LAMZEDE 10mg powder infusion solution medication leaflet

Lamzede 10 mg powder for solution for infusion

One vial contains 10 mg of velmanase alfa*.

After reconstitution, one mL of the solution contains 2 mg of velmanase alfa (10 mg/5 mL).

For the full list of excipients, see section 6.1.

*Velmanase alfa is produced in mammalian Chinese Hamster Ovary (CHO) cells using recombinant

DNA technology.

Powder for solution for infusion

White to off-white powder.

Enzyme replacement therapy for the treatment of non-neurological manifestations in patients withmild to moderate alpha-mannosidosis. See sections 4.4 and 5.1.

The treatment should be supervised by a physician experienced in the management of patients withalpha-mannosidosis or in the administration of other enzyme replacement therapies (ERT) forlysosomal storage disorder. Administration of Lamzede should be carried out by a healthcareprofessional with the ability to manage ERT and medical emergencies.

The recommended dose regimen is 1 mg/kg of body weight administered once every week byintravenous infusion at a controlled speed.

The effects of treatment with velmanase alfa should be periodically evaluated and discontinuation oftreatment considered in cases where no clear benefits could be observed.

No data are available and no relevant use in elderly patients is described.

No dose adjustment is necessary for patients with renal or hepatic impairment.

No dose adjustment is necessary for the paediatric population.

For intravenous infusion use only.

Instructions on reconstitution of the medicinal product before administration

The reconstituted solution should be clear. Do not use if opaque particles are observed or if thesolution is discoloured (see section 6.6).

The reconstituted solution of Lamzede should be administered using an infusion set equipped with apump and an in-line low protein-binding 0.22 µm filter. The infusion duration should be calculatedindividually considering a maximum infusion rate of 25 mL/hour to control the protein load. Theinfusion duration should be a minimum of 50 minutes. A slower infusion rate may be prescribed whenclinically appropriate according to the physician’s judgment, for example at the beginning of thetreatment or in case of previous infusion-related reactions (IRRs).

For the calculation of the infusion rate and the infusion time based on body weight see the table insection 6.6.

The patient should be observed for IRRs for at least one hour after the infusion according to clinicalconditions and the physician’s judgment. For further instructions, see section 4.4.

Home infusion

Infusion of Lamzede at home may be considered for patients who are tolerating their infusions well.

The decision to have a patient move to home infusion should be made after evaluation andrecommendation by the treating physician. Patients experiencing infusion-related reactions, includinghypersensitivity reactions or anaphylactic reactions, during the home infusion need to immediatelyreduce the infusion rate or to stop the infusion process considering the severity of the reaction andseek the attention of a healthcare professional. Dose and infusion rate in home setting should remainthe same used in the hospital setting; they could be changed only under the supervision of a healthcareprofessional and treating physician.

Appropriate training should be given by the treating physician and/or nurse to the patient and/orcaregiver prior to initiation of home infusion.

Severe allergic reaction to the active substance or to any of the excipients listed in section 6.1.

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

General consideration on the treatment

As the accumulation of end organ damage progresses over time, it is more difficult for the treatment toreverse the damage or to show improvements. As with other enzyme replacement therapies, velmanasealfa does not cross the blood-brain-barrier. It should be considered by the treating physician that theadministration of velmanase alfa does not affect the irreversible complications (i.e. skeletaldeformities, disostosis multiplex, neurological manifestations and impaired cognitive function).

Hypersensitivity reactions have been reported in patients in clinical studies. Appropriate medicalsupport should be readily available when velmanase alfa is administered. If severe allergic oranaphylactic-type reactions occur, immediate discontinuation of velmanase alfa is recommended andcurrent medical standards for emergency treatment are to be followed.

Infusion-related reaction

Administration of velmanase alfa may result in an IRR, including anaphylactoid reaction (seesection 4.8). The IRRs observed in clinical studies of velmanase alfa were characterised by a rapidonset of symptoms and were of mild to moderate severity.

The management of IRRs should be based on the severity of the reaction and includes slowing theinfusion rate, treatment with medicinal products such as antihistamines, antipyretics and/orcorticosteroids, and/or stopping and resuming treatment with increased infusion time. Pre-treatmentwith antihistamines and/or corticosteroids may prevent subsequent reactions in those cases wheresymptomatic treatment was required. Most of the patients were not routinely pre-medicated prior toinfusion of velmanase alfa during clinical studies.

In case symptoms such as angioedema (tongue or throat swelling), upper airway obstruction orhypotension occur during or immediately after infusion, anaphylaxis or an anaphylactoid reactionshould be suspected. In such a case, treatment with an antihistamine and corticosteroids should beconsidered as being appropriate. In the most severe cases, the current medical standards for emergencytreatment are to be observed.

The patient should be kept under observation for IRRs for one hour or longer after the infusion,according to the treating physician’s judgement.

Antibodies may play a role in treatment-related reactions observed with the use of velmanase alfa. Tofurther evaluate the relationship, in instances of development of severe IRRs or lack or loss oftreatment effect, patients should be tested for the presence of anti-velmanase alfa antibodies. In casethe patient’s condition deteriorates during ERT, cessation of treatment should be considered.

There is a potential for immunogenicity.

In the exploratory and pivotal clinical studies at any time under treatment, 8 patients out of 33 (24%)developed IgG-class antibodies to velmanase alfa.

In a paediatric clinical study in patients below 6 years, 4 patients out of 5 (80%) developed IgG-classantibodies to velmanase alfa. In this study, the immunogenicity test was performed with a differentand more sensitive method and therefore the incidence of patients developing IgG-class antibodies tovelmanase alfa was higher but not comparable to data of the previous studies.

No clear correlation was found between antibody titres (velmanase alfa IgG antibody level) andreduction in efficacy or occurrence of anaphylaxis or other hypersensitivity reactions.

The development of antibodies has not been shown to affect clinical efficacy or safety.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

There are no data from the use of velmanase alfa in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturitionor postnatal development (see section 5.3). As velmanase alfa aims at normalizing alpha-mannosidasein alpha-mannosidosis patients, Lamzede is not recommended to be used during pregnancy unless theclinical condition of the woman requires treatment with velmanase alfa.

It is unknown whether velmanase alfa or its metabolites are excreted in human milk. Nevertheless, theabsorption of any ingested milk-containing velmanase alfa in the breastfed child is considered to beminimal and no untoward effects are therefore anticipated. Lamzede can be used during breastfeeding.

There are no clinical data on the effects of velmanase alfa on fertility. Animal studies do not showevidence of impaired fertility.

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

The most common adverse reactions observed were weight increase (15%), IRRs (13%), diarrhoea(10%), headache (7%), arthralgia (7%), increased appetite (5%) and pain in extremity (5%).

The majority of these adverse reactions were non-serious. IRRs include hypersensitivity in 3 patientsand anaphylactoid reaction in 1 patient. These reactions were mild to moderate in intensity.

A total of 4 serious adverse reactions (loss of consciousness in 1 patient, acute renal failure in1 patient, chills and hyperthermia in 1 patient) were observed. In all cases the patients recoveredwithout sequelae.

The adverse reactions reflecting exposure of 38 patients treated with velmanase alfa in clinical studiesare listed in the table 1 below. Adverse reactions are classified by system organ class and preferredterm according to the MedDRA frequency convention. Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness. Frequency is 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) or not known (cannot be estimated from the available data).

Table 1: Adverse reactions reported from clinical studies, post-authorization safety studies andspontaneous reporting in patients with alpha-mannosidosis treated with velmanase alfa

System organ class Adverse reaction Frequency

Infections and infestations Bacterial disease carrier Not known

Endocarditis Not known

Furuncle Not known

Staphylococcal infection Not known

Immune system disorders Hypersensitivity(1) Common

Anaphylactoid reaction(1) Common

Metabolism and nutrition disorders Increased appetite Common

Decreased appetite Not known

Psychiatric disorders Psychotic behaviour Common

Initial insomnia Common

Agitation Not known

Encopresis Not known

Psychotic disorder Not known

Nervousness Not known

Nervous system disorders Loss of consciousness(2) Common

Tremor Common

Confusional state Common

Syncope Common

Headache Common

Dizziness Common

Ataxia Not known

Nervous system disorder Not known

Somnolence Not known

Eye disorders Eyelid oedema Common

Eye irritation Common

Ocular hyperaemia Common

Lacrimation increased Not known

Ear and labyrinth disorders Deafness Not known

Cardiac disorders Cyanosis(1) Common

Bradycardia Common

Aortic valve incompetence Not known

Palpitations Not known

Tachycardia Not known

Vascular disorders Hypotension Not known

Vascular fragility Not known

Respiratory, thoracic and Epistaxis Commonmediastinal disorders Oropharyngeal pain Not known

Pharyngeal oedema Not known

Wheezing Not known

Gastrointestinal disorders Diarrhoea Very common

Vomiting(1) Common

Abdominal pain upper Common

Nausea(1) Common

Abdominal pain Common

Reflux gastritis Common

Odynophagia Not known

Skin and subcutaneous tissue Urticaria(1) Commondisorders Hyperhidrosis(1) Common

Angioedema Not known

Erythema Not known

Rash Not known

System organ class Adverse reaction Frequency

Musculoskeletal and connective Arthralgia Commontissue disorders Pain in extremity Common

Joint stiffness Common

Myalgia Common

Back pain Common

Joint swelling Not known

Joint warmth Not known

Renal and urinary disorders Renal failure acute(2) Common

General disorder and Pyrexia(1) Very commonadministration site conditions Chills(1) Common

Catheter site pain Common

Feeling hot(1) Common

Fatigue Common

Malaise(1) Common

Asthenia Not known

Investigations Weight increase Very common

Injury, poisoning and procedural Procedural headache Commoncomplications Infusion related reaction Not known(1) Preferred terms considered as IRR as described in the section below(2) Selected adverse reaction as described in the section below

Infusion-related reaction

IRRs (including hypersensitivity, cyanosis, nausea, vomiting, pyrexia, chills, feeling hot, malaise,urticaria, anaphylactoid reaction and hyperhidrosis) were reported in 13% of the patients (5 out of38 patients) in clinical studies. All were mild or moderate in severity and 2 were reported as a seriousadverse reaction (see section 5.1). All patients who experienced IRRs recovered.

In the clinical studies, one patient experienced acute renal failure considered possibly related to thestudy treatment. Acute renal failure was of moderate severity leading to temporary discontinuation ofthe study treatment and fully resolved within 3 months. Concomitant long-term treatment with highdoses of ibuprofen was noted during the occurrence of the event.

Loss of consciousness

In one patient, one event of loss of consciousness was reported during the treatment in the clinicaltrials. The event occurred 8 days after last infusion and after 14 months of treatment. A connection tothe test drug could not be ruled out despite the long period from last infusion and until the eventoccurred. The patient recovered within few seconds and was taken to the hospital, where she/hereceived sodium chloride 9 mg/mL (0.9%) solution for infusion and was then discharged after 6-hourobservation. The patient continued in the study with no change in dose level.

No other related event of loss of consciousness has been reported either in the clinical either in thecommercial setting.

Children age below 6 years old

A total of 5 patients with alpha-mannosidosis below 6 years received velmanase alfa in a clinicalstudy. The safety profile was similar to that observed in the previous studies, with similar frequency,type and severity of adverse events.

Children age group 6 to 17 years old

The safety profile of velmanase alfa in clinical studies involving children and adolescents was similarto that observed in adult patients. Overall, 58% of patients (19 out of 33) with alpha-mannosidosisreceiving velmanase alfa in clinical studies were aged 6 to 17 years at the start of the study.

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.

There is no experience with overdose of velmanase alfa. The maximum dose of velmanase alfa inclinical studies was a single administration of 100 units/kg (approximately corresponding to3.2 mg/kg). During the infusion with this higher dose, fever of mild intensity and short duration(5 hours) was observed in one patient. No treatment was administered.

For the management of adverse reactions, see sections 4.4 and 4.8.

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

ATC code: A16AB15.

Velmanase alfa, the active substance of Lamzede, is a recombinant form of human alpha-mannosidase.

The amino acid sequence of the monomeric protein is identical to the naturally occurring humanenzyme, alpha-mannosidase.

Velmanase alfa is intended to supplement or replace natural alpha-mannosidase, an enzyme thatcatalyses the sequential degradation of hybrid and complex high-mannose oligosaccharides in thelysosome, reducing the amount of accumulated mannose-rich oligosaccharides.

A total of 33 patients enrolled in the exploratory and pivotal studies (20 males and 13 females, rangingin age from 6 to 35 years) were exposed to velmanase alfa in five clinical studies. Patients werediagnosed based on alpha-mannosidase activity <10% of normal activity in blood leukocytes. Patientswith the most severe rapidly progressing phenotype (with a deterioration within one year and centralnervous system involvement) were excluded. Based on this criteria mild to moderate patients,presenting heterogeneous severity with ability to perform endurance tests, large variability of clinicalmanifestations and age of onset were enrolled.

Overall effects of treatment were evaluated in the domains of pharmacodynamics (reduction of serumoligosaccharides), functional (three-minute stair climbing test (3MSCT), six-minute walking test(6MWT), and forced vital capacity (FVC) % predicted) and quality of life (childhood healthassessment questionnaire (CHAQ) disability index (DI) and CHAQ VAS pain (visual analoguescale)).

In the phase 3 pivotal multi-centre, double-blind, randomised, placebo-controlled, parallel group studyrhLAMAN-05, the efficacy and safety of repeated administrations of velmanase alfa over 52 weeks ata dose of 1 mg/kg given weekly as intravenous infusion were investigated. A total of 25 patients wereenrolled, including 12 paediatric subjects (age range: 6 to 17 years; mean: 10.9 years) and 13 adultsubjects (age range: 18 to 35 years; mean: 24.6). All but one patient were naïve to the treatment withvelmanase alfa. In total 15 patients (7 paediatrics and 8 adults) received active treatment and10 patients received placebo (5 paediatrics and 5 adults). The results (serum oligosaccharideconcentration, 3MSCT, 6MWT and FVC%) are presented in table 2. A pharmacodynamic effect withstatistically significant decrease of serum oligosaccharides in comparison to placebo wasdemonstrated. The results observed in patients below 18 years of age showed an improvement. Inpatients over 18 years old a stabilisation has been demonstrated. The numerical improvement of mostclinical endpoints over placebo (2 to 8%) observed in the year of observation could be suggestive ofthe ability of velmanase alfa to slow down the existing disease progression.

Table 2: Results from placebo-controlled clinical study rhLAMAN-05 (source data:rhLAMAN-05)

Treatment with Treatment with Velmanasevelmanase alfa for 12 months placebo for 12 months alfa(n=15) (n=10) vs. placebo

Patients Baseline Absolute Baseline Absolute Adjustedactual value change from actual value change from mean

Mean (SD) baseline Mean (SD) baseline difference

Mean Mean

Serum oligosaccharide concentration (μmol/l)

Overall(1) 6.8 (1.2) -5.11 6.6 (1.9) -1.61 -3.50[95% CI] [-5.66; -4.56] [-2.28; -0.94] [-4.37; -2.62]p-value p<0.001<18 years(2) 7.3 (1.1) -5.2 (1.5) 6.0 (2.4) -0.8 (1.7) -≥18 years(2) 6.3 (1.1) -5.1 (1.0) 7.2 (1.0) -2.4 (1.4)3MSCT (steps/min)

Overall(1) 52.9 (11.2) 0.46 55.5 (16.0) -2.16 2.62[95% CI] [-3.58; 4.50] [-7.12; 2.80] [-3.81; 9.05]p-value p=0.406<18 years(2) 56.2 (12.5) 3.5 (10.0) 57.8 (12.6) -2.3 (5.4) -≥18 years(2) 50.0 (9.8) -1.9 (6.7) 53.2 (20.1) -2.5 (6.2)6MWT (metres)

Overall(1) 459.6 (72.26) 3.74 465.7 (140.5) -3.61 7.35[95% CI] [-20.32; 27.80] [-33.10; 25.87] [-30.76; 45.46]p-value p=0.692<18 years(2) 452.4 (63.9) 12.3 (43.2) 468.8 (79.5) 3.6 (43.0) -≥18 years(2) 465.9 (82.7) -2.5 (50.4) 462.6 (195.1) -12.8 (41.6)

Treatment with Treatment with Velmanasevelmanase alfa for 12 months placebo for 12 months alfa(n=15) (n=10) vs. placebo

Patients Baseline Absolute Baseline Absolute Adjustedactual value change from actual value change from mean

Mean (SD) baseline Mean (SD) baseline difference

Mean Mean

FVC (% of predicted)

Overall(1) 81.67 (20.66) 8.20 90.44 (10.39) 2.30 5.91[95% CI] [1.79; 14.63] [-6.19; 10.79] [-4.78; 16.60]p-value p=0.278<18 years(2) 69.7 (16.8) 14.2 (8.7) 88.0 (10.9) 8.0 (4.2) -≥18 years(2) 93.7 (17.7) 2.2 (7.2) 92.4 (10.8) -2.8 (15.5)(1) For overall: adjusted mean change and adjusted mean difference estimated by ANCOVA model arepresented(2) By age: unadjusted mean and SD are presented.

The long-term efficacy and safety of velmanase alfa was investigated in the uncontrolled, open label,phase 3 clinical study rhLAMAN-10 in 33 subjects (19 paediatrics and 14 adults, from 6 to 35 years attreatment initiation) who previously participated in velmanase alfa studies. An integrated database wascreated by pooling cumulative databases from all studies with velmanase alfa. Statistically significantimprovements were detected in serum oligosaccharide levels, 3MSCT, pulmonary function, serum IgGand EQ-5D-5L (euro quality of life-5 dimensions) over time, up to the last observation (table 3). Theeffects of velmanase alfa were more evident in patients younger than 18 years.

Table 3: Change of clinical endpoints from baseline to the last observation in rhLAMAN-10study (source data: rhLAMAN-10)

Parameter Patients Baseline Last p-valuen=33 actual value observation [95% CI]

Mean % change(SD) from baseline(SD)

Serum oligosaccharide Overall 6.90 -62.8 <0.001concentration (µmol/L) (2.30) (33.61) [-74.7; -50.8]3MSCT (steps/min) Overall 53.60 13.77 0.004(12.53) (25.83) [4.609; 22.92]6MWT (metres) Overall 466.6 7.1 0.071(90.1) (22.0) [-0.7; 14.9]

FVC (% of predicted) Overall 84.9 10.5 0.011(18.6) (20.9) [2.6; 18.5]

Data suggest that the beneficial effects of the treatment with velmanase alfa diminish with the increaseof disease burden and disease-related respiratory infections.

A post-hoc multiparametric responders analysis supports the benefit of longer treatment withvelmanase alfa in 87.9% of responders in at least 2 domains at last observation (table 4).

Table 4: Multiparametric responder analysis: MCID(1) Responders Rates by Endpoints and

Domains (source data: rhLAMAN-05; rhLAMAN-10)

Responders RatesrhLAMAN-05 study rhLAMAN-10 study

Domain Criterion n=25 n=33

Placebo Lamzede Lamzede12 months 12 months Last Observation

Pharmacodynamic Oligosaccharides 20.0% 100% 91.0%

Pharmacodynamic Domain

Response Oligosaccharides 20.0% 100% 91.0%

Functional 3MSCT 10.0% 20.0% 48.5%6MWT 10.0% 20.0% 48.5%

FVC (%) 20.0% 33.3% 39.4%

Functional Domain Response Combined 30.0% 60.0% 72.7%

Quality of Life CHAQ-DI 20.0% 20.0% 42.2%

CHAQ-VAS 33.3% 40.0% 45.5%

QoL Domain Combined 40.0% 40.0% 66.7%

Overall response Three domains 0 13.3% 45.5%

Two domains 30.0% 73.3% 42.4%

One domain 30.0% 13.3% 9.1%

No domains 40.0% 0 3.0%(1) MCID: minimal clinically important difference

Children below 6 years old

Use of velmanase alfa in the children below 6 years is supported by the evidence of the clinical studyrhLAMAN08.

Overall, there were no safety issues from use of velmanase alfa in paediatric patients below 6 years ofage with alpha-mannosidosis. Four of 5 patients developed anti-velmanase alfa antibodies during thestudy, and 3 patients developed neutralising/inhibitory antibodies. Two Patients (both anti-velmanasealfa antibodies positive) experienced a total of 12 IRRs, all manageable, with no event leading todiscontinuation of study treatment. Two IRRs were assessed as serious and resolved on the same dayof occurrence. Premedication before infusion was used, when necessary, as a measure to furtherreduce risks related to IRRs. Efficacy analysis demonstrated reduction in concentrations of serumoligosaccharides, increase in IgG levels, and suggested improved endurance and hearing. Lack ofaccumulation of velmanase alfa at steady state and the safety/efficacy results confirm that the dose of1 mg/kg is appropriate in paediatric patients (aged below 6 years). The study suggests benefits of earlytreatment with velmanase alfa in children aged below 6 years.

Children age group 6 to 17 years old

Use of velmanase alfa in the age group 6 to 17 years is supported by evidence from clinical studies inpaediatric (19 out of 33 patients enrolled in the exploratory and pivotal studies) and adult patients.

Exceptional circumstances authorisation

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease, it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

There were no apparent pharmacokinetic gender differences in patients with alpha-mannosidosisdisease.

Lamzede is administered through intravenous infusion. At steady-state after weekly infusionadministration of 1 mg/kg of velmanase alfa, the mean maximum plasma concentration was about8 µg/mL and was reached at 1.8 hours after the start of administration corresponding to the meaninfusion duration time.

As expected for a protein of this size, the steady-state volume of distribution was low (0.27 L/kg),indicating distribution confined to plasma. The clearance of velmanase alfa from plasma (mean6.7 mL/h/kg) is consistent with a rapid cellular uptake of velmanase alfa via mannose receptors.

The metabolic pathway of velmanase alfa is predicted to be similar to other natural occurring proteinsthat degrade into small peptides and finally into amino acids.

After the end of the infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with amean terminal elimination half-life of about 30 hours.

Linearity/(Non)linearity

Velmanase alfa exhibited a linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUCincreased proportionally to the dose with doses ranging from 0.8 to 3.2 mg/kg (corresponding to 25and 100 units/kg).

Velmanase alfa is a protein and is predicted to be metabolically degraded into amino acids. Proteinslarger than 50 000 Da, such as velmanase alfa, are not eliminated renally. Consequently, hepatic andrenal impairment are not expected to affect the pharmacokinetic of velmanase alfa.

As no patients older than 41 years have been identified across Europe, no relevant use in elderlypatients is expected.

Pharmacokinetic data from paediatric patients recapitulate the data from the adult population. Inparticular, lack of accumulation of velmanase alfa at steady state, as well as the safety/efficacy data,confirm that the dose of 1 mg/kg is appropriate also in patients younger than 6 years.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, juvenile toxicity and toxicity to reproduction and development.

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate

Mannitol (E 421)

Glycine

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

3 years.

Reconstituted solution for infusion

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2°C to 8°C.

Store and transport refrigerated (2°C - 8°C). Do not freeze.

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

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

10 mL vial (Type I glass) with a bromobutyl rubber stopper, an aluminium seal and a polypropyleneflip off cap.

Each vial contains 10 mg of velmanase alfa.

Pack sizes of 1, 5 or 10 vials per carton.

Not all pack sizes may be marketed.

Lamzede requires reconstitution and is intended for intravenous infusion only.

Each vial is for single use only.

Instructions for reconstitution and administration

Lamzede should be reconstituted and administrated by a healthcare professional.

Aseptic technique is to be used during preparation. Filter needles must not be used during preparation.

a) The number of vials to be used should be calculated based on the individual patient’s weight.

The recommended dose of 1 mg/kg is determined using the following calculation:

- Patient’s weight (kg) × dose (mg/kg) = Patient dose (in mg).

- Patient dose (in mg) divided by 10 mg/vial (content of one vial) = number of vials toreconstitute. If the number of calculated vials includes a fraction, it should be rounded upto the next whole number.

- Approximately 30 minutes prior to reconstitution, the required number of vials should beremoved from the refrigerator. The vials should reach ambient temperature (between15°C and 25°C) prior to reconstitution.

Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of thewall of each vial. Each mL of reconstituted solution contains 2 mg of velmanase alfa. Only thevolume corresponding to the recommended dose should be administered.

Example:

- Patient’s weight (44 kg) × dose (1 mg/kg) = Patient dose (44 mg).

- 44 mg divided by 10 mg/vial = 4.4 vials, therefore, 5 vials should be reconstituted.

- From the total reconstituted volume, only 22 mL (corresponding to 44 mg) should beadministered.

b) The powder should be reconstituted in the vial by a slow drop-wise addition of the water forinjections down the inside of the vial and not directly onto the lyophilised powder. Forcefullyejecting the water for injections from the syringe onto the powder should be avoided tominimise foaming. The reconstituted vials should stand on the table for about 5-10 minutes.

Thereafter each vial should be tilted and rolled gently for 15-20 seconds to enhance thedissolution process. The vial should not be inverted, swirled, or shaken.

c) An immediate visual inspection of the solution for particulate matter and discoloration shouldbe performed after reconstitution. The solution should be clear and not used if opaqueparticles are observed or if the solution is discoloured. Due to the nature of the medicinalproduct, the reconstituted solution may occasionally contain some proteinaceous particles inform of thin white strands or translucent fibers which will be removed by the in-line filterduring infusion (see point e).

d) The reconstituted solution is to be slowly withdrawn from each vial with caution to avoidfoaming in the syringe. If the volume of the solution exceeds one syringe capacity, the requirednumber of syringes should be prepared in order to replace the syringe quickly during theinfusion.

e) The reconstituted solution should be administered using an infusion set equipped with a pumpand an in-line low protein-binding 0.22 μm filter.

The total volume of infusion is determined by the patient’s weight and should be administratedover a minimum of 50 minutes. It is recommended to use always the same dilution (2 mg/ml).

For patients weighing less than 18 kg, and receiving less than 9 mL reconstituted solution, theinfusion rate should be calculated so that the infusion time is ≥50 minutes. The maximuminfusion rate is 25 mL/hour (see section 4.2). The infusion time can be calculated from thefollowing table:

Patient Dose Maximum Minimum Patient Dose Maximum Minimumweight (mL) infusion infusion weight (mL) infusion infusion(kg) rate time (min) (kg) rate time (min)(mL/h) (mL/h)5 2.5 3 50 53 26.5 25 646 3 3.6 50 54 27 25 657 3.5 4.2 50 55 27.5 25 678 4 4.8 50 56 28 25 679 4.5 5.4 50 57 28.5 25 6810 5 6 50 58 29 25 70

Patient Dose Maximum Minimum Patient Dose Maximum Minimumweight (mL) infusion infusion weight (mL) infusion infusion(kg) rate time (min) (kg) rate time (min)(mL/h) (mL/h)11 5.5 6.6 50 59 29.5 25 7112 6 7.2 50 60 30 25 7213 6.5 7.8 50 61 30.5 25 7314 7 8.4 50 62 31 25 7415 7.5 9 50 63 31.5 25 7616 8 9.6 50 64 32 25 7717 8.5 10.2 50 65 32.5 25 7818 9 10.8 50 66 33 25 7919 9.5 11.4 50 67 33.5 25 8020 10 12 50 68 34 25 8221 10.5 12.6 50 69 34.5 25 8322 11 13.2 50 70 35 25 8423 11.5 13.8 50 71 35.5 25 8524 12 14.4 50 72 36 25 8625 12.5 15 50 73 36.5 25 8826 13 15.6 50 74 37 25 8927 13.5 16.2 50 75 37.5 25 9028 14 16.8 50 76 38 25 9129 14.5 17.4 50 77 38.5 25 9230 15 18 50 78 39 25 9431 15.5 18.6 50 79 39.5 25 9532 16 19.2 50 80 40 25 9633 16.5 19.8 50 81 40.5 25 9734 17 20.4 50 82 41 25 9835 17.5 21 50 83 41.5 25 10036 18 21.6 50 84 42 25 10137 18.5 22.2 50 85 42.5 25 10238 19 22.8 50 86 43 25 10339 19.5 23.4 50 87 43.5 25 10440 20 24 50 88 44 25 10641 20.5 24.6 50 89 44.5 25 10742 21 25 50 90 45 25 10843 21.5 25 52 91 45.5 25 10944 22 25 53 92 46 25 11045 22.5 25 54 93 46.5 25 11246 23 25 55 94 47 25 11347 23.5 25 56 95 47.5 25 11448 24 25 58 96 48 25 11549 24.5 25 59 97 48.5 25 11650 25 25 60 98 49 25 11851 25.5 25 61 99 49.5 25 11952 26 25 62f) When the last syringe is empty, the dose syringe is replaced with a 20 mL syringe filled withsodium chloride 9 mg/mL (0.9%) solution for injection. A volume of 10 mL sodium chloridesolution should be administered through the infusion system to infuse the remaining fraction of

Lamzede in the line to the patient.

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

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/17/1258/001

EU/1/17/1258/002

EU/1/17/1258/003

Date of first authorisation: 23 March 2018

Date of latest renewal:

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

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