Pembroria (Concentrate) Instructions for Use

Marketing Authorization Holder

PK-137, LLC (Russia)

Manufactured By

Biocad, JSC (Russia)

Or

PK-137, LLC (Russia)

ATC Code

L01FF02 (Pembrolizumab)

Active Substance

Pembrolizumab (Rec.INN registered by WHO)

Dosage Form

Pembroria

Concentrate for solution for infusion 25 mg/1 ml: vial 4 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear or opalescent, colorless to light brown liquid.

Excipients: trehalose dihydrate – 80 mg, glycine – 1.5 mg, poloxamer 188 – 1 mg, histidine hydrochloride monohydrate – 0.75 mg, histidine – 0.221 mg, water for injections – up to 1 ml.

4 ml – vials of colorless glass (1) – cardboard packs.
4 ml – vials of colorless glass (1) – contour cell packs (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

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

Pharmacological Action

Antitumor agent, a humanized monoclonal antibody. It selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Pembrolizumab is an immunoglobulin of the IgG4 kappa isotype with a molecular weight of approximately 149 kDa.

PD-1 is a receptor that is an immune checkpoint, which limits the activity of T-lymphocytes in peripheral tissues. Tumor cells can use the PD-1 signaling pathway to inhibit active T-cell immunological surveillance.

Pembrolizumab is a high-affinity antibody to the PD-1 receptor; its inhibition results in a dual blockade of the PD-1 signaling pathway involving PD-L1 and PD-L2 ligands on tumor or antigen-presenting cells. As a result of inhibiting the binding of the PD-1 receptor to its ligands, Pembrolizumab reactivates tumor-specific cytotoxic T-lymphocytes in the tumor microenvironment and thus reactivates antitumor immunity.

In the peripheral blood of patients who received Pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks, an increase in the percentage of activated (i.e., HLA-DR+) CD4+ and CD8+ T-cells was observed after treatment with all doses and regimens without an increase in the total number of circulating T-lymphocytes.

Pharmacokinetics

Administered intravenously, therefore Pembrolizumab immediately and completely becomes bioavailable.

In accordance with limited extravascular distribution, the V_d of pembrolizumab at steady state is low (approximately 7.5 L; coefficient of variation (CV): 21%). Like other antibodies, Pembrolizumab does not bind to plasma proteins in a specific manner.

Pembrolizumab undergoes catabolism by non-specific pathways; the metabolism of the drug does not affect its clearance.

The systemic clearance of pembrolizumab is approximately 0.2 L/day (CV: 37%); the terminal T_1/2 is approximately 26 days (CV: 37%). The exposure of pembrolizumab, expressed as C_max or AUC, increased proportionally to the dose within the range of effective doses. Upon repeated administration, the clearance of pembrolizumab was shown to be time-independent, and systemic accumulation was approximately 2.2 times higher when administered every 3 weeks. Pembrolizumab concentrations close to steady state were achieved by week 18; the median C_min at week 18 was approximately 22.8 µg/ml with a dosing regimen of 2 mg/kg every 3 weeks.

Indications

Unresectable or metastatic melanoma.

As first-line therapy in patients with advanced non-small cell lung cancer with PD-L1 expression ≥50% in tumor cells, determined by a validated test, in the absence of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene mutations.

Advanced non-small cell lung cancer with PD-L1 expression ≥1% in tumor cells, determined by a validated test, in patients who have previously received therapy including platinum-based drugs. In the presence of EGFR or ALK gene mutations, patients should receive appropriate specific therapy prior to treatment with pembrolizumab.

ICD codes

Dosage Regimen

Administer as an intravenous infusion over 30 minutes every 3 weeks.

Calculate the dose based on patient weight and indication. Use 200 mg for first-line treatment of non-small cell lung cancer.

Use 2 mg/kg for melanoma and for previously treated non-small cell lung cancer.

Do not administer as an intravenous push or bolus. Prepare the infusion solution by diluting the required dose in 0.9% Sodium Chloride or 5% Dextrose solution to a final concentration of 1 mg/ml to 10 mg/ml.

Discard the vial if the solution is cloudy, discolored, or contains visible particulate matter. Use the prepared infusion solution immediately or store for no more than 24 hours at 2°C to 8°C and up to 6 hours at room temperature, including infusion time.

Monitor patients during the infusion for signs of infusion-related reactions. Continue treatment until disease progression or unacceptable toxicity occurs.

Withhold or permanently discontinue Pembrolizumab to manage severe or life-threatening immune-mediated adverse reactions. Administer corticosteroids for severe immune-mediated reactions.

Adverse Reactions

Immune-mediated adverse reactions hypothyroidism, hyperthyroidism, diabetes mellitus, pneumonitis, hypophysitis, nephritis, colitis, hepatitis.

Metabolism and nutrition disorders hyperglycemia, hypertriglyceridemia, hyponatremia, hypercholesterolemia, hypoalbuminemia, decreased bicarbonate concentration, hypocalcemia.

Blood and lymphatic system disorders: anemia, lymphopenia.

Respiratory, thoracic and mediastinal disorders cough, dyspnea.

Nervous system disorders headache.

Gastrointestinal disorders decreased appetite, nausea, vomiting, constipation, diarrhea, abdominal pain, increased AST, ALT, ALP activity.

Skin and subcutaneous tissue disorders pruritus, rash, vitiligo.

Musculoskeletal and connective tissue disorders arthralgia, back pain.

General disorders and administration site conditions fatigue, pyrexia, asthenia.

Contraindications

Severe renal failure; moderate and severe hepatic failure; age under 18 years; pregnancy; lactation (breastfeeding); hypersensitivity to pembrolizumab.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use reliable methods of contraception during treatment with pembrolizumab and for at least 4 months after the last infusion of pembrolizumab.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Special Precautions

If immune-mediated adverse reactions are suspected, a thorough evaluation is required to confirm the etiology and exclude other possible causes. Based on the severity of the adverse reaction, it is necessary to temporarily discontinue Pembrolizumab and administer corticosteroids.

Drug Interactions

The use of systemic corticosteroids or immunosuppressants should be avoided prior to the initiation of pembrolizumab therapy, considering their possible impact on the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after the initiation of pembrolizumab treatment for the therapy of immune-mediated adverse reactions.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°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.