Forteca^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

ATC Code

L01FF08 (Prolgolimab)

Active Substance

Prolgolimab

Dosage Form

Forteca®

Concentrate for solution for infusion 20 mg/1 ml: vial 5 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear or slightly opalescent liquid from colorless to light yellow.

Excipients: sodium acetate trihydrate – 1.742 mg, trehalose dihydrate – 100 mg, glacial acetic acid – to pH 5.0, water for injections – to 1 ml.

5 ml – vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies and their drug conjugates; PD-1/PDL-1 (programmed cell death protein I/its ligand) inhibitors

Pharmacological Action

A human monoclonal antibody that specifically binds to the programmed cell death receptor PD-1 and blocks its interaction with the ligands PD-L1 and PD-L2. Prolgolimab is an immunoglobulin of the IgG1 isotype, a lambda-kappa hybrid with a molecular weight of approximately 149 kDa.

The Fc fragment of prolgolimab is modified to prevent cytotoxic action on target cells expressing PD-1. As a result of inhibiting the binding of the PD-1 receptor to its ligands, Prolgolimab reactivates tumor-specific cytotoxic T-lymphocytes and thus reactivates antitumor immunity.

Pharmacokinetics

It is administered intravenously, therefore Prolgolimab immediately and completely becomes bioavailable. After the first administration, the C_max in the dosing regimen of 1 mg/kg every 2 weeks averaged 35078 ng/ml, AUC_0-336h – 5306962 ng/ml. Before the second administration, the C_min in the dosing regimen of 1 mg/kg every 2 weeks averaged 9011 ng/ml.

After the first administration, the C_max in the dosing regimen of 3 mg/kg every 3 weeks averaged 82924 ng/ml. AUC_0-504h – 14952949 ng/ml. Before the second administration, the C_min in the dosing regimen of 3 mg/kg every 3 weeks averaged 24411 ng/ml. With repeated administration of prolgolimab, both at a dose of 1 mg/kg and at a dose of 3 mg/kg, C_min does not decrease.

In accordance with the limited extravascular distribution, the V_d of prolgolimab at equilibrium is insignificant (approximately 3.9 l; coefficient of variation 88%). Like other antibodies, Prolgolimab does not bind to plasma proteins in a specific way.

Prolgolimab is catabolized by non-specific pathways; the metabolism of the drug does not affect its clearance. The systemic clearance of prolgolimab is approximately 0.5 l/day (coefficient of variation 67%); the terminal T_1/2 is approximately 14 days (coefficient of variation 96%). The elimination characteristics of prolgolimab show no signs of dose dependence and are typical for monoclonal antibody-based drugs.

Indications

Treatment of adult patients with inoperable or metastatic melanoma.

ICD codes

Dosage Regimen

Administer as an intravenous infusion over 30 minutes.

Use a sterile, low-protein binding, in-line filter (pore size 0.2-0.22 µm).

The recommended dose is 1 mg/kg of body weight.

Calculate the required dose and volume for each patient immediately prior to administration.

Do not administer as an intravenous push or bolus.

Administer the calculated dose every 2 weeks until disease progression or unacceptable toxicity occurs.

Withhold or permanently discontinue treatment based on the severity of adverse reactions.

For grade 2 immune-mediated adverse reactions, withhold dosing until the event resolves to grade 1 or less.

Permanently discontinue for severe or life-threatening (grade 3 or 4) immune-mediated reactions.

Do not resume treatment after a severe infusion reaction.

Visually inspect the solution for particulate matter and discoloration prior to administration.

Discard the vial if the solution is cloudy, contains particulates, or is discolored.

Do not mix Forteca^® with other medicinal products.

Administer using a separate infusion line.

Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion.

Adverse Reactions

The most frequently occurring therapy-related adverse reactions were deviations in complete blood count parameters (lymphopenia, anemia), thyroid disorders (hypothyroidism or hyperthyroidism, thyroiditis) and skin disorders (rash, pruritus).

From the hematopoietic system common – anemia, lymphopenia, neutropenia, lymphocytosis, thrombocytopenia;

Infectious and parasitic diseases uncommon – pneumonia.

From the endocrine system very common – thyroiditis; common – hyperthyroidism, hypothyroidism, increased TSH level; uncommon – decreased TSH level.

From the nervous system uncommon – memory impairment, headache.

From the organ of vision uncommon – uveitis.

From the cardiovascular system common – increased blood pressure; uncommon – tachycardia, cardiac arrhythmia, tumor node bleeding.

From the respiratory system common – pneumonitis.

From the digestive system uncommon – decreased appetite, nausea, dry mouth.

From the skin and subcutaneous tissue common – rash, pruritus.

From the musculoskeletal system uncommon – myalgia, myositis.

Other common – asthenia, pyrexia; uncommon – edema, chills, subfebrile temperature, sweating, flu-like syndrome.

From metabolism uncommon – hyperglycemia.

Data from laboratory and instrumental studies common – increased alkaline phosphatase activity; uncommon – increased AST activity.

Contraindications

Hypersensitivity to prolgolimab; renal failure; hepatic failure; pregnancy, breastfeeding period; age under 18 years.

With caution severe autoimmune diseases in the active stage, in which further activation of the immune system may pose a potential threat to life.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in hepatic failure.

Use in Renal Impairment

Contraindicated for use in renal failure.

Pediatric Use

Contraindicated for use under the age of 18 years.

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

Immune-mediated adverse reactions were observed in patients treated with Prolgolimab. Most immune-mediated adverse reactions observed in clinical studies were reversible and managed by temporarily withholding prolgolimab, using corticosteroids and/or symptomatic therapy. Immune-mediated adverse reactions involving more than one body system may develop simultaneously.

If an immune-mediated adverse reaction is suspected, a thorough evaluation is required to confirm the etiology and exclude other possible causes.

Cases of pneumonitis have been reported in patients treated with Prolgolimab. Patients should be actively monitored for signs and symptoms of pneumonitis. If pneumonitis is suspected, a radiological examination should be performed to rule out other causes. Corticosteroid therapy is prescribed for pneumonitis of grade 2 severity or higher.

Prolgolimab should be temporarily withheld for pneumonitis of grade 2 (moderate) severity and permanently discontinued for pneumonitis of grade 3 (severe) or 4 (life-threatening) severity or recurrence of grade 2 (moderate) pneumonitis.

Cases of colitis are known to occur with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. Patients should be actively monitored for signs and symptoms of colitis and other causes should be excluded. Corticosteroid therapy is prescribed for grade 2 severity or higher.

Prolgolimab should be temporarily withheld for colitis of grade 2 (moderate) or 3 (severe) severity and permanently discontinued for colitis of grade 4 (life-threatening) severity.

Cases of hepatitis are known to occur with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. Patients should be monitored for changes in liver function tests (at the start of treatment, periodically during therapy, and based on clinical assessment) and symptoms of hepatitis, and other causes should be excluded.

Corticosteroid therapy is prescribed for hepatitis of grade 2 severity and for hepatitis of grade 3 severity or higher. Prolgolimab should be temporarily or permanently discontinued according to the level of increase in liver enzyme activity.

Cases of nephritis have been reported with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. Patients should be monitored for changes in renal function and other causes should be excluded. Corticosteroid therapy is prescribed for the development of adverse events of grade 2 severity and higher.

Prolgolimab should be temporarily withheld in case of nephritis of grade 2 (moderate) severity and permanently discontinued for nephritis of grade 3 (severe) or 4 (life-threatening) severity.

Cases of hypophysitis are known to occur with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. Patients should be monitored for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and other causes should be excluded.

In case of manifestation of secondary adrenal insufficiency, corticosteroid therapy or other replacement hormonal therapy is prescribed according to clinical assessment. Prolgolimab should be temporarily withheld in case of hypophysitis of grade 2 (moderate) severity, and Prolgolimab should be permanently discontinued for hypophysitis of grade 3 (severe) or 4 (life-threatening) severity.

Cases of type 1 diabetes mellitus, including cases of diabetic ketoacidosis, have been reported with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. Patients should be monitored for hyperglycemia or other signs and symptoms of diabetes mellitus.

Insulin is prescribed for type 1 diabetes mellitus, and in cases of severe hyperglycemia, prolgolimab should be temporarily withheld until metabolic control is achieved.

Thyroid disorders have been reported in patients treated with Prolgolimab; they can develop at any time during treatment. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during therapy, and based on clinical assessment) and clinical signs and symptoms of thyroid dysfunction.

Treatment of hypothyroidism can be carried out by replacement therapy without interrupting treatment and without the use of corticosteroids. Symptomatic treatment is possible for hyperthyroidism. Prolgolimab should be temporarily or permanently discontinued for hyperthyroidism of grade 3 (severe) or 4 (life-threatening) severity.

In patients with grade 3 (severe) or 4 (life-threatening) endocrinopathy, if improvement to grade 2 severity or lower occurs and control is achieved with replacement hormone therapy, continuation of prolgolimab may be considered.

Severe forms of rash and pruritus were observed in patients treated with Prolgolimab. Prolgolimab should be suspended for skin reactions of grade 3 severity and discontinued without reinstatement for grade 4 severity. Corticosteroid treatment is prescribed for severe skin reactions, followed by a gradual dose reduction.

Prolgolimab should be used with caution in patients who have previously experienced severe or life-threatening adverse skin reactions during treatment with other immunostimulatory anticancer drugs.

Cases of severe infusion reactions are known to occur with the use of other monoclonal antibody drugs against PD-1. Given the similar mechanism of action, this adverse reaction may develop with the use of prolgolimab. In case of a severe infusion reaction, the infusion should be interrupted and prolgolimab should be permanently discontinued.

In patients with mild or moderate severity of infusion reactions, the possibility of continuing prolgolimab under the close supervision of an oncologist may be considered when premedication is administered in accordance with the standards for the prevention of infusion reactions.

Effect on ability to drive vehicles and operate machinery

Prolgolimab may have a minor effect on the ability to drive a car and operate machinery. Fatigue has been reported after administration of prolgolimab.

Drug Interactions

The administration of systemic corticosteroids or immunosuppressants should be avoided before the start of therapy due to the possible influence of these agents on the pharmacodynamic activity and efficacy of prolgolimab. However, systemic corticosteroids or other immunosuppressants may be used after starting treatment with prolgolimab for the therapy of immune-mediated adverse reactions.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.