Qarziba (Concentrate) Instructions for Use

Marketing Authorization Holder

Pharmamondo-Biomedica, LLC (Russia)

Manufactured By

Patheon Italia, S.P.A. (Italy)

Packaging and Quality Control Release

MILLMOUNT HEALTHCARE, Limited (Ireland)

ATC Code

L01FX06 (Dinutuximab beta)

Active Substance

Dinutuximab beta (Rec.INN registered by WHO)

Dosage Form

Qarziba

Concentrate for solution for infusion 4.5 mg/1 ml: fl. 1 pc.

Dosage Form, Packaging, and Composition

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

Excipients: histidine, sucrose, polysorbate 20, water for injections, hydrochloric acid (for pH adjustment).

4.5 ml – glass vials with a volume of 6 ml (1) – cardboard packs with a holder^×.

^× the pack is equipped with two transparent first-opening control labels; one first-opening control label is placed on each reclosable flap of the pack.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents; monoclonal antibodies and their drug conjugates; other monoclonal antibodies and their drug conjugates

Pharmacological Action

Antineoplastic agent. It is a chimeric monoclonal IgG1 antibody specifically targeting the carbohydrate moiety of disialoganglioside 2 (GD2), which is highly expressed on neuroblastoma cells.

Dinutuximab beta has been shown to bind to neuroblastoma cell lines known to express GD2 and to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In the presence of human effector cells, including peripheral blood mononuclear cells and granulocytes obtained from healthy donors, Dinutuximab beta was found to mediate dose-dependent lysis of human neuroblastoma and melanoma cell lines. Furthermore, studies have shown that Dinutuximab beta may suppress liver metastases.

Neurotoxicity associated with dinutuximab beta is likely due to the induction of mechanical allodynia, which may be mediated by the reaction of dinutuximab beta with the GD2 antigen located on the surface of peripheral nerve fibers and myelin.

Pharmacokinetics

Calculations of the pharmacokinetic parameters of dinutuximab beta are based on measurements using non-validated bioanalytical methods. Depending on the dose, the C_max in plasma was 12-16.5 µg/ml and was reached on days 5-10 of the infusion. Dinutuximab beta is a protein for which the expected metabolic pathway of biotransformation is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Biotransformation studies have not been conducted. T_1/2 was 190 h.

Indications

Treatment of high-risk neuroblastoma in patients aged 12 months and older, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, and in patients with a history of recurrent or refractory neuroblastoma, with or without residual disease.

ICD codes

Dosage Regimen

Administer Qarziba as an intravenous infusion. The total dose per treatment cycle is 100 mg/m² of body surface area.

Complete five consecutive 35-day cycles. For each cycle, administer the total dose as a continuous infusion over 10 days. Divide the daily dose equally over a 24-hour period.

Calculate the dose based on body surface area at the beginning of each cycle. Dilute the concentrate in sodium chloride 9 mg/mL (0.9%) solution for infusion before administration. Use a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein-binding filter (0.2 μm).

Initiate treatment only in a specialized clinical setting with continuous patient monitoring. Premedicate with intravenous analgesics, antihistamines, and antipyretics approximately 30 minutes before starting the infusion to mitigate infusion-related reactions and neuropathic pain.

For patients with recurrent or refractory neuroblastoma, or those who did not achieve a complete response after first-line therapy, administer Qarziba in combination with subcutaneous interleukin-2 (IL-2). Follow the specific IL-2 dosing schedule as prescribed.

Monitor vital signs, including blood pressure, heart rate, respiratory rate, and oxygen saturation, closely during and after the infusion. Regularly assess liver function, electrolyte levels, and hematological parameters throughout the treatment course.

Adjust the infusion rate or temporarily interrupt administration if severe adverse reactions occur. Permanently discontinue treatment for specific grade 3 or 4 toxicities, including severe anaphylaxis, persistent grade 2 motor neuropathy, grade 3 peripheral sensory neuropathy, grade 3 ocular toxicity, recurrent grade 4 capillary leak syndrome, or grade 4 hyponatremia unresponsive to correction.

Adverse Reactions

Infections and parasitic diseases very common – infection (including pneumonia, skin infection, herpesvirus infection, myelitis, encephalomyelitis), device-related infection; common – sepsis.

Blood and lymphatic system disorders very common – anemia, leukopenia, neutropenia, thrombocytopenia, increased body weight; common – lymphopenia, prolonged aPTT; uncommon – DIC syndrome, eosinophilia.

Immune system disorders very common – hypersensitivity, cytokine release syndrome; common – anaphylactic reaction; uncommon – serum sickness.

Metabolism and nutrition disorders very common – fluid retention; common – decreased appetite, hypoalbuminemia, hyponatremia, hypokalemia, hypophosphatemia, hypomagnesemia, hypocalcemia, dehydration, weight loss, hypertriglyceridemia.

Psychiatric disorders common – agitation, anxiety.

Nervous system disorders very common – headache; common – peripheral neuropathy, seizures, paresthesia, dizziness, tremor; uncommon – increased intracranial pressure, posterior reversible encephalopathy syndrome.

Eye disorders very common – mydriasis, neurotonic pupillary reaction, eye edema (eyelid edema, periorbital edema); common – ophthalmoplegia, optic disc edema, accommodation disorder, blurred vision, photophobia.

Cardiac and vascular disorders very common – tachycardia, arterial hypotension, capillary leak syndrome; common – heart failure, left ventricular dysfunction, pericardial effusion, arterial hypertension; uncommon – hypovolemic shock, veno-occlusive disease.

Respiratory, thoracic and mediastinal disorders very common – hypoxia, cough; common – bronchospasm, dyspnea, respiratory failure, pulmonary infiltration, pulmonary edema, pleural effusion, tachypnea, laryngospasm.

Gastrointestinal disorders very common – vomiting, diarrhea, constipation, stomatitis, increased transaminase activity,
Increased GGT activity, blood bilirubin concentration; common – nausea, lip edema, ascites, abdominal distension, intestinal obstruction, dry lips; uncommon – enterocolitis, hepatocellular injury.

Skin and subcutaneous tissue disorders very common – skin itching, skin rash, urticaria; common – dermatitis (including
Exfoliative dermatitis), erythema, dry skin, hyperhidrosis, petechiae, photosensitivity reaction.

Musculoskeletal and connective tissue disorders common – muscle spasms.

Renal and urinary disorders common – oliguria, urinary retention, hyperphosphaturia, hematuria, proteinuria, increased blood creatinine concentration; uncommon – renal failure, decreased GFR

General disorders and administration site conditions very common – fever, chills, pain, peripheral edema, facial edema.

Contraindications

Hypersensitivity to the active substance; acute graft-versus-host disease (GvHD) grade 3 or 4 or extensive chronic GvHD; pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

Safety and efficacy in children under 12 months of age have not been established.

Data for children under 2 years of age are very limited and insufficient for dosing regimen assessment.

Geriatric Use

Age does not affect the pharmacokinetics of dinutuximab beta.

Special Precautions

Before treating recurrent neuroblastoma, any actively progressive disease should be stabilized by other appropriate therapeutic methods.

In patients with recurrent/refractory disease and in patients who did not achieve a complete response after first-line therapy, Dinutuximab beta should be combined with interleukin-2 (IL-2).

Treatment with dinutuximab beta must be permanently discontinued if the following toxic manifestations occur: grade 3 or 4 anaphylaxis; persistent grade 2 peripheral motor neuropathy; grade 3 peripheral neuropathy; grade 3 ocular toxicity; grade 4 hyponatremia (< 120 mEq/L) despite adequate fluid balance correction; recurrent adverse reactions or grade 4 capillary leak syndrome (requiring ventilatory support).

Neuropathic pain usually occurs at the beginning of treatment, and premedication with analgesics, including intravenous opioids, is required before each infusion of dinutuximab beta. For pain management, triple therapy including non-opioid analgesics (according to WHO recommendation), gabapentin, and opioid analgesics is recommended. The individual dose of these drugs may vary significantly.

Non-opioid analgesics, such as paracetamol or ibuprofen, should be used continuously during treatment.

Three days before the dinutuximab beta infusion, the patient should be prescribed gabapentin orally at a dose of 10 mg/kg/day. Gabapentin is used according to a specific schedule.

The use of opioid analgesics is a standard procedure during the administration of dinutuximab beta.

Severe infusion reactions, including cytokine release syndrome (CRS), anaphylactic reactions, and hypersensitivity reactions, may occur despite premedication. The occurrence of a severe infusion reaction (including CRS) requires immediate discontinuation of dinutuximab beta therapy and may require intensive care.

CRS often manifests within minutes or hours after the start of the first infusion and is characterized by systemic symptoms such as fever, arterial hypotension, and urticaria.

Anaphylactic reactions may occur as early as within minutes after the first infusion of dinutuximab beta and are usually combined with bronchospasm and urticaria

Premedication with antihistamines (e.g., diphenhydramine) should be administered by intravenous injection approximately 20 minutes before the start of each dinutuximab beta infusion. Close monitoring for manifestations of anaphylaxis and allergic reactions is necessary, especially during the first and second treatment cycles.

An intravenous antihistamine, epinephrine, and intravenous prednisolone must be immediately available during the administration of dinutuximab beta to manage life-threatening allergic reactions.

Careful monitoring of circulatory and respiratory functions is necessary during the treatment period.

In case of visual accommodation impairment, which can be corrected with glasses, dose modification is not required, provided the dose is well tolerated. Treatment should be temporarily suspended in patients with grade 3 ocular toxic manifestations (subtotal vision loss on the toxicity grading scale). In case of ocular disorders, patients should be immediately referred to an ophthalmologist.

Cases of motor or sensory neuropathy lasting more than 4 days should be evaluated, and non-inflammatory causes such as disease progression, infections, metabolic syndrome, and concomitant medications should be excluded.

Treatment must be permanently discontinued in patients experiencing any objective persistent weakness associated with the administration of dinutuximab beta. In patients with moderate grade 2 neuropathy (motor with or without sensory), treatment should be interrupted and may be resumed after resolution of neurological symptoms.

As a result of prior therapy, patients are likely to be immunocompromised. Since patients typically have a central venous catheter in place, they are at risk of developing systemic infection. Before starting therapy, patients should have no signs of systemic infection and any identified infection should be controlled.

Regular monitoring of liver function and electrolyte concentrations is recommended during treatment with dinutuximab beta.

Results of preclinical studies

Dinutuximab beta was administered to young (male and female) guinea pigs, as well as to young (male and female) cynomolgus monkeys in multiple-dose regimens exceeding the recommended clinical dose. Notable changes included a (decrease) in thymus weight, as well as changes in the bone marrow (atrophy affecting myeloid and erythroid progenitor cell lines). The changes in the bone marrow ranged from minor to serious. Complete recovery was observed after discontinuation of dinutuximab beta administration. No effects on cardiovascular function (ECG, BP) were observed in monkeys.

Preclinical studies of carcinogenicity, genotoxicity, or toxic effects of dinutuximab beta on reproductive function and development have not been conducted. In repeated dose toxicity studies in guinea pigs and cynomolgus monkeys, no effects of dinutuximab beta on reproductive organs were observed at exposure levels above clinical levels.

Effect on ability to drive and use machines

Dinutuximab beta has a significant effect on the ability to drive and use machines. Patients should not drive vehicles or operate machinery during treatment with dinutuximab beta.

Drug Interactions

The risk of mediated reduction in CYP enzyme activity due to elevated levels of TNFα and IL-6 and, consequently, interactions with concomitantly used medicinal products cannot be excluded.

Due to the immunosuppressive effect of corticosteroids, their concomitant use is not recommended for 2 weeks before the first treatment cycle and for up to 1 week after the last treatment cycle with dinutuximab beta, except for their use in managing life-threatening conditions.

Vaccination should be avoided during the administration of dinutuximab beta and for up to 10 weeks after the last treatment cycle, due to immune stimulation by dinutuximab beta and the possible risk of rare neurological toxic manifestations.

Concomitant intravenous administration of immunoglobulins is not recommended, as they may interfere with dinutuximab beta-mediated cellular cytotoxicity.

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.