterable platinum upon IV administration are almost identical; the T_1/2 of carboplatin is 1-2 hours. Carboplatin itself does not bind to proteins but decomposes to platinum-containing products, which bind very quickly to proteins. Within the first 4 hours after carboplatin administration, less than 24% of platinum is bound to plasma proteins; after 24 hours, the amount of bound platinum is 87%.

The concentration of carboplatin and ultrafilterable platinum decreases according to a biphasic model.

The concentration of total platinum decreases according to a triphasic model. With normal renal function, the T_1/2 of carboplatin and ultrafilterable platinum is 2-3 hours. The terminal T_1/2 of total platinum is 4-6 days.

Carboplatin and its platinum-containing metabolites are mainly excreted in the urine.

With normal renal function, about 65% of the carboplatin dose is excreted in the urine within 12 hours; 71% of the dose is excreted within 24 hours. A significant portion is excreted as unchanged carboplatin. Carboplatin (as ultrafilterable carboplatin) is effectively removed by hemodialysis.

In urine after 24 hours, all platinum is present as carboplatin.

Only 3-5% of the administered platinum is excreted in the urine during the 24-96 hour period.

Since Carboplatin is excreted almost entirely by glomerular filtration, only a very low concentration of carboplatin is present in the renal tubules, which may explain the low nephrotoxic potential of the drug compared to cisplatin.

Indications

• Ovarian cancer;
• Germ cell tumors in men and women;
• Lung cancer;
• Cervical cancer;
• Malignant tumors of the head and neck;
• Transitional cell carcinoma of the bladder.

ICD codes

Dosage Regimen

Paract can be used both as monotherapy and in combination with other antineoplastic drugs. When choosing the dose and regimen in each individual case, specialized literature should be used.

The drug is administered intravenously in the following dosage regimens

• 300-400 mg/m² IV drip over 15-60 minutes or as a 24-hour infusion;
• 100 mg/m² IV drip over 15-60 minutes daily for 5 days;

Paract administration is repeated at intervals of at least 4 weeks, provided platelet counts are not less than 100,000 cells/µl of blood and neutrophil counts are not less than 2,000 cells/µl of blood at the time of the next administration.

Fluid administration before or after Paract use, as well as forced diuresis, is not required.

Depending on the bone marrow status or renal function, the therapeutic dose of Paract may be adjusted as follows

• If the platelet count decreased to 50,000/µl and/or neutrophils to 500/µl during previous courses of carboplatin therapy, dose adjustment is not required.
• If observed nadir platelet counts were less than 50,000/µl and/or neutrophils less than 500/µl during the previous course of carboplatin therapy, a reduction of the next dose by 25% should be considered, both in monotherapy and in combination treatment regimens.
• In case of impaired renal function (CrCl less than 60 ml/min), the risk of carboplatin toxic effects increases, therefore the recommended carboplatin doses are: with creatinine clearance of 41-59 ml/min – 250 mg/m², with creatinine clearance of 16-40 ml/min – 200 mg/m².
• For patients with risk factors, such as previously administered myelosuppressive therapy, age over 65 years, low performance status (ECOG-Zubrod 2-4 or Karnofsky score below 80%), a reduction of the initial carboplatin dose by 20-25% is recommended.

Dose determination by formula

The initial dose of the drug in milligrams can be determined by the Calvert formula, which describes the dependence on the glomerular filtration rate (GFR in ml/min) and the desired drug concentration over time (AUC in mg/ml x min)

Total dose (mg) = AUC x (GFR + 25)

Rules for preparation of infusion solution

Before administration, the drug is diluted to a concentration of 0.5 mg/ml with 5% dextrose solution or 0.9% sodium chloride solution.

The diluted drug solutions are stable for 8 hours at a temperature of 25°C (77°F) and for 24 hours when stored in a refrigerator at 4°C (39.2°F).

Adverse Reactions

From the hematopoietic organs the main dose-limiting toxic factor of carboplatin is suppression of bone marrow hematopoietic function.

Myelosuppression is dose-dependent. The nadir of platelet and leukocyte/granulocyte counts is typically reached 2-3 weeks after starting the drug, with thrombocytopenia occurring more frequently. Adequate recovery to a level allowing the next dose of carboplatin generally takes at least 4 weeks. A considerable number of patients may also exhibit symptoms of anemia (hemoglobin level less than 11 g/dl), the intensity of which depends on the cumulative dose of the drug. Transfusion therapy may be necessary, especially in patients undergoing long-term treatment (e.g., more than 6 cycles of the drug). There is also a possibility of clinical complications such as fever, infectious diseases, sepsis/septic shock, and bleeding.

From the digestive system nausea, vomiting (can be prevented by prior administration of antiemetics, continuous intravenous infusion of carboplatin over 24 hours, or fractional administration of the dose over 5 consecutive days), stomatitis, diarrhea or constipation, abdominal pain, decreased appetite, impaired liver function (increased AST, ALP activity and serum bilirubin concentration).

From the CNS asthenia, peripheral polyneuropathy (paresthesia, decreased deep tendon reflexes), decreased visual acuity up to complete loss of vision or loss of color discrimination (improvement or complete recovery of vision usually occurs within a few weeks after discontinuation of the drug; cortical blindness has been observed in patients with impaired renal function treated with high doses of carboplatin), hearing loss, tinnitus. Long-term therapy with the drug may lead to cumulative neurotoxicity.

From the genitourinary system increased serum creatinine and urea concentrations (acute kidney damage was rarely observed, the risk of nephrotoxicity with carboplatin increases with higher carboplatin doses, and in patients previously treated with cisplatin), azoospermia, amenorrhea.

From the water-electrolyte balance : hypokalemia, hypocalcemia, hyponatremia and hypomagnesemia.

Allergic reactions erythematous rash, fever, pruritus, urticaria, bronchospasm, decreased blood pressure, anaphylactoid reactions, allergic reactions at the injection site. Rarely – exfoliative dermatitis.

Other taste changes, alopecia, flu-like symptoms (fever, pyrexia), hemolytic-uremic syndrome, myalgia/arthralgia, heart failure, cerebrovascular disorders.

Contraindications

• Hypersensitivity to carboplatin or other platinum-containing compounds;
• Severe renal impairment;
• Severe myelosuppression;
• Severe bleeding;
• Pregnancy and breastfeeding;
• Childhood (efficacy and safety have not been sufficiently studied).

With caution in bone marrow suppression (including against the background of concomitant radiation or chemotherapy), prior therapy with nephrotoxic drugs (e.g., cisplatin), hearing impairment, acute infectious diseases of viral, fungal or bacterial nature, post-vaccination period.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Use in Renal Impairment

The drug is contraindicated in severe renal impairment.

Pediatric Use

The drug is contraindicated in children.

Geriatric Use

For elderly patients (over 65 years), a reduction of the initial drug dose by 20-25% is recommended.

Special Precautions

Treatment with Paract should be carried out under the supervision of a physician experienced in the use of cytotoxic drugs.

Needles, syringes, catheters, and infusion systems containing aluminum, which can react with carboplatin leading to precipitate formation or loss of drug activity, should not be used for preparation and administration.

Regularly (e.g., once a week) perform peripheral blood cell counts and monitor renal function (the most sensitive indicator is creatinine clearance).

Periodic neurological examinations are recommended, especially in patients previously treated with cisplatin and in patients over 65 years of age.

Since Paract can cause cumulative ototoxic effects, patients are recommended to undergo audiographic examinations before and during treatment. In case of clinically significant hearing impairment, appropriate dose adjustment or discontinuation of treatment may be required.

Women and men during treatment with Paract should use reliable methods of contraception.

All standard instructions adopted for the use of cytotoxic drugs must be observed when using Paract.

Vaccination of patients is not recommended during treatment.

Overdose

No specific antidotes for carboplatin overdose are known. In case of overdose, more pronounced above-mentioned adverse reactions should be expected. Treatment is symptomatic. Hemodialysis can be used within the first 3 hours after drug administration.

Drug Interactions

The use of carboplatin in combination with other myelosuppressive drugs or radiation therapy may increase the risk of hematological toxicity.

The use of carboplatin in combination with aminoglycosides, as well as with other nephrotoxic drugs, increases the risk of nephrotoxic and/or ototoxic effects.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 18 months. Do not use the drug 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.