4.1. Therapeutic indications

KANUMA is indicated for long-term enzyme replacement therapy (ERT) in patients of all ages with lysosomal acid lipase (LAL) deficiency.

4.2. Posology and method of administration

KANUMA treatment should be supervised by a healthcare professional experienced in the management of patients with LAL deficiency, other metabolic disorders, or chronic liver diseases. KANUMA should be administered by a trained healthcare professional who can manage medical emergencies.

Posology

It is important to initiate treatment as early as possible after diagnosis of LAL deficiency.

For instructions on the preventive measures and monitoring of hypersensitivity reactions, see section 4.4. Following the occurrence of a hypersensitivity reaction, appropriate pre-treatment should be considered according to the standard of care (see section 4.4).

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive LAL deficiency is either 1 mg/kg or 3 mg/kg administered as an intravenous infusion once weekly, depending on the clinical status of the patient. A higher starting dose of 3 mg/kg should be considered based on the severity of the disease and rapid disease progression.

Dose escalations should be considered based on suboptimal response to clinical and biochemical criteria, including, e.g., poor growth (especially mid-upper arm circumference, MUAC), deteriorating biochemical markers (e.g. liver transaminases, ferritin, C-reactive Protein, and coagulation parameters), persistent or worsening organomegaly, increased frequency of intercurrent infections, and persistent worsening of other symptoms (e.g. gastrointestinal symptoms):

- a dose escalation to 3 mg/kg should be considered in case of suboptimal clinical response after a minimum of 4 infusions;

- a further dose escalation up to 5 mg/kg should be considered in case of persistent suboptimal clinical response.

Further dose adjustments, as a reduction of the dose or an extension of the dose interval, can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies evaluated doses ranging from 0.35 to 5 mg/kg once weekly, with one patient receiving a higher dose of 7.5 mg/kg once weekly. Doses higher than 7.5 mg/kg have not been studied.

Paediatric and Adult Patients with LAL Deficiency

The recommended dose in children and adults who do not present with rapidly progressive LAL deficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once every other week. Dose escalation to 3 mg/kg once every other week should be considered based on suboptimal response to clinical biochemical criteria, including: e.g., poor growth persistent or deteriorating biochemical markers (e.g., parameters of liver injury (ALT, AST), parameters of lipid metabolism (TC, LDL-c, HDL-c, TG), persistent or worsening organomegaly, and persistent worsening of other symptoms (e.g., gastrointestinal symptoms).

Special populations

Renal impairment

No dosing adjustment is recommended in patients with renal impairment based on current knowledge of the pharmacokinetics and pharmacodynamics of sebelipase alfa (see section 5.2).

Hepatic impairment

No dosing adjustment is recommended in patients with hepatic impairment based on current knowledge of the pharmacokinetics and pharmacodynamics of sebelipase alfa (see section 5.2).

Elderly population (≥ 65 years old)

The safety and efficacy of sebelipase alfa in patients older than 65 years have not been evaluated and no alternative dose regimens can be recommended for these patients (see section 5.1).

Overweight patients

The safety and efficacy of sebelipase alfa in overweight patients have not been thoroughly evaluated and therefore no alternative dose regimens can be recommended for these patients at this time.

Paediatric population

Administration of sebelipase alfa to infants with confirmed multiple-organ failure should be at the discretion of the treating physician.

Method of administration

KANUMA is for intravenous (IV) use only.

The total volume of the infusion should be administered over approximately 2 hours. A 1-hour infusion may be considered for those patients receiving the 1mg/kg dose after patient tolerability is established (for recommended infusion volumes, see section 6.6). The infusion period may be extended in the event of dose escalation.

KANUMA should be administered through a 0.2 μm filter (see section 6.6).

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance when attempts to rechallenge are unsuccessful, or to egg or any of the excipients listed in section 6.1, (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions including anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with sebelipase alfa; see section 4.8. Therefore, appropriate medical support must be readily available when sebelipase alfa is administered. If severe reactions occur, the sebelipase alfa infusion should be immediately stopped and appropriate medical treatment should be initiated. The risks and benefits of re-administering sebelipase alfa following a severe reaction should be considered.

Following the first sebelipase alfa infusion, including the first infusion after a dose escalation, patients should be observed for 1 hour in order to monitor for any signs or symptoms of anaphylaxis or a severe hypersensitivity reaction.

The management of hypersensitivity reactions may include temporarily interrupting the infusion, lowering the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids.

For patients who have experienced allergic reactions during infusion, caution should be exercised upon re-administration. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions in those cases where symptomatic treatment was required.

In cases of severe infusion reactions and in cases of lack or loss of effect, patients should be tested for the presence of antibodies.

This medicinal product may contain traces of egg proteins. Patients with known egg allergies were excluded from clinical studies (see section 4.3).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In the sebelipase alfa clinical program, patients were routinely tested for anti-sebelipase alfa anti-drug antibodies (ADAs) to determine the immunogenicity potential of sebelipase alfa. Patients who tested positive for ADAs were also tested for inhibitory antibody activity. The presence of inhibitory activity has been detected at some postbaseline timepoints in clinical studies (see section 4.8). Overall, no conclusion on the relationship between development of ADAs/NAbs and associated hypersensitivity reactions or suboptimal clinical response can be made.

In clinical studies, 3 patients homozygous for a deletion affecting both alleles of genes Lipase A, lysosomal acid [LIPA] and Cholesterol 25-Hydroxylase developed inhibitory antibody activity associated with a suboptimal clinical response. These patients underwent either immunomodulatory therapy alone or in combination with haematopoietic stem cell transplant (HSCT) or bone marrow transplant (BMT), resulting in improved clinical response to sebelipase alfa.

Excipients

This medicinal product contains 33 mg sodium per vial equivalent to 1.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. It is administered in sodium chloride 9 mg/ml (0.9%) solution for infusion (see section 6.6). This should be taken into consideration by patients on a controlled sodium diet.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Because it is a recombinant human protein, sebelipase alfa is an unlikely candidate for cytochrome P450 mediated or other drug-drug interactions.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of sebelipase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid use of sebelipase alfa during pregnancy.

Breast-feeding

There are no data from studies in breast-feeding women. It is not known whether sebelipase alfa is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sebelipase alfa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on the effects of sebelipase alfa on fertility. Animal studies show no evidence of impaired fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

KANUMA may have a minor influence on the ability to drive and use machines. Adverse events of dizziness have been reported with the use of sebelipase alfa, which could affect the ability to drive or use machines (see section 4.8).

4.8. Undesirable effects

Summary of safety profile

The data described below reflect the exposure to sebelipase alfa in 125 patients at doses ranging from 0.35 mg/kg once every other week to 7.5 mg/kg once weekly in clinical studies (see section 5.1), with a treatment duration range from 1 day to 60.5 months (5 years).

Of the 106 children and adults enrolled in clinical studies, 102 (96.2%) have received sebelipase alfa at a dosage regimen of 1 mg/kg once every other week, with a median duration of exposure of 33 months (6, 59 months). The median duration of exposure for the 19 infants enrolled in clinical studies was 35.5 months (1 day to 60 months).

The most serious adverse reactions experienced by 4% of patients in clinical studies were signs and symptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctival hyperaemia, dyspnoea, hyperaemia, eyelid oedema, rhinorrhoea, severe respiratory distress, tachycardia, tachypnoea, irritability, flushing, pruritus, urticaria, stridor, hypoxia, pallor and diarrhoea.

Tabulated list of adverse reactions

The data in Table 1 describe adverse reactions reported in infants who received sebelipase alfa in clinical studies. The data in Table 2 describe adverse reactions reported in children and adults who received sebelipase alfa in clinical studies.

Adverse reactions are listed by system organ class (SOC) and frequency. Frequencies are defined according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 1: Adverse reactions reported in infants receiving sebelipase alfa (N = 19 patients)

MedDRA System organ class

MedDRA Preferred Term

Frequency

Immune system disorders

Hypersensitivitya

Anaphylactic reactionb

Very common

Eye Disorders

Eyelid oedema

Very common

Cardiac disorders

Tachycardia

Very common

Respiratory, thoracic and mediastinal disorders

Respiratory distress

Very common

Gastrointestinal disorders

Vomiting

Diarrhoea

Very common

Skin and subcutaneous tissue disorders

Rash

Rash maculo-papular

Very common

General disorders and administration site conditions

Pyrexia

Hyperthermia

Very common

Investigations

Drug specific antibody present

Body temperature increased

Oxygen saturation decreased

Blood pressure increased

Heart rate increased

Respiratory rate increased

Very common

a May include: irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor, and drug hypersensitivity

b Occurred in 3 infant patients treated in clinical studies. Based on Preferred Term 'anaphylactic reaction' and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.

Table 2: Adverse reactions reported in children and adults receiving sebelipase alfa (N = 106 patients)

MedDRA System organ class

MedDRA preferred term

Frequency

Immune system disorders

Hypersensitivityb

Very Common

Anaphylactic reactiona

Common

Nervous system disorders

Dizziness

Very common

Cardiac disorders

Tachycardia

Common

Vascular disorders

Hyperaemia

Hypotension

Common

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Common

Gastrointestinal disorders

Abdominal pain

Diarrhoea

Very common

Abdominal distension

Common

Skin and subcutaneous tissue disorders

Rash

Rash papular

Common

General disorders and administration site conditions

Fatigue

Pyrexia

Very common

Chest discomfort

Infusion site reactionc

Common

Investigations

Body temperature increased

Common

a Occurred in 2 patients treated in clinical studies. Based on Preferred Term 'anaphylactic reaction' and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.

b May include: chills, eczema, laryngeal oedema, nausea, pruritus, urticaria.

c Includes: infusion site extravasation, infusion site pain and infusion site urticaria

Description of selected adverse reactions

Hypersensitivity

Five of 125 (4%) patients treated with sebelipase alfa, including 3 of 19 (16%) infants and 2 of 106 (2%) children and adults, in clinical studies experienced serious signs and symptoms consistent with anaphylaxis to sebelipase alfa. Anaphylaxis occurred during the infusion as late as 1 year after treatment initiation.

In clinical studies, 59 of 125 (47%) sebelipase alfa-treated patients, including 13 of 19 (68%) infants and 46 of 106 (43%) children and adults, experienced at least 1 hypersensitivity reaction (selected using a validated, pre-determined set of terms grouped together to identify potential hypersensitivity reactions). Signs and symptoms either consistent with or that may be related to a hypersensitivity reaction occurring in two or more patients included but were not limited to abdominal pain, agitation, bronchospasm, chills, diarrhoea, eyelid oedema, eczema, face oedema, hypertension, irritability, laryngeal oedema, lip swelling, nausea, oedema, pallor, pruritus, pyrexia/body temperature increased, rash, tachycardia, urticaria, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of the infusion.

Transient hyperlipidaemia

Consistent with its known mechanism of action, asymptomatic increases in circulating cholesterol and triglycerides have been observed following initiation of treatment. These increases have generally occurred within the first 2 to 4 weeks and improved within a further 8 weeks of treatment. See section 5.1.

Immunogenicity

There is potential for immunogenicity (see section 4.4). Patients have developed anti-drug antibodies (ADA) to sebelipase alfa. Compared to children and adults, an increased occurrence of ADA positivity was observed within the infant population (10/19 patients).

Among 125 patients with LAL Deficiency enrolled in the clinical studies, 19/125 (15.0%) patients tested positive for anti-drug antibodies (ADAs) at some timepoint after starting treatment with sebelipase alfa (9 children and adult patients and 10 infants). For children and adult patients with LAL Deficiency, ADA positivity was transient with generally low titers of ADAs reported. Persistence of ADA positivity was observed for all 10 infants and persistence of high titer ADAs was observed for 3 of the 10 infants. Among those 19 patients, 11 (58%) also showed the presence of inhibitory antibody activity (NAbs) at some postbaseline timepoint.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical studies, doses of sebelipase alfa were explored up to 7.5 mg/kg once weekly and no specific signs or symptoms were identified following the higher doses. For management of adverse reactions, see sections 4.4 and 4.8.