VIMIZIM 1mg / ml concentrate for solution for infusion medication leaflet

Vimizim 1 mg/ml concentrate for solution for infusion

Each ml of solution contains 1 mg elosulfase alfa*. Each vial of 5 ml contains 5 mg elosulfase alfa.

*Elosulfase alfa is a recombinant form of human N-acetylgalactosamine-6-sulfatase (rhGALNS) andis produced in Chinese Hamster Ovary cell culture by recombinant DNA technology.

Each 5 ml vial contains 8 mg sodium and 100 mg sorbitol (E420).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (Sterile concentrate).

A clear to slightly opalescent and colourless to pale yellow solution.

Vimizim is indicated for the treatment of mucopolysaccharidosis, type IVA (Morquio A Syndrome,

MPS IVA) in patients of all ages.

Treatment should be supervised by a physician experienced in the management of patients with

MPS IVA or other inherited metabolic diseases. Administration of Vimizim should be carried out byan appropriately trained healthcare professional with the ability to manage medical emergencies.

Home administration under the supervision of an appropriately trained healthcare professional may beconsidered for patients who are tolerating their infusions well.

The recommended dose of elosulfase alfa is 2 mg/kg of body weight administered once a week. Thetotal volume of the infusion should be delivered over approximately 4 hours (see Table 1).

Because of the potential for hypersensitivity reactions with elosulfase alfa, patients should receiveantihistamines with or without antipyretics 30 to 60 minutes prior to start of infusion (see section 4.4).

Elderly patients (≥ 65 years old)

The safety and efficacy of Vimizim in patients older than 65 years has not been established, and noalternative treatment regimen can be recommended in these patients. It is not known whether elderlypatients respond differently from younger patients.

The posology in the paediatric population is the same as in adults. Currently available data aredescribed in section 4.8 and section 5.1.

For intravenous infusion only.

Patients weighing less than 25 kg should receive a total volume of 100 ml. When diluted in 100 ml, theinitial infusion rate should be 3 ml/hr. The infusion rate may be increased as tolerated, every15 minutes as follows: first increase the rate to 6 ml/hr, then increase the rate every 15 minutes by6 ml/hr increments until a maximum rate of 36 ml/hr is reached.

Patients weighing 25 kg or more should receive a total volume of 250 ml. When diluted in 250 ml, theinitial infusion rate should be 6 ml/hr. The infusion rate may be increased as tolerated, every15 minutes as follows: first increase the rate to 12 ml/hr, then increase the rate every 15 minutes by12 ml/hr increments until a maximum rate of 72 ml/hr is reached.

Table 1: Recommended infusion volumes and rates*

Patient Total Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7weight infusion Initial 15-30 30-45 45-60 60-75 75-90 90+(kg) volume infusion minutes minutes minutes minutes minutes minutes(ml) rate 0-15 (ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr)minutes(ml/hr)< 25 100 3 6 12 18 24 30 36≥ 25 250 6 12 24 36 48 60 72

* Infusion rate may be increased as tolerated by patient.

For instructions for dilution of the medicinal product prior to administration, see section 6.6.

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of theexcipients listed in section 6.1 (see section 4.4).

Anaphylaxis and severe allergic reactions

Anaphylaxis and severe allergic reactions have been reported in clinical studies. Therefore, appropriatemedical support must be readily available when elosulfase alfa is administered. If these reactionsoccur, immediately stop the infusion and initiate appropriate medical treatment. The current medicalstandards for emergency treatment are to be followed. For patients who have experienced allergicreactions during infusion, caution should be exercised upon re-administration.

Infusion reactions

Infusion reactions (IRs) were the most commonly observed adverse reactions in clinical studies. IRsmay include allergic reactions. Patients should receive antihistamines with or without antipyreticsprior to infusion (see section 4.2). Management of IRs should be based on the severity of the reactionand include slowing or temporary interruption of the infusion and/or administration of additionalantihistamines, antipyretics, and/or corticosteroids. If severe IRs occur, immediately stop the infusionand initiate appropriate treatment. Re-administration after a severe reaction should be carried out withcaution and close monitoring by the treating physician.

Spinal/Cervical cord compression

In clinical studies, spinal/cervical cord compression (SCC) was observed both in patients receiving

Vimizim and patients receiving placebo. Patients should be monitored for signs and symptoms of SCC(including back pain, paralysis of limbs below the level of compression, urinary and faecalincontinence) and given appropriate clinical care.

Sodium restricted diet

This medicinal product contains 8 mg sodium per vial, equivalent to 0.4% of the WHO recommendedmaximum daily intake of 2 g sodium for an adult, and is administered in sodium chloride 9 mg/ml(0.9%) solution for infusion (see section 6.6).

This medicinal product contains 100 mg sorbitol in each vial which is equivalent to 40 mg/kg.

Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unlessstrictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructoseintolerance (HFI). Medicinal products containing sorbitol/fructose given intravenously may be life-threatening. The treatment benefit to the child compared to the associated risks must be fully evaluatedprior to treatment.

A detailed history with regard to HFI symptoms has to be taken for each patient prior to being giventhis medicinal product.

No interaction studies have been performed.

There are no data on the use of Vimizim in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see section 5.3). These studies however, are of limited relevance. As aprecautionary measure, it is preferable to avoid the use of Vimizim during pregnancy, unless clearlynecessary.

Available reproductive data in animals have shown excretion of elosulfase alfa in milk. It is not knownwhether elosulfase alfa is excreted in human breast milk, but systemic exposure via breast milk is notexpected. Due to lack of human data, Vimizim should only be administered to breast-feeding womanif the potential benefit is considered to outweigh the potential risk to the infant.

No impairment of fertility has been observed in nonclinical studies (see section 5.3) with elosulfasealfa.

Vimizim has minor influence on the ability to drive and use machines. Dizziness was reported during

Vimizim infusions; if dizziness occurs after the infusion, the ability to drive and use machines may beaffected.

The assessment of adverse reactions is based on the exposure of 176 patients with MPS IVA, ages 5 to57 years old to 2 mg/kg elosulfase alfa once a week (n=58), 2 mg/kg elosulfase alfa once every otherweek (n=59), or placebo (n=59) in a randomised, double-blind, placebo-controlled study.

The majority of adverse reactions in clinical studies were IRs, which are defined as reactions occurringafter initiation of infusion until the end of the day following the infusion. Serious IRs were observed inclinical studies and included anaphylaxis, hypersensitivity and vomiting. The most common symptomsof IRs (occurring in ≥ 10% of patients treated with Vimizim and ≥ 5% more when compared toplacebo) were headache, nausea, vomiting, pyrexia, chills and abdominal pain. IRs were generallymild or moderate, and the frequency was higher during the first 12 weeks of treatment and tended tooccur less frequently with time.

The data in Table 2 below describes adverse reactions from clinical studies in patients treated with

Vimizim.

Frequencies are defined as: 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 beestimated from available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 2: Adverse reactions in patients treated with Vimizim

MedDRA MedDRA Frequency

System organ class Preferred term

Immune system disorders Anaphylaxis Uncommon

Hypersensitivity Common

Nervous system disorders Headache Very common

Dizziness Very common

Respiratory, thoracic, and Dyspnoea Very commonmediastinal disorders

Gastrointestinal disorders Diarrhoea, vomiting, Very commonoropharyngeal pain, upperabdominal pain, abdominal pain,nausea

Musculoskeletal and connective Myalgia Commontissue disorders Chills Very common

General disorders and Pyrexia Very commonadministration site conditions

All patients developed antibodies to elosulfase alfa in clinical studies. Approximately 80% of patientsdeveloped neutralizing antibodies capable of inhibiting the elosulfase alfa from binding to the cation-independent mannose-6-phosphate receptor. Sustained improvements in efficacy measures andreductions in urine keratan sulphate (KS) over time were observed across studies, despite the presenceof anti elosulfase alfa antibodies. No correlations were found between higher antibody titres orneutralizing antibody positivity and reductions in efficacy measurements or occurrence of anaphylaxisor other hypersensitivity reactions. IgE antibodies against elosulfase alfa were detected in ≤ 10% oftreated patients and have not consistently been related to anaphylaxis or other hypersensitivityreactions and/or treatment withdrawal.

In patients < 5 years of age, the overall safety profile of Vimizim at 2 mg/kg/week was consistent withthe safety profile of Vimizim observed in older children.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, doses of elosulfase alfa were explored up to 4 mg/kg per week and no specific signsor symptoms were identified following the higher doses. No differences in the safety profile wereobserved. For management of adverse reactions, see sections 4.4 and 4.8.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code:

A16AB12.

Mucopolysaccharidoses comprises a group of lysosomal storage disorders caused by the deficiency ofspecific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). MPS IVA ischaracterised by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. Thesulfatase activity deficiency results in the accumulation of the GAG substrates, KS and chondroitin 6sulphate (C6S), in the lysosomal compartment of cells throughout the body. The accumulation leads towidespread cellular, tissue, and organ dysfunction. Elosulfase alfa is intended to provide theexogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes andincrease the catabolism of the GAGs KS and C6S. Enzyme uptake by cells into lysosomes is mediatedby cation independent mannose-6-phosphate receptors leading to restored GALNS activity andclearance of KS and C6S.

Clinical studies performed with Vimizim assessed the impact of treatment on the systemicmanifestations of MPS IVA in various domains including endurance, respiratory function, growthvelocity, and mobility, as well as urine KS.

A total of 235 patients with MPS IVA were enrolled and exposed to Vimizim in six clinical studies.

The safety and efficacy of Vimizim was assessed in a randomised, double-blind, placebo-controlled,

Phase 3 clinical study of 176 patients with MPS IVA, ranging in age from 5 to 57 years. The majorityof the patients presented with short stature, impaired endurance, and musculoskeletal symptoms.

Patients who could walk more than 30 meters (m) but less than 325 m in a 6 Minute Walk Test(MWT) at baseline were enrolled in the study.

Patients received elosulfase alfa 2 mg/kg every week (n=58) or 2 mg/kg every other week (n=59), orplacebo (n=59) for a total of 24 weeks. All patients were treated with antihistamines prior to eachinfusion. The primary endpoint was the change from baseline in the 6 MWT distance compared toplacebo at Week 24. The secondary endpoints were the change from baseline in the 3 Minute Stair

Climb Test (MSCT) and urine KS levels at Week 24. A total of 173 patients subsequently enrolled inan extension study in which patients received 2 mg/kg of elosulfase alfa every week or 2 mg/kg everyother week, and then all were switched to 2 mg/kg every week upon availability of the Week 24results.

The primary and secondary endpoints were evaluated at Week 24 (see Table 3). The modelledtreatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9;p=0.0174) for the 2 mg/kg per week regimen. The modelled treatment effect in stairs climbed perminute, compared to placebo, was 1.1 stairs/minute (CI95, -2.1, pct. 4.4; p=0.4935) for the 2 mg/kg perweek regimen. The modelled treatment effect for the percent change in urine KS, compared toplacebo, was -40.7 % (CI95, -49.0, -32.4; p<0.0001) for the 2 mg/kg per week regimen. The differencewas greatest between the placebo group and the weekly treatment group for all endpoints. The resultsfrom the every other week regimen in the distance walked in 6 minutes or in stairs climbed per minutewere comparable to placebo.

Table 3: Results from placebo-controlled clinical study at 2 mg per kg per week

Vimizim Placebo Vimizim vs.placebo

Baselin Week Chang Baselin Week 24 Changee 24 e e Difference in

N 58 57* 57 59 59 59 changes6-Minute walk test (meters)

Mean 203.9 243.3 36.5 211.9 225.4 13.5±76.32 ±83.53 ±58.49 ±69.88 ±83.22 ±50.63

SD

Model-based mean‡ 22.5(95%CI) (CI95, 4.0, 40.9)p-value (p = 0.0174)3-Minute stair climb test (stairs/minute)

Mean 29.6 34.9 4.8 30.0 33.6 3.6±16.44 ± 18.39 ± 8.06 ± 14.05 ± 18.36 ± 8.51

SD

Model-based mean‡ 1.1(95%CI) (CI95, -2.1, pct. 4.4)p-value (p = 0.4935)

* One patient in the Vimizim group dropped out after 1 infusion‡ Model-based mean of Vimizim versus placebo, adjusted for baseline

In additional extension studies, patients receiving elosulfase alfa 2 mg/kg every week, showedmaintenance of initial improvement in endurance and sustained reduction of urinary KS up to156 weeks.

It is important to initiate treatment as early as possible.

The majority of patients who received Vimizim during clinical studies were in the paediatric andadolescent age range (5 to 17 years). In an open-label study, 15 paediatric patients with MPS IVAunder the age of 5 years (9 months to <5 years) received 2 mg/kg of Vimizim once a week for52 weeks. Patients continued a long-term follow-up observational study for at least another 52 weeks,for a total of 104 weeks. Safety and pharmacodynamic results in these patients are consistent withresults observed in the first 52 weeks (see section 4.8). The baseline mean (±SD) normalised standingheight z-score was - 1.6 (±1.61). After the first 52 weeks of treatment the normalised standing heightz-score was -1.9 (±1.62). At Week 104 mean (±SD) normalised standing height z-score was -3.1 (±1.13).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Vimizim in one or more subsets of the paediatric population in MPS IVA. See section 4.2 forinformation on paediatric use.

The pharmacokinetic parameters of elosulfase alfa were evaluated in 23 patients with MPS IVA whoreceived weekly intravenous infusions of 2 mg/kg of elosulfase alfa over approximately 4 hours for22 weeks and the parameters at Week 0 and Week 22 were compared. At Week 22, the mean AUC0-tand Cmax increased by 181% and 192%, respectively, when compared to Week 0

Table 4: Pharmacokinetic properties

Week 0 Week 22

Pharmacokinetic parameter Mean (SD) Mean (SD)

AUC0-t, minute * µg/ml* 238 (100) 577 (416)

Cmax, µg/ml† 1.49 (0.534) 4.04 (3.24)

CL, ml/minute/kg‡ 10.0 (3.73) 7.08 (13.0)t1/2, minute§ 7.52 (5.48) 35.9 (21.5)

T , minute¶max 172 (75.3) 202 ( 90.8)

* AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurableconcentration;† Cmax, observed maximum plasma concentration;‡ CL, total clearance of elosulfase alfa after intravenous administration;§ t1/2, elimination half-life;¶ Tmax, time from zero to maximum plasma concentration

Elosulfase 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 elosulfase alfa.

Renal elimination of elosulfase alfa is considered a minor pathway for clearance. Mean half-life (t1/2)increased from 7.52 minutes at Week 0 to 35.9 minutes at Week 22. Male and female patients hadcomparable elosulfase alfa clearance, and clearance did not trend with age or weight at week 22.

Impact of antibodies on elosulfase alfa pharmacokinetics was assessed. No association was apparentbetween the total antibody titre and elosulfase clearance. However, patients with positive neutralizingantibodies responses had decreased total clearance (CL) values and prolonged t1/2. Despite thealteration of the pharmacokinetics profile, presence of neutralizing antibodies did not affectpharmacodynamics, efficacy, or safety of the patients who were treated with elosulfase alfa. Noaccumulation of elosulfase alfa in plasma was evident following weekly dosing

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology evaluating central nervous, respiratory and cardiovascular systems, single-dose andrepeated-dose toxicity in rats and monkeys or fertility and embryo-foetal development in rats orrabbits. The evaluation of the peri- and postnatal development study in rats is hampered due tosubsequent administration of DPH, and therefore of limited relevance.

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenicpotential have not been performed with elosulfase alfa. Reproduction studies have been performed inrats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility orreproductive performance.

Sodium acetate trihydrate

Sodium dihydrogen phosphate monohydrate

Arginine hydrochloride

Polysorbate 20

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years

Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2°C - 8°C followedby up to 24 hours at 23°C - 27°C.

From a microbiological safety point of view, the diluted solution should be used immediately. If notused immediately, in-use storage times and conditions are the responsibility of the user and shouldnormally not be longer than 24 hours at 2°C - 8°C followed by up to 24 hours at 23°C - 27°C duringadministration.

Store in a refrigerator (2°C - 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 butyl rubber stopper and a flip-off crimp seal (aluminium) with aplastic cap.

Pack sizes: 1 vial

Each vial of Vimizim is intended for single use only. Vimizim has to be diluted with sodium chloride9 mg/ml (0.9 %) solution for infusion using aseptic technique. The diluted solution is administered topatients using an infusion set. An infusion set equipped with an in-line 0.2 μm filter can be used.

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

Preparation of the Vimizim infusion

Aseptic technique is to be used.

Vimizim must be diluted prior to administration.

The number of vials to be diluted is based on the individual patient's weight. The recommended dose is2 mg per kg.

1. The number of vials to be diluted based on the individual patient’s weight and therecommended dose of 2 mg/kg is determined, using the following calculation:

- Patient weight (kg) multiplied by 2 (mg/kg) = Patient dose (mg)

- Patient dose (mg) divided by 1 (mg/ml concentrate of Vimizim) = Total number of ml of

Vimizim

- Total amount (ml) Vimizim divided by 5 ml per vial = Total number of vials2. The calculated total number of vials is rounded up to the next whole vial. The appropriatenumber of vials is removed from the refrigerator. Do not heat or microwave vials. Do notshake vials.

3. An infusion bag containing sodium chloride 9 mg/ml (0.9 %) solution for infusion is obtainedsuitable for intravenous administration. The total volume of the infusion is determined by thepatient’s body weight.

- Patients weighing less than 25 kg should receive a total volume of 100 ml.

- Patients weighing 25 kg or more should receive a total volume of 250 ml.

4. Before withdrawing Vimizim from the vial, each vial is visually inspected for particulatematter and discoloration. Because this is a protein solution, slight flocculation (thin translucentfibres) may occur. The Vimizim solution should be clear to slightly opalescent and colourlessto pale yellow. Do not use if the solution is discoloured or if there is particulate matter in thesolution.

5. A volume of the sodium chloride 9 mg/ml (0.9 %) solution for infusion is to be withdrawn anddiscarded from the infusion bag, equal to the volume of Vimizim concentrate to be added.

6. The calculated volume of Vimizim from the appropriate number of vials is slowly withdrawnusing caution to avoid excessive agitation.

7. Vimizim is slowly added to the infusion bag using care to avoid agitation.8. The infusion bag is gently rotated to ensure proper distribution of Vimizim. Do not shake thesolution.9. The diluted solution is administered to patients using an infusion set. An infusion set equippedwith an in-line 0.2µm filter can be used.

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork, P43 R298

Ireland

EU/1/14/914/001

Date of first authorisation: 28 April 2014

Date of last renewal:

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.