Nurdati^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

ATC Code

L01XY (Antineoplastic drug combinations)

Active Substances

Prolgolimab (Rec.INN registered by WHO)

Nurulimab (Rec.INN registered by WHO)

Dosage Form

Nurdati®

Concentrate for solution for infusion 5 mg+15 mg/1 ml: fl. 20 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a transparent or slightly opalescent, colorless to light yellow liquid.

Excipients: trehalose dihydrate, sodium acetate trihydrate (contains 0.013 mmol (or 0.299 mg) of sodium per 1 ml), glacial acetic acid, water for injections.

20 ml – colorless glass bottles (1) – cardboard packs.

It is allowed to affix a first-opening control label on the cardboard pack.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents; combinations of antineoplastic agents

Pharmacological Action

A combined drug containing a monoclonal IgG1 antibody against CTLA-4 (Nurulimab) and a monoclonal IgG1 antibody against PD-1 (Prolgolimab). These antibodies belong to immune checkpoint inhibitors.

Nurulimab blocks the interaction of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) glycoprotein with its ligands. CTLA-4 is a negative regulator of the antitumor activity of T-cells. Inhibition of CTLA-4 enhances the activation and proliferation of T-cells, including the activation and proliferation of tumor-infiltrating antitumor T-effector cells. Inhibition of CTLA-4 may also reduce the function of T-regulatory cells, which may contribute to an overall increase in T-cell reactivity, including the antitumor immune response.

Prolgolimab is a monoclonal antibody that specifically binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with the PD-L1 and PD-L2 ligands. The Fc fragment of prolgolimab is modified to prevent cytotoxic action on target cells expressing PD-1. PD-1 is a protein receptor – an immune checkpoint – that limits the activity of T-lymphocytes. Tumor cells may use the PD-1-mediated signaling cascade to inhibit the T-cell immune response. When the PD-1 receptor is bound by prolgolimab, a dual blockade of the PD-1-mediated signaling pathway involving the PD-L1 and PD-L2 ligands on tumor or immune cells is carried out. As a result, Prolgolimab reactivates tumor-specific cytotoxic T-lymphocytes and thus reactivates antitumor immunity.

Analysis of pharmacodynamic parameters and their relationship with efficacy indicators showed that during the period of best response compared to baseline, a significant increase in the level of activated cytotoxic T-lymphocytes and ICOS+ T-helpers was observed among subjects responding to therapy. The change in the level of type 9 T-helpers and the concentration of IL-8 was not statistically significant.

Binding and neutralizing antibodies to the monoclonal antibody against CTLA-4 were detected in 2.1% of cases at 8 weeks or more after the fourth administration of the drug containing this combination, and were not detected at 36 weeks or more. During the analyzed period corresponding to 12 months of therapy, no immunogenicity of the monoclonal antibody against anti-PD-1 was noted in the group receiving this combination and prolgolimab in the group receiving Prolgolimab.

Pharmacokinetics

The drug containing Nurulimab + Prolgolimab is administered intravenously, therefore, it immediately and completely becomes bioavailable. In accordance with the limited extravascular distribution, V_d is 3.848 L for the anti-CTLA-4 component, 3.029 L for the anti-PD-1 component. The parameter value for prolgolimab when used as monotherapy is 3.066 L.

The median C_max of the anti-CTLA-4 component of the combination after the first administration was 20688 ng/ml, the time to reach it was 3.5 h. AUC of anti-CTLA-4 from 0 h to 505.5 h – 3510347 (ng/ml)×h, AUC of anti-CTLA-4 from 0 h to infinity – 4546947 (ng/ml)×h, T_1/2 – 169.06 h. The median minimum concentration of the anti-CTLA-4 component of the combination before the second administration was 3624 ng/ml, the time to reach it was 505.5 h.

The median C_max of the anti-PD-1 component of the combination after the first administration was 79372 ng/ml, the time to reach it was 5.5 h. AUC of anti-PD-1 from 0 h to 505.5 h – 14787828.0 (ng/ml)×h, AUC of anti-PD-1 from 0 h to infinity – 20209216 (ng/ml)×h, T_1/2 – 187.337 h. The median C_max of the anti-PD-1 component of the combination before the second administration in the BCD-217 group was 15167.8 ng/ml, the time to reach it was 505.5 h.

The components of the combination undergo catabolism by nonspecific pathways.

Clearance for the anti-CTLA-4 component after the first dose is 20.146 ml/h. Clearance of the anti-PD-1 component of the combination is 15.341 ml/h.

T_1/2 of the anti-CTLA-4 component of the combination after the first dose infusion is 7 days (169.06 h). T_1/2 of the anti-PD-1 component after the first dose is 7.8 days (187.337 h). T_1/2 of prolgolimab after the first dose is 9.3 days (223.596 h).

Indications

Unresectable or metastatic melanoma.

ICD codes

Dosage Regimen

For intravenous administration both in outpatient and inpatient settings.

The infusion should be initiated and conducted under the supervision of qualified and experienced oncologists.

All patients should be observed for at least 1 hour after the end of the infusion. Patients should be under the supervision of an oncologist (for at least 12 weeks after the last dose administration), since adverse reactions due to the action of this combination may develop at any time during use or after discontinuation of therapy.

The volume of concentrate is calculated using a special formula.

It is administered once every 3 weeks for a total of 4 intravenous infusions.

Upon completion of 4 infusions, 3 weeks after the 4th infusion of this combination, treatment continues with prolgolimab until disease progression or the development of intolerable toxicity.

Adverse Reactions

Infections and infestations common – pneumonia; uncommon – fungal pharyngitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps) common – pain associated with malignant disease, bleeding tumor.

Blood and lymphatic system disorders very common – anemia, lymphopenia, thrombocytopenia; common – leukopenia, neutropenia; uncommon – febrile neutropenia.

Endocrine system disorders very common – hypothyroidism, hyperthyroidism; common – adrenal insufficiency, thyroiditis.

Metabolism and nutrition disorders very common – increased blood urea, increased blood uric acid; common – increased amylase activity, weight increased, weight decreased, hyperglycemia, decreased appetite, hyperglycemia, increased TSH, increased thyroxine; uncommon – hypocalcemia, diabetes mellitus.

Psychiatric disorders common – insomnia, depression, irritability, anxiety; uncommon – sleep disorder.

Nervous system disorders common – headache, dizziness, paresthesia, memory impairment; uncommon – dysgeusia.

Eye disorders uncommon – iridocyclitis, uveitis.

Cardiac disorders common – sinus bradycardia, sinus tachycardia, arrhythmia, arterial hypertension; uncommon – autoimmune myocarditis, atrial fibrillation.

Respiratory, thoracic and mediastinal disorders common – dyspnea, cough, pneumonitis.

Gastrointestinal disorders very common – nausea; common – pain in the upper abdomen, colitis, vomiting, nausea, diarrhea.

Hepatobiliary disorders very common – increased AST, ALT, LDH, increased conjugated bilirubin; common – increased ALP, increased bilirubin, hepatitis.

Skin and subcutaneous tissue disorders common – pruritus, hyperhidrosis, skin hypopigmentation, rash; uncommon – alopecia, dry skin.

Musculoskeletal and connective tissue disorders common – arthralgia, groin pain; uncommon – pain in extremity, bone pain, back pain, myositis.

Renal and urinary disorders common – increased creatinine.

General disorders and administration site conditions very common – asthenia, fatigue; common – peripheral edema, pyrexia.

Contraindications

Hypersensitivity to nurulimab, prolgolimab; pregnancy, breastfeeding period; age under 18 years.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

The safety and efficacy of the nurulimab + prolgolimab combination in patients with hepatic impairment have not been studied.

Use in Renal Impairment

The safety and efficacy of the nurulimab + prolgolimab combination in patients with renal impairment have not been studied.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Dosage adjustment in elderly patients is not required.

Special Precautions

Treatment of patients with this combination should be carried out only under the supervision of a physician experienced in anticancer therapy. Due to its mechanism of action, the Nurulimab + Prolgolimab combination may contribute to the development of immune-mediated adverse reactions, including severe and life-threatening ones.

If an immune-mediated reaction is suspected, appropriate evaluation is required to confirm the immune etiology and exclude other causes. In case of development and confirmation of a suspected immune-mediated reaction, depending on the severity, temporary suspension of the use of this combination and the administration of corticosteroids is required. In case of severe and life-threatening immune-mediated adverse reactions, therapy with this combination is not resumed.

In case of a high severity or life-threatening infusion reaction, the infusion of the drug containing this combination should be immediately interrupted and appropriate therapy should be prescribed to relieve the infusion reaction. In patients with mild or moderate severity of infusion reactions, the possibility of continuing use under close supervision of an oncologist may be considered when premedication is administered in accordance with the standards for the prevention of infusion reactions.

Due to the peculiarities of the mechanism of action of nurulimab, the increase in T-cell reactivity induced by it may reduce the effectiveness of immunosuppressive therapy with an increased risk of exacerbation of a concomitant autoimmune disease or transplant rejection. The use of this combination should be avoided in patients with serious active autoimmune diseases in whom immune system activation may lead to serious complications. In other patients with autoimmune diseases, this combination should be used with caution with a thorough assessment of the individual benefit-risk ratio of therapy.

Effect on ability to drive vehicles and mechanisms

Considering that episodes of dizziness have been observed during therapy with other monoclonal antibody drugs against PD-1 and CTLA-4, patients experiencing dizziness when using the Nurulimab + Prolgolimab combination are not recommended to drive vehicles and mechanisms until the dizziness stops.

Drug Interactions

The use of systemic corticosteroids or immunosuppressants should be avoided before starting therapy with the Nurulimab + Prolgolimab combination, given their possible effect on the pharmacodynamic activity and efficacy of this combination. However, systemic corticosteroids or other immunosuppressants may be used after initiation of treatment with this combination for the therapy of immune-mediated adverse reactions.

Any anticoagulants and/or antiplatelet agents should be used with caution, given the risk of gastrointestinal bleeding (a possible variant of immune-mediated adverse events) while taking monoclonal antibodies against CTLA-4.

Immune-mediated serious adverse reactions have been reported during the combined use of nurulimab + prolgolimab and cisplatin, therefore concomitant use with platinum-containing chemotherapy is not recommended until additional information is obtained.

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.