Kanuma (Concentrate) Instructions for Use

Marketing Authorization Holder

Alexion Europe SAS (France)

Manufactured By

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

Or

Baxter Oncology, GmbH (Germany)

Packaging and Quality Control Release

ALMAC PHARMA SERVICES, Limited (United Kingdom)

Or

ALEXION PHARMA INTERNATIONAL OPERATIONS, Unlimited Company (Ireland)

ATC Code

A16AB14 (Sebelipase alfa)

Active Substance

Sebelipase alfa (Rec.INN registered by WHO)

Dosage Form

Kanuma

Concentrate for solution for infusion 2 mg/1 ml: 10 ml vial

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear to slightly opalescent, colorless to light yellow with a greenish tint liquid without visible foreign particles; translucent protein-like particles may be present.

Excipients: trisodium citrate dihydrate – 13.7 mg, citric acid monohydrate – 1.57 mg, human serum albumin – 10 mg, water for injections – up to 1 ml.

10 ml – colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Drugs for the treatment of digestive tract and metabolism disorders – enzymes

Pharmacological Action

Agent for enzyme replacement therapy. Recombinant lysosomal acid lipase is an enzyme used as enzyme replacement therapy to improve lipid metabolism and reduce the accumulation of cholesteryl esters and triglycerides in patients of all ages with lysosomal acid lipase deficiency (LAL-D).

Lysosomal acid lipase deficiency (historically Wolman disease, cholesteryl ester storage disease) is a rare autosomal recessive lysosomal storage disease characterized by a genetic defect in the LAL gene and leading to a marked decrease or loss of lysosomal acid lipase (LAL) enzyme activity. This deficiency is characterized by the absence of cleavage of cholesteryl esters and triglycerides in lysosomes.

Lysosomal accumulation of cholesteryl esters and triglycerides in the liver leads to hepatomegaly, an increase in the proportion of fat in liver tissue, elevated transaminase levels indicating chronic liver damage, as well as progression to fibrosis, cirrhosis, and complications of end-stage liver failure. In the spleen, LAL-D causes splenomegaly, and in the blood – anemia and thrombocytopenia. Lipid accumulation in the intestinal wall leads to malabsorption and impaired growth and development. Dyslipidemia is often accompanied by elevated LDL and triglyceride levels and decreased HDL and is associated with an increase in the proportion of fat in liver tissue and elevated blood transaminase levels. Patients with LAL-D have an increased risk of developing cardiovascular disease and a higher rate of atherosclerosis development. The enzyme deficiency also leads to decreased production of free cholesterol, which results in increased synthesis of apo-B-containing lipoproteins and delayed formation of HDL particles.

Other lipid-modifying agents may reduce LDL cholesterol levels in patients with LAL-D, but they do not affect the progression of liver disease because these agents do not address the underlying cause of the enzyme deficiency.

Based on experimental pharmacological data and conducted clinical studies, it has been shown that Sebelipase alfa, being a pathogenetic agent for the therapy of LAL-D, contributes to the improvement of lipid metabolism and normalization of liver enzyme levels in conditions associated with LAL-D.

Sebelipase alfa binds to cell membrane receptors via glycans expressed on the protein and is subsequently taken up by lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides into free cholesterol, glycerol, and free fatty acids. Replacement of LAL enzyme activity leads to a decrease in the proportion of fat in liver tissue and normalization of blood transaminase levels, and also restores the metabolism of cholesteryl esters and triglycerides in lysosomes, which results in decreased levels of LDL cholesterol and very low-density lipoproteins (VLDL), triglycerides, and an increase in HDL cholesterol levels. Improvement in growth and development occurs as a result of reduced lipid accumulation in the intestinal wall and, consequently, improved nutrient absorption.

Pharmacokinetics

The pharmacokinetics of sebelipase alfa is considered to be apparently nonlinear with a large dose-proportional increase in exposure observed between doses of 1 and 3 mg/kg. Sebelipase alfa is a protein; it is expected to be broken down during metabolism through peptide hydrolysis. The T_1/2 of sebelipase alfa from the systemic circulation is 0.1 h at a dose of 3 mg/kg once weekly. Renal elimination of sebelipase alfa is considered a minor route of excretion.

Indications

For long-term enzyme replacement therapy (ERT) in patients of all ages with lysosomal acid lipase deficiency.

ICD codes

Dosage Regimen

Administer intravenously.

Treatment should be conducted under the guidance of an experienced physician well acquainted with the principles of managing patients with LAL-D, other metabolic disorders, or chronic liver diseases.

It is important to initiate treatment as early as possible after the diagnosis of LAL-D is established.

Initial dose – 1 mg/kg once weekly. If necessary, the dose may be gradually increased to 3 mg/kg once weekly, depending on the clinical response.

Adverse Reactions

Immune system disorders: common – anaphylactic reaction, eyelid edema; in infants most common – eyelid edema.

Psychiatric disorders: common – anxiety, insomnia; in infants most common – agitation, irritability.

Blood and lymphatic system disorders: common – dizziness; in infants most common – muscle hypotonia.

Cardiac disorders: flushing, arterial hypotension, tachycardia; in infants most common – arterial hypertension, pallor, tachycardia.

Respiratory, thoracic and mediastinal disorders: common – laryngeal edema, dyspnea; in infants most common – respiratory distress, wheezing, cough, rhinitis, nasal congestion and sneezing.

Gastrointestinal disorders: common – diarrhea, abdominal pain, abdominal distension, nausea; in infants most common – diarrhea, gastroesophageal reflux, retching, vomiting.

Skin and subcutaneous tissue disorders: common – urticaria, rash (including papular and pruritic), pruritus, eczema; in infants most common – urticaria, rash (including maculopapular), eczema, pruritus.

Metabolism and nutrition disorders: common – transient hypercholesterolemia, transient hypertriglyceridemia.

Renal and urinary disorders: common – urinary tract infection.

Reproductive system and breast disorders: common – menorrhagia.

General disorders and administration site conditions: common – infusion-related reaction, chills, hyperthermia, pyrexia, edema; in infants most common – chills, hyperthermia, pyrexia, edema.

Investigations: common – increased body temperature; in infants most common – increased body temperature, decreased oxygen saturation, increased blood pressure, increased heart rate, increased respiratory rate.

Contraindications

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance after unsuccessful attempts at re-administration of the drug.

Use in Pregnancy and Lactation

As a precaution, the use of sebelipase alfa during pregnancy should be avoided if possible. It is not known whether Sebelipase alfa is excreted in human breast milk. A decision should be made either to discontinue breastfeeding or to discontinue sebelipase alfa therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Use in Hepatic Impairment

The drug is approved for use in hepatic impairment

Use in Renal Impairment

The drug is approved for use in renal impairment

Pediatric Use

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

Geriatric Use

The drug is approved for use in elderly patients

Special Precautions

Administration of the drug should be carried out in settings that allow for emergency medical treatment of anaphylactic reactions. In the event of such reactions, the administration of the drug should be immediately discontinued and appropriate therapeutic treatment initiated. In doing so, current medical standards for emergency care should be followed.

The risk and benefit of re-attempting administration of sebelipase alfa after the occurrence of severe reactions should be weighed. For patients who have experienced allergic reactions during infusion, caution should be exercised upon re-administration of the drug.

In cases of severe infusion reaction, as well as when the therapeutic effect is insufficient, patients should be tested for the presence of antibodies.

After the first infusion of sebelipase alfa, including the first infusion after a dose increase, patients should be observed for at least one hour to monitor their condition and detect symptoms and signs of anaphylaxis or severe hypersensitivity reaction.

Effect on ability to drive and use machines

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor 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.