NAGLAZYME 1mg / ml perfusive solution concentrate medication leaflet

Naglazyme 1 mg/ml concentrate for solution for infusion

Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase.

Galsulfase is a recombinant form of human N-acetylgalactosamine 4-sulfatase and is produced byrecombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion.

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

Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmeddiagnosis of Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-sulfatase deficiency;

Maroteaux-Lamy syndrome) (see section 5.1).

As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, toinitiate treatment as early as possible, before appearance of non-reversible clinical manifestations ofthe disease.

Naglazyme treatment should be supervised by a physician experienced in the management of patientswith MPS VI or other inherited metabolic diseases. Administration of Naglazyme should be carriedout in an appropriate clinical setting where resuscitation equipment to manage medical emergencieswould be readily available.

The recommended dose regimen for galsulfase is 1 mg/kg body weight administered once every weekas an intravenous infusion over 4 hours.

The safety and efficacy of Naglazyme in patients older than 65 years has not been established, and noalternative dose regimen can be recommended in these patients.

The safety and efficacy of Naglazyme in patients with renal or hepatic insufficiency have not beenevaluated (see section 5.2) and no alternative dose regimen can be recommended in these patients.

There is no evidence for special considerations when Naglazyme is administered to the paediatricpopulation. Currently available data are described in section 5.1.

The initial infusion rate is adjusted so that approximately 2.5% of the total solution is infused duringthe first hour, with infusion of the remaining volume (approximately 97.5%) over the next 3 hours.

100 ml infusion bags should be considered for patients who are susceptible to fluid volume overloadand weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the totalduration remains no less than 4 hours.

For information on pre-treatment see section 4.4 and for further instructions see section 6.6.

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, ifhypersensitivity is not controllable.

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

Management of compromised airways

Caution must be exercised in the management and treatment of patients with compromised airways bylimitation or careful monitoring of antihistamine and other sedative medicinal product use. Institutionof positive-airway pressure during sleep as well as potential tracheostomy in clinically appropriatesituations should also be considered.

Patients who present with an acute febrile or respiratory illness may need to have their Naglazymeinfusions delayed.

Management of infusion-associated reactions

Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as anyadverse reactions occurring during the infusion or until the end of the infusion day (see section 4.8).

Based on data obtained during Naglazyme clinical trials, the majority of patients are expected todevelop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation.

In the Naglazyme clinical trials, IARs were usually manageable by interrupting or slowing the rate ofinfusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thusenabling the patient to continue treatment.

As there is little experience on resumption of treatment following prolonged interruption, caution is tobe used due to the theoretical increased risk of hypersensitivity reaction.

With administration of Naglazyme it is recommended that patients be administered pre-treatmentmedicinal products (antihistamines with or without antipyretics) approximately 30-60 minutes prior tothe start of the infusion, to minimise the potential occurrence of IARs.

In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should beconsidered and/or a reduction in the infusion rate to half the rate at which the reaction occurred.

In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved andtreatment with antihistamines and paracetamol should be considered. The infusion can be restartedwith a reduction of the infusion rate to 50% - 25% of the rate at which the reaction occurred.

In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should beconsidered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rateto 50% - 25% of the rate at which the previous reaction occurred.

As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions arepossible. If these reactions occur, immediate discontinuation of Naglazyme is recommended andappropriate medical treatment should be initiated. The current medical standards for emergencytreatment are to be observed. In patients who have experienced allergic reactions during infusion with

Naglazyme, caution should be exercised upon rechallenge; appropriately trained personnel andequipment for emergency resuscitation (including epinephrine) should be available during infusions.

Severe, or potentially life-threatening hypersensitivity is a contraindication to rechallenge, ifhypersensitivity is not controllable. See also section 4.3.

Spinal or cervical cord compression

Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and seriouscomplication that can be due to MPS VI. There have been post-marketing reports of patients treatedwith Naglazyme who experienced the onset or worsening of SCC requiring decompression surgery.

Patients should be monitored for signs and symptoms of spinal/cervical cord compression (includingback pain, paralysis of limbs below the level of compression, urinary and faecal incontinence) andgiven appropriate clinical care.

Risk of Acute Cardio-respiratory Failure

Caution should be exercised when administering Naglazyme to patients susceptible to fluid volumeoverload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness,or patients with compromised cardiac and/or respiratory function, because congestive heart failuremay occur. Appropriate medical support and monitoring measures should be readily available during

Naglazyme infusion, and some patients may require prolonged observation times that should be basedon the individual needs of the patient (see section 4.2).

Immune-mediated Reactions

Type III immune complex-mediated reactions including membranous glomerulonephritis have beenobserved with Naglazyme. If immune-mediated reactions occur, discontinuation of the administrationof Naglazyme should be considered, and appropriate medical treatment initiated. The risks andbenefits of re-administering Naglazyme following an immune-mediated reaction should be considered(see section 4.2).

Sodium restricted diet

This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodiumchloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients ona controlled sodium diet.

No interaction studies have been performed.

For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy or embryo-foetal development (seesection 5.3). Naglazyme should not be used during pregnancy unless clearly necessary.

It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stoppedduring Naglazyme treatment.

Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and haverevealed no evidence of impaired fertility or harm to the embryo or foetus due to Naglazyme.

No studies on the effects on the ability to drive and use machines have been performed.

Due to the low number of patients in clinical trials, adverse event (AE) data from all Naglazymestudies have been pooled and reviewed in a single, clinical trial safety analysis.

All patients treated with NAGLAZYME (59/59) reported at least one AE. The majority (42/59; 71%)of patients experienced at least one Adverse Drug Reaction. The most common adverse reactions werepyrexia, rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting anddypsnoea. Serious adverse reactions included laryngeal edema, apnoea, pyrexia, urticaria, respiratorydistress, angioedema, asthma and anaphylactoid reaction.

Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions or until the endof the infusion day, were observed in 33 (56%) of the 59 patients treated with Naglazyme across fiveclinical studies. Infusion reactions began as early as Week 1 and as late as Week 146 of Naglazymetreatment, and occurred during multiple infusions though not always in consecutive weeks. Verycommon symptoms of these infusion reactions were pyrexia, chills/rigors, rash, urticaria anddyspnoea. Common symptoms of infusion reactions were pruritus, vomiting, abdominal pain, nausea,hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress,tremor, conjunctivitis, malaise, bronchospasm and arthralgia.

Adverse reactions are listed in Table 1 by System Organ Class.

The reactions are listed following the MedDRA frequency convention. Very common adversereactions are those with a frequency of 1/10. Common reactions have a frequency of 1/100 to<1/10. Due to the small patient population, an adverse reaction in a single patient is classified ascommon.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported during the Post Marketing period are included at a frequency category of“unknown”.

Overall, one case of sleep apnoea was experienced from all clinical studies.

Table 1: Frequency of adverse drug reactions with Naglazyme

MedDRA MedDRA Frequency

System Organ Class Preferred Term

Immune system disorders Anaphylaxis, shock Unknown

Infections and infestations Pharyngitis1, gastroenteritis1 Very common

Nervous system disorders Areflexia1, headache Very common

Tremor Common

Paresthesia Unknown

Eye disorders Conjunctivitis1, corneal opacity1 Very common

Cardiac disorders Bradycardia, tachycardia, cyanosis Unknown

Ear and labyrinth disorders Ear pain1, hearing impaired1 Very common

Vascular disorders Hypertension1 Very common

Hypotension Common

Pallor Unknown

Respiratory, thoracic, and mediastinal Dyspnoea1, nasal congestion1 Very commondisorders

Apnoea1, cough, respiratory distress, Commonasthma, bronchospasm

Laryngeal oedema, hypoxia, Unknowntachypnoea

Gastrointestinal disorders Abdominal pain1, umbilical hernia1, Very commonvomiting, nausea

Skin and subcutaneous tissue Angioeodema1, rash1, urticaria, pruritus Very Commondisorders Erythema Common

General disorders and administration Pain1, chest pain1, rigors1, malaise1, Very Commonsite conditions pyrexia

Musculoskeletal and Connective Arthralgia Very common

Tissue Disorders1Reactions reported more frequently in the active arm of the placebo-controlled study than the placeboarm; frequency determined from 39 patients of the blinded Phase 3 study.

Other reactions with known frequency were reported from 59 patients treated with Naglazyme from allfive clinical trials.

Reactions of unknown frequency were reported post-marketing.

In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differin a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and wasconsistent with the safety profile of Naglazyme in older children.

Out of the 59 patients treated with Naglazyme in the clinical studies, 54 were tested for IgGantibodies. 53/54 patients (98%) were positive for IgG antibodies to galsulfase.

A comprehensive antibody analysis based on data from three clinical studies has been carried out in48 patients.

Although a larger proportion of subjects with high total antibody titres experienced recurrent infusionreactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre.

Likewise, antibody development is not predictive of decreased efficacy although subjects with limitedresponse in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peakanti-galsulfase titres than those with good response.

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.

Several patients have received their total dose of Naglazyme at approximately twice the recommendedinfusion rate without apparent adverse events.

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

A16AB08

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymesrequired for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous andmultisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, alysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan,dermatan sulfate. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in theaccumulation of dermatan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient tohydrolyze the accumulated substrate and to prevent further accumulation.

Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoproteinwith a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids aftercleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites.

After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cellsinto lysosomes, most likely via mannose-6 phosphate receptors.

The three clinical studies performed with Naglazyme focused on assessing the systemic manifestationsof MPS VI such as endurance, joint mobility, joint pain and stiffness, upper airway obstruction,manual dexterity and visual acuity.

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

Phase 3 study of 39 MPS VI patients, ranging in age from 5 to 29 years. The majority of the patientspresented with short stature, impaired endurance, and musculoskeletal symptoms. Patients who couldwalk more than 5 meters (m) but less than 250 m in 6 minutes of a 12 Minute Walk test or less than400 m at the 12 minute time point at baseline were enrolled in the study.

Patients received either 1 mg/kg of galsulfase or placebo every week for a total of 24 weeks. Theprimary efficacy endpoint was the numbers of meters walked in 12 minutes at Week 24 compared tothe number of meters walked at baseline. The secondary efficacy endpoints were the rate of stairsclimbed in three minutes and the urinary glycosaminoglycan excretion of treated patients compared toplacebo at Week 24. Thirty-eight patients subsequently enrolled in an Open Label extension studywhere they received 1 mg/kg of galsulfase every week.

Following 24 weeks of therapy, Naglazyme-treated patients experienced a 92 ± 40 m improvement inthe distance walked in 12 minutes relative to placebo-treated patients (p = 0.025). Treated patientsexperienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treatedpatients. Treated patients also experienced a mean decrease in urinary glycosaminoglycan excretion of238 ± 17.8 μg/mg creatinine ( Standard Error [SE]) following 24 weeks of treatment relative toplacebo-treated patients. GAG results approached the normal range for age in the Naglazymetreatment group.

In an additional Phase 4, randomised, two-dose level study, four MPS VI patients <1 year of age weretreated at 1 or 2 mg/kg/week for 53 to 153 weeks.

Although limited by the very small number of patients that were enrolled, the conclusions that can bedrawn from this study are the following:

Treatment with Naglazyme showed improvement, or lack of worsening, of facial dysmorphism. It didnot prevent the progression of skeletal dysplasia and development of hernias and did not prevent theprogression of corneal clouding. Growth rate remained normal over this limited follow-up period.

Improved hearing was noted in at least one ear for all four subjects. Urinary GAG levels decreased bymore than 70%, consistent with results in older patients.

The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kgof galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean ( Standard Deviation [SD])maximum plasma concentration (Cmax) was 2,357 (± 1,560) ng/ml and the mean ( SD) area under theplasma concentration-time curve (AUC0-t) was 5,860 ( 4,184) h  ng/ml. The mean ( SD) volume ofdistribution (Vz) was 316 ( 752) ml/kg and the mean ( SD) plasma clearance (CL) was7.9 ( 14.7) ml/min/kg. The mean ( SD) elimination half-life (t1/2) was 22.8 ( 10.7) minutes at

Week 24.

Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through atleast 194 weeks).

Galsulfase 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 galsulfase in aclinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance(see section 4.2).

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, single-dose toxicity, repeated-dose toxicity or on general reproductive performance orembryo-foetal development in rats or rabbits. Peri- and post-natal toxicity has not been investigated.

Genotoxic and carcinogenic potential are not expected.

The cause of clinical relevance of the hepatic toxicity (bile duct hyperplasia/periportal inflammation)seen at clinically relevant doses in the repeated dose monkey toxicity study is not known.

Sodium chloride

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Polysorbate 80

Water for injections

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

Unopened vials: 3 years.

Diluted solutions: Chemical and physical in-use stability has been demonstrated for up to 4 days atroom temperature (23°C - 27°C).

From a microbiological safety point of view, Naglazyme should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and should normallynot be longer than 24 hours at 2°C - 8°C followed by up to 24 hours at room temperature(23°C - 27°C) during administration.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

Vial (type I glass) with a stopper (siliconized butyl or chlorobutyl rubber) and a seal (aluminium) witha flip- off cap (polypropylene).

Pack sizes: 1 and 6 vials.

Not all package sizes may be marketed.

Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion hasto be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It isrecommended that the diluted Naglazyme solution be administered to patients using an infusion setequipped with a 0.2 µm in-line filter.

Any unused product or waste material is to be disposed of in accordance with local requirements.

Preparation of the Naglazyme infusion (aseptic technique is to be used)

The number of vials to be diluted based on the individual patient's weight must be determined andremoved from the refrigerator approximately 20 minutes in advance in order to allow them to reachroom temperature.

Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear toslightly opalescent and colourless to pale yellow solution must be free of visible particles.

A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn anddiscarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 mlinfusion bags should be considered for patients who are susceptible to fluid volume overload andweigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the totalduration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may beadded directly to the infusion bag.

The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution forinfusion.

The solution is to be mixed gently before infusion.

The solution is to be visually inspected for particulate matter prior to use. Only clear and colourlesssolutions without visible particles should be used.

BioMarin International Limited

Shanbally, Ringaskiddy,

County Cork, P43 R298

Ireland

EU/1/05/324/001

EU/1/05/324/002

Date of first authorisation: 24 January 2006

Date of latest renewal: 26 January 2011

MM/YYYY

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