KANUMA 2 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 2 mg sebelipase alfa*. Each vial of 10 ml contains 20 mg sebelipase alfa.

*Sebelipase alfa is produced in egg white of transgenic Gallus by recombinant DNA (rDNA) technology.

Excipient with known effect:

Each vial contains 33 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to slightly coloured solution.

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

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).

Infants (< 6 months of age)

The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive LAL deficiency is 1 mg/kg administered as an intravenous infusion once weekly. Dose escalation to 3 mg/kg once weekly should be considered based on clinical response.

Children and adults

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.

Special populations

Renal or hepatic impairment

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

Paediatric population

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

Overweight patients

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

Elderly population (≥ 65 years old)

The safety and efficacy of KANUMA in patients older than 65 years have not been eva luated and no alternative dose regimens can be recommended for these patients. See section 5.1.

Method of administration

KANUMA is for intravenous use only.

The total volume of the infusion should be administered over approximately 2 hours. A 1-hour infusion may be considered after patient tolerability is established. 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.

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).

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 and 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 KANUMA 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 KANUMA

^a Very common = Reported in ≥ 1 patient receiving KANUMA

^b Reported in ≥ 2 patients receiving KANUMA

^c Age at first dose: 1 to 6 months

Table 2: Adverse reactions reported in children and adults^d receiving KANUMA

^a Common = Reported in ≥ 1 patient receiving KANUMA

^b Reported at the same frequency in patients receiving KANUMA 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 KANUMA in LAL-CL02

^d Age at first dose: 4 to 58 years

^e Reported in ≥ 2 patients receiving KANUMA

Description of selected adverse reactions

Hypersensitivity

Three patients of 106 (3%) patients treated with KANUMA, 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%) KANUMA-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 eva luable infants (57%) developed ADA during treatment with KANUMA. 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 eva luable patients developed antibodies that inhibit in vitro enzyme activity and cellular uptake of the enzyme.

In LAL-CL02, 5 of 35 eva luable children and adults (14%) who were administered KANUMA 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Alexion Pharma UK Ltd on Uk.adverseevents@alxn.com, Freephone: 0800 321 3902, Ireland Freephone: 1 800 936 544

In clinical studies, doses of sebelipase alfa were explored up to 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.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Enzymes; ATC code: not yet assigned

Lysosomal acid lipase (LAL) deficiency

LAL deficiency is a rare disease associated with significant morbidity and mortality, which affects individuals from infancy through adulthood. LAL deficiency presenting in infants is a medical emergency with rapid disease progression over a period of weeks that is typically fatal within the first 6 months of life. LAL deficiency is an autosomal recessive lysosomal storage disorder characterised by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme.

Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters and triglycerides. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content, transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, and complications of end stage liver disease. In the spleen, LAL deficiency results in splenomegaly, anemia, and thrombocytopenia. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Dyslipidemia is common with elevated LDL and triglycerides and low HDL, associated with increase liver fat content and transaminase elevations. In addition to liver disease, patients with LAL deficiency experience increased risk for cardiovascular disease and accelerated atherosclerosis.

Mechanism of action

Sebelipase alfa is a recombinant human lysosomal acid lipase (rhLAL).

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyses the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids. Replacement of LAL enzyme activity leads to reductions in liver fat content and transaminases, and enables metabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in low-density lipoprotein (LDL) cholesterol and non-high-density lipoprotein (HDL) cholesterol, triglycerides, and increases in HDL cholesterol. Improvement in growth occurs as a result of substrate reduction in the intestine.

Clinical studies

Infants presenting with LAL deficiency

LAL-CL03 was a multicentre, open-label, single-arm study of KANUMA in 9 patients with LAL deficiency with growth failure or other evidence of rapidly progressive disease prior to 6 months of age. Patients also had rapidly progressive liver disease and severe hepatosplenomegaly. The age range at study entry was 1-6 months. Patients received sebelipase alfa at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weekly occurred as early as 1 month and up to 20 months after starting treatment at 1 mg/kg. A further dose escalation to 5 mg/kg once weekly was allowed.

Efficacy was assessed by comparing the survival experience of KANUMA-treated patients who survived past 12 months of age in LAL-CL03 with a historical cohort of untreated infants presenting with LAL deficiency with similar clinical characteristics. In LAL-CL03, 6 of 9 KANUMA-treated infants survived beyond 12 months (67% 12-month survival, 95% CI: 30% to 93%). With continued treatment beyond 12 months of age, 1 additional patient died at age 15 months. In the historical cohort, 0 of 21 patients survived beyond 8 months of age (0% 12-month survival, 95% CI: 0% to 16%).

KANUMA at doses up to 1 mg/kg once weekly resulted in improvements in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and weight gain within the first several weeks of treatment. From baseline to week 48, the mean reductions for ALT and AST were -34.0 U/l and -44.5 U/l, respectively. Dose escalation to 3 mg/kg once weekly was associated with additional improvements in weight gain, lymphadenopathy and serum albumin. From baseline to week 48, mean weight-for-age percentile improved from 12.74% to 29.83% and mean serum albumin levels increased from 26.7 g/l to 38.7 g/l.

One infant was treated with 5 mg/kg once weekly in LAL-CL03; no new adverse reactions were reported at this dose. In the absence of more clinical data, this dose is not recommended.

Children and adults with LAL deficiency

LAL-CL02 was a multicentre, double-blind, placebo-controlled study in 66 children and adults with LAL deficiency. Patients were randomised to receive KANUMA at a dose of 1 mg/kg (n = 36) or placebo (n = 30) once every other week for 20 weeks in the double-blind period. The age range at randomisation was 4-58 years old (71% were < 18 years old). For study entry, patients were required to have ALT levels of ≥1.5 X upper limit of normal (ULN). The majority of patients (58%) had LDL-cholesterol > 190 mg/dl at study entry, and 24% of patients with LDL-cholesterol > 190 mg/dl were on lipid lowering medicinal products. Of the 32 patients who had a liver biopsy at study entry, 100% had fibrosis and 31% had cirrhosis. The age range of patients with biopsy evidence of cirrhosis was 4-21 years old.

The following endpoints were assessed: normalisation of ALT, decrease in LDL-cholesterol, decrease in non-HDL-cholesterol, normalisation of AST, decrease in triglycerides, increase in HDL-cholesterol, decrease in liver fat content assessed by multi-echo gradient echo magnetic resonance imaging (MEGE-MRI), and improvement in hepatic steatosis measured by morphometry.

A statistically significant improvement in multiple endpoints was observed in the sebelipase alfa-treated group as compared to the placebo group at the completion of the 20-week double-blind period of the study, as shown in Table 3. The absolute reduction in mean ALT level was -57.9 U/l (-53%) in the sebelipase alfa-treated group and -6.7 U/l (-6%) in the placebo group.

^a Proportion of patients who achieved normalisation defined as 34 or 43 U/l, depending on age and gender.

^b Proportion of patients who achieved normalisation defined as 34-59 U/l, depending on age and gender. eva luated in patients with abnormal baseline values (n = 36 for KANUMA; n = 29 for placebo).

^c eva luated in patients with MEGE-MRI assessments performed (n = 32 for KANUMA; n = 25 for placebo).

^d P-values are from Fisher's exact test for normalisation endpoints and Wilcoxon rank-sum test for all other endpoints.

Paired liver biopsies at baseline and week 20 were available in a subset of patients (n = 26). Of patients with paired liver biopsies, 63% (10/16) of KANUMA-treated patients had improvement in hepatic steatosis (at least ≥ 5% reduction) as measured by morphometry compared to 40% (4/10) of placebo patients. This difference was not statistically significant.

Open-label period

Sixty-five of 66 patients entered the open-label period (up to 130 weeks) at a KANUMA dose of 1 mg/kg once every other week. In patients who had received KANUMA during the double-blind period, reductions in ALT levels during the first 20 weeks of treatment were maintained and further improvements were seen in lipid parameters including LDL-cholesterol and HDL-cholesterol levels. Four (4) of 65 patients in the open label period were dose escalated to 3 mg/kg once every other week based on clinical response.

Placebo patients had persistently elevated serum transaminase and abnormal serum lipid levels during the double-blind period. Consistent with what was observed in KANUMA-treated patients during the double-blind period, initiation of treatment with KANUMA during the open-label period produced rapid improvements in ALT levels and in lipid parameters including LDL-cholesterol and HDL-cholesterol levels.

In a separate open-label study (LAL-CL01/LAL-CL04) in adult patients with LAL deficiency, improvements in serum transaminase and lipid levels were sustained through the 104-week treatment period.

Paediatric population

Fifty-six of 84 patients (67%) who received sebelipase alfa during clinical studies (LAL-CL01/LAL-CL04, LAL-CL02 and LAL-CL03) were in the paediatric and adolescent age range (1 month up to 18 years).

The European Medicines Agency has deferred the obligation to submit the results of studies with KANUMA in one or more subsets of the paediatric population in LAL deficiency (see section 4.2 for information on paediatric use).

LAL deficiency registry

Medical or healthcare professionals are encouraged to participate and enrol all patients diagnosed with LAL deficiency in the LAL deficiency registry.

Children and adults

The pharmacokinetics of sebelipase alfa in children and adults were determined using a population pharmacokinetic analysis of 65 patients with LAL deficiency who received intravenous infusions of KANUMA at 1 mg/kg once every other week in LAL-CL02. Twenty-four patients were aged 4-11 years, 23 were aged 12-17 years, and 18 were aged ≥ 18 years (Table 4). Based on a non-compartmental analysis of data from adults (LAL-CL01/LAL-CL-04), the pharmacokinetics of sebelipase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure observed between the 1 and 3 mg/kg dosages. No accumulation was seen at 1 mg/kg (once weekly or once every other week) or 3 mg/kg once weekly.

Table 4: Mean Population Pharmacokinetic Parameters

^* Week 22 for placebo patients reset to Week 0, i.e. first week of active treatment^.

AUC_ss = Area under the plasma concentration time curve at steady-state

C_max = Maximum concentration

T_max = Time to maximum concentration

CL = Clearance

V_c = Central volume of distribution

T_1/2 = Half-life

Infants (< 6 months of age)

In LAL-CL03, sebelipase alfa was eliminated from the systemic circulation with a median T_1/2 of 0.1 hr (range: 0.1-0.2) at the 3 mg/kg once weekly dose (n = 4). The difference in exposures to sebelipase alfa between the once weekly 0.35 mg/kg and 3 mg/kg groups was more than dose proportional, with a 8.6-fold increase in dose resulting in a 9.6-fold increase in exposure for AUC and a 10.0-fold increase for C_max.

Linearity/non-linearity

Based on these data, the pharmacokinetics of sebelipase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure observed between the 1 and 3 mg/kg dose.

Special populations

During the covariate analysis of the population pharmacokinetics model for sebelipase alfa, age, body weight, and sex were not found to have a significant influence on CL and V_c of sebelipase alfa. Sebelipase alfa has not been investigated in patients 2 to 4 years of age or patients aged 65 years or older.

There is limited information of sebelipase alfa pharmacokinetics in non-Caucasian ethnic groups.

Sebelipase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of sebelipase alfa. There is a lack of data in patients with severe hepatic impairment.

Renal elimination of sebelipase alfa is considered a minor pathway for clearance. There is a lack of data in patients with renal impairment.

There is limited information on the impact of anti-drug antibodies on sebelipase alfa pharmacokinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity in rats and monkeys, or fertility, embryo-foetal and peri- and postnatal development in rats and rabbits. Chronic toxicity studies in juvenile cynomolgous monkeys showed no toxicity at doses up to 3 times the recommended dose in infants and 10 times the recommended dose in adults/children. No adverse findings were observed in rat and rabbit embryofoetal development studies at doses up to at least 10 times the adult/children recommended dose and in rat fertility and peri- postnatal development studies at doses up to 10 times the adult/children recommended dose.

Studies to eva luate the mutagenic and carcinogenic potential of sebelipase alfa have not been performed.

Trisodium citrate dihydrate

Citric acid monohydrate

Human serum albumin

Water for injections

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

Unopened vials: 2 years.

After dilution: Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2°C to 8°C, or up to 12 hours below 25°C.

From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, or up to 12 hours below 25°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Clear glass vial (Type I) with a siliconised butyl rubber stopper, and an aluminium seal with a plastic flip-off cap, containing 10 ml of concentrate.

Pack size: 1 vial

Each vial of KANUMA is intended for single use only. KANUMA has to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique.

The diluted solution should be administered to patients using a low-protein binding infusion set equipped with an in-line, low-protein binding 0.2 μm filter, with a surface area of greater than 4.5 cm² as available in order to avoid filter occlusion.

Preparation of the sebelipase alfa infusion

KANUMA should be prepared and used according to the following steps. Aseptic technique should be used.

a. The number of vials to be diluted for infusion should be determined based on the patient's weight and prescribed dose.

b. It is recommended to allow KANUMA vials to reach a temperature between 15°C and 25°C prior to reconstitution to minimize the potential for the formation of sebelipase alfa protein particles in solution. The vials should not be left outside the refrigerator longer than 24 hours prior to dilution for infusion. The vials should not be frozen, heated or microwaved and should be protected from light.

c. The vials should not be shaken. Prior to dilution, the solution in the vials should be inspected visually; the solution should be clear to slightly opalescent, colourless to slightly coloured (yellow). Due to the proteinaceous nature of the product, slight flocculation (e.g., thin translucent fibres) may be present in the vialed solution and is acceptable for use.

d. Do not use if the solution is cloudy, or if foreign particulate matter is present.

e. Up to 10 ml of solution should be slowly withdrawn from each vial and diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion. See Table 5 for recommended total infusion volumes by weight range. The solution should be mixed gently, and not be shaken.

Table 5: Recommended infusion volumes (1 mg/kg dose)*

* The infusion volume should be based on the prescribed dose and should be prepared to a final sebelipase alfa concentration of 0.1-1.5 mg/ml.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Alexion Europe SAS

1-15, avenue Edouard Belin

92500 Rueil-Malmaison

France

EU/1/15/1033/001

28 August 2015

05/10/2015

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.