KANUMA Concentrate for solution for infusion Ref.[7581] Active ingredients: Sebelipase alfa

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal 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).

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

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.

Pregnancy

There are no 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).

KANUMA has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The most serious adverse reactions experienced by 3% of patients in clinical studies were signs and symptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctival injection, dyspnoea, generalised and itchy rash, hyperaemia, mild eyelid oedema, rhinorrhoea, severe respiratory distress, tachycardia, tachypnoea and urticaria.

Tabulated list of adverse reactions

The data in Table 1 describe adverse reactions reported in infants who received sebelipase alfa in clinical studies at doses up to 3 mg/kg weekly. The data in Table 2 describe adverse reactions reported in children and adults who received sebelipase alfa in clinical studies at a dose of 1 mg/kg once every other week.

Adverse reactions are listed by system organ class 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions reported in infants^c receiving sebelipase alfa:

Immune system disorders

Very common^a: Eyelid oedema

Psychiatric disorders

Very common^a: Agitation^b, irritability^b

Nervous system disorders

Very common^a: Hypotonia

Cardiac disorders

Very common^a: Tachycardia^b

Vascular disorders

Very common^a: Hypertension, pallor^b

Respiratory, thoracic and mediastinal disorders

Very common^a: Respiratory distress, wheezing, cough, rhinitis, nasal congestion, sneezing

Gastrointestinal disorders

Very common^a: Diarrhoea, gastro-oesophageal reflux disease, retching, vomiting^b

Skin and subcutaneous tissue disorders

Very common^a: Urticaria^b, rash^b, eczema^b, pruritis, rash maculo-papular

General disorders and administration site conditions

Very common^a: Chills, hyperthermia, pyrexia^b, oedema

Investigations

Very common^a: Body temperature increased, oxygen saturation decreased, blood pressure increased, heart rate increased, respiratory rate increased

^a Very common = Reported in ≥1 patient receiving sebelipase alfa
^b Reported in ≥2 patients receiving sebelipase alfa
^c Age at first dose: 1 to 6 months

Table 2. Adverse reactions reported in children and adultsd receiving sebelipase alfa:

Infections and infestations

Common^a: Urinary tract infection

Immune system disorders

Common^a: Anaphylactic reaction, eyelid oedema

Metabolism and nutrition disorders

Common^a: Transient hypercholesterolaemia, transient hypertriglyceridaemia

Psychiatric disorders

Common^a: Anxiety^c, insomnia

Nervous system disorders

Common^a: Dizziness

Cardiac disorders

Common^a: Tachycardia

Vascular disorders

Common^a: Hyperaemia^e, hypotension

Respiratory, thoracic and mediastinal disorders

Common^a: Laryngeal oedema^e, dyspnoea^b,c,e

Gastrointestinal disorders

Common^a: Diarrhoea^b,e, abdominal pain^b,e, abdominal distension, nausea^b,e

Skin and subcutaneous tissue disorders

Common^a: Urticaria, rash^c,e (including rash papular and rash pruritic), pruritus^e, eczema^e

Reproductive system and breast disorders

Common^a: Menorrhagia

General disorders and administration site conditions

Common^a: Chills, chest discomfort^c,e, oedema, fatigue, infusion site induration, pyrexia

Investigations

Common^a: Body temperature increased^b,c

Injury, poisoning and procedural complications

Common^a: Infusion related reaction^c

^a Common = Reported in ≥1 patient receiving sebelipase alfa
^b Reported at the same frequency in patients receiving sebelipase alfa or placebo or more frequently in patients receiving placebo during the double-blind period of LAL-CL02
^c Reported as part of an adverse reaction in a single patient receiving sebelipase alfa in LAL-CL02
^d Age at first dose: 4 to 58 years e Reported in ≥2 patients receiving sebelipase alfa

Description of selected adverse reactions

Hypersensitivity

Three patients of 106 (3%) patients treated with sebelipase alfa, including 1 of 14 (7%) infants and 2 of 92 (2%) children and adults, in clinical studies experienced signs and symptoms consistent with anaphylaxis. Anaphylaxis occurred during the infusion as late as 1 year after treatment initiation.

In clinical studies, 21 of 106 (20%) sebelipase alfa-treated patients, including 9 of 14 (64%) infants and 12 of 92 (13%) children and adults, experienced signs and symptoms either consistent with or that may be related to a hypersensitivity reaction. These reported signs and symptoms occurring in two or more patients included abdominal pain, agitation, chills, diarrhoea, eczema, hypertension, irritability, laryngeal oedema, 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

Patients have developed anti-drug antibodies (ADA) to sebelipase alfa. Based on the limited data currently available the development of ADA seems to occur more frequently in infants.'

In LAL-CL03, 4 of 7 evaluable infants (57%) developed ADA during treatment with sebelipase alfa. At the time of initial ADA positivity, 3 patients were receiving a dose of 1 mg/kg once weekly and 1 patient was receiving a dose of 3 mg/kg once weekly. Most patients who developed ADA did so within the first 2 months of exposure. ADA titres decreased to undetectable levels during continued treatment in 3 of the 4 patients. Two patients were determined to be positive for antibodies that inhibit in vitro enzyme activity and cellular uptake of the enzyme. In a separate study in infants, one of five evaluable patients developed antibodies that inhibit in vitro enzyme activity and cellular uptake of the enzyme.

In LAL-CL02, 5 of 35 evaluable children and adults (14%) who were administered sebelipase alfa during the 20-week double-blind period of the study developed ADA. All patients were receiving 1 mg/kg once every other week. Those patients who developed ADA did so within the first 3 months of exposure. ADA titres decreased to undetectable levels during continued treatment in all patients. Two patients were positive at only a single time point. No patients developed antibodies that inhibited in vitro enzyme activity and one patient developed antibodies that inhibited cellular uptake of the enzyme in vitro.

The association between the development of ADA to sebelipase alfa and reductions in treatment effect or the occurrence of adverse reactions has not been determined.

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 national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.