SUMMARY OF PRODUCT CHARACTERISTICS

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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.

4.1 Therapeutic indications

Enzyme replacement therapy for the treatment of non-neurological manifestations in patients with mild 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 with alpha-mannosidosis or in the administration of other enzyme replacement therapies (ERT) for lysosomal storage disorder. Administration of Lamzede should be carried out by a healthcare professional with the ability to manage ERT and medical emergencies.

Posology

The recommended dose regimen is 1 mg/kg of body weight administered once every week by intravenous infusion at a controlled speed. For infusion rate see section “Method of administration”.

Special populations

Renal or hepatic impairment

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

Elderly

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

Paediatric population

No dose adjustment is necessary for the paediatric population.

Method of administration

For intravenous infusion use only.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

The reconstituted solution of Lamzede should be administered using an infusion set equipped with a pump and an in-line low protein-binding 0.22 µm filter. The infusion duration should be calculated individually considering a maximum infusion rate of 25 mL/hour to control the protein load. The infusion duration should be a minimum of 50 minutes. A slower infusion rate may be prescribed when clinically appropriate according to the physician’s judgment, for example at the beginning of the treatment 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 in section 6.6.

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

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

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

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

Hypersensitivity

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

Infusion-related reaction

Administration of velmanase alfa may result in an IRR, including anaphylactoid reaction (see section 4.8). The IRRs observed in clinical studies of velmanase alfa were characterised by a rapid onset 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 the infusion rate, treatment with medicinal products such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion time. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to infusion of velmanase alfa during clinical studies.

In case symptoms such as angioedema (tongue or throat swelling), upper airway obstruction or hypotension occur during or immediately after infusion, anaphylaxis or an anaphylactoid reaction should be suspected. In such a case, treatment with an antihistamine and corticosteroids should be

considered as being appropriate. In the most severe cases, the current medical standards for emergency treatment 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.

Immunogenicity

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

There is a potential for immunogenicity. In the clinical studies at any time under treatment, 8 patients out of 33 (24%) developed IgG-class antibodies to velmanase alfa. No clear correlation was found between antibody titres (velmanase alfa IgG antibody level) and reduction in efficacy or occurrence of anaphylaxis or other hypersensitivity reactions.

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

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.

Pregnancy

There are no data from the use of velmanase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As velmanase alfa aims at normalizing alpha-mannosidase in alpha-mannosidosis patients, Lamzede should be used during pregnancy only when strictly needed.

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

The most common adverse reactions observed were weight increase (18%), IRRs (9%), diarrhoea (12%), headache (9%), arthralgia (9%), increased appetite (6%) and pain in extremity (6%).

All of these adverse reactions were non-serious. IRRs include hypersensitivity in 3 patients and anaphylactoid reaction in 1 patient. These reactions were non-serious and mild to moderate in intensity.

A total of 2 serious adverse reactions (loss of consciousness in 1 patient and acute renal failure in 1 patient) were observed. In both cases the patients recovered without sequelae.

Tabulated list of adverse reactions

The adverse reactions reflecting exposure of 33 patients treated with velmanase alfa in clinical studies are listed in the table 1 below. Adverse reactions are classified by system organ class and preferred term according to the MedDRA frequency convention. 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).

(1) Preferred terms considered as IRR as described in the section below

(2) Selected adverse reaction as described in the section below

Description of selected adverse reactions

Infusion-related reaction

IRRs (including hypersensitivity, nausea, vomiting, pyrexia, chills, feeling hot, malaise, urticaria, anaphylactoid reaction and hyperhidrosis) were reported in 9% of the patients (3 out of 33 patients) in clinical studies. All were mild or moderate in severity and none were reported as a serious adverse event. All patients who experienced IRRs recovered.

Acute renal failure

In the clinical studies, one patient experienced acute renal failure considered possibly related to the study treatment. Acute renal failure was of moderate severity leading to temporary discontinuation of the study treatment and fully resolved within 3 months. Concomitant long-term treatment with high doses of ibuprofen was noted as a potentially causative contributor to the occurrence of the event.

Loss of consciousness

In one patient, loss of consciousness considered related to the study treatment with recovery after a few seconds was reported. The patient received saline infusion in a hospital setting and was then discharged after 6-hour observation.

The patient later experienced epileptic seizures that were considered not related. Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no experience with overdose of velmanase alfa. The maximum dose of velmanase alfa in clinical studies was a single administration of 100 units/kg (approximately corresponding to

3.2 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB15.

Mechanism of action

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 human enzyme, alpha-mannosidase.

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

Clinical efficacy and safety

A total of 33 patients (20 males and 13 females, ranging in age from 6 to 35 years) were exposed to velmanase alfa in five clinical studies. Patients were diagnosed based on alpha-mannosidase activity

<10% of normal activity in blood leukocytes. Patients with the most severe rapidly progressing phenotype (with a deterioration within one year and central nervous system involvement) were excluded. Based on this criteria mild to moderate patients, presenting heterogeneous severity with ability to perform endurance tests, large variability of clinical manifestations and age of onset were enrolled.

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

In the phase 3 pivotal multi-centre, double-blind, randomised, placebo-controlled, parallel group study rhLAMAN-05, the efficacy and safety of repeated administrations of velmanase alfa over 52 weeks at a dose of 1 mg/kg given weekly as intravenous infusion were investigated. A total of 25 patients were enrolled, including 12 paediatric subjects (age range: 6 to 17 years; mean: 10.9 years) and 13 adult subjects (age range: 18 to 35 years; mean: 24.6). All but one patient were naïve to the treatment with velmanase alfa. In total 15 patients (7 paediatrics and 8 adults) received active treatment and

10 patients received placebo (5 paediatrics and 5 adults). The results (serum oligosaccharide concentration, 3MSCT, 6MWT and FVC%) are presented in table 2. A pharmacodynamic effect with statistically significant decrease of serum oligosaccharides in comparison to placebo was demonstrated. The results observed in patients below 18 years of age showed an improvement. In patients over 18 years old a stabilisation has been demonstrated. The numerical improvement of most clinical endpoints over placebo (2 to 8 %) observed in the year of observation could be suggestive of the ability of velmanase alfa to slow down the existing disease progression.

(1) For overall: adjusted mean change and adjusted mean difference estimated by ANCOVA model are presented

(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 at treatment initiation) who previously participated in velmanase alfa studies. An integrated database was created by pooling cumulative databases from all studies with velmanase alfa. Statistically significant improvements were detected in serum oligosaccharide levels, 3MSCT, pulmonary function, serum IgG

and EQ-5D-5L (euro quality of life-5 dimensions) over time, up to the last observation (table 3). The effects of velmanase alfa were more evident in patients younger than 18 years.

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

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

(1) MCID: minimal clinically important difference Paediatric population

Use of velmanase alfa in the age group 6 to 17 years is supported by evidence from clinical studies in paediatric (19 out of 33 patients) and adult patients. No clinical data are available in children below the age of 6 years.

The European Medicines Agency has deferred the obligation to submit the results of studies with Lamzede in one or more subsets of the paediatric population in the treatment of alpha-mannosidosis disease (see section 4.2 for information on paediatric use).

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

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

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

Absorption

Lamzede is administered through intravenous infusion. At steady-state after weekly infusion administration of 1 mg/kg of velmanase alfa, the mean maximum plasma concentration was about 8 µg/mL and was reached at 1.8 hours after the start of administration corresponding to the mean infusion duration time.

Distribution

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 (mean

6.7 mL/h/kg) is consistent with a rapid cellular uptake of velmanase alfa via mannose receptors.

Biotransformation

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

Elimination

After the end of the infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with a mean 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 AUC increased proportionally to the dose with doses ranging from 0.8 to 3.2 mg/kg (corresponding to 25 and 100 units/kg).

Special populations

Velmanase alfa is a protein and is predicted to be metabolically degraded into amino acids. Proteins larger than 50,000 Da, such as velmanase alfa, are not eliminated renally. Consequently hepatic and renal 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 elderly patients is expected.

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

6.1 List of excipients

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate Mannitol

Glycine

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

2 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 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.

Store and transport refrigerated (2°C - 8°C).

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 polypropylene flip 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 to reconstitute. If the number of calculated vials includes a fraction, it should be rounded up to the next whole number.

- Approximately 30 minutes prior to reconstitution, the required number of vials should be removed from the refrigerator. The vials should reach ambient temperature (between 15°C and 25°C) prior to reconstitution.

Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of the wall of each vial. Each mL of reconstituted solution contains 2 mg of velmanase alfa. Only the volume 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 be administered.

b) The powder should be reconstituted in the vial by a slow drop-wise addition of the water for injections down the inside of the vial and not directly onto the lyophilised powder. Forcefully ejecting the water for injections from the syringe onto the powder should be avoided to minimise 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 the dissolution process. The vial should not be inverted, swirled, or shaken.

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

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

e) The reconstituted solution should be administered using an infusion set equipped with a pump and 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 administrated over a minimum of 50 minutes. For patients weighing less than 18 kg, and receiving less than 9 mL reconstituted solution, the infusion rate should be calculated so that the infusion time is

≥50 minutes. The maximum infusion rate is 25 mL/hour (see section 4.2). The infusion time can be calculated from the following table:

f) When the last syringe is empty, the dosage syringe is replaced with a 20 mL syringe filled with sodium chloride 9 mg/mL (0.9%) solution for injection. A volume of 10 mL sodium chloride solution should be administered through the infusion system to infuse the remaining fraction of Lamzede in the line to the patient.

Disposal

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

Chiesi Farmaceutici S.p.A. Via Palermo 26/A

43122 Parma Italy

EU/1/17/1258/001 EU/1/17/1258/002 EU/1/17/1258/003

Date of first authorisation: {DD/MM/YYYY}

{MM/YYYY}

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

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

E. SPECIFIC OBLIGATION TO COMPLETE POST- AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

Rentschler Biopharma SE Erwin-Rentschler-Strasse 21

88471 Laupheim Germany

Name and address of the manufacturer responsible for batch release

Chiesi Farmaceutici S.p.A. Via San Leonardo, 96 43122 Parma

Italy

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

· Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

· Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

· At the request of the European Medicines Agency;

· Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures:

LABELLING AND PACKAGE LEAFLET

A. LABELLING

Lamzede 10 mg powder for solution for infusion velmanase alfa

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).

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate Mannitol

Glycine

Powder for solution for infusion 1 vial

5 vials 10 vials

Read the package leaflet before use. Intravenous use.

Keep out of the sight and reach of children.

EXP

Store and transport refrigerated.

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

After reconstitution, the medicinal product should be used immediately. If not used immediately, the reconstituted solution should be stored in a refrigerator for no longer than 24 hours.

Chiesi Farmaceutici S.p.A. Via Palermo 26/A

43122 Parma Italy

EU/1/17/1258/001 EU/1/17/1258/002 EU/1/17/1258/003

Lot

Justification for not including Braille accepted.

2D barcode carrying the unique identifier included.

PC: {number} SN: {number} NN: {number}

Lamzede 10 mg powder for solution for infusion velmanase alfa

Intravenous use

Read the package leaflet before use

EXP

Lot

10 mg velmanase alfa

Package leaflet: Information for the patient

Lamzede 10 mg powder for solution for infusion

velmanase alfa

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor.

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

1. What Lamzede is and what it is used for

2. What you need to know before Lamzede is used

3. How Lamzede is used

4. Possible side effects

5. How Lamzede is stored

6. Contents of the pack and other information

Lamzede contains the active substance velmanase alfa which belongs to a group of medicines known as enzyme replacement therapies. It is used to treat patients with mild to moderate alpha-mannosidosis disease. It is given for the treatment of non-neurological symptoms of the disease.

Alpha-mannosidosis disease is a rare genetic disorder caused by a lack of an enzyme named

alpha-mannosidase, which is needed to break down certain sugar compounds (called ‘mannose-rich oligosaccharides’) in the body. When this enzyme is missing or does not work properly, these sugar compounds build up inside cells and cause the signs and symptoms of the disease. The typical manifestations of the disease include distinctive facial features, mental retardation, difficulty in controlling movements, difficulties in hearing and speaking, frequent infections, skeletal problems, muscle pain and weakness.

Velmanase alfa is designed to replace the missing enzyme in patients with alpha-mannosidosis disease. This may improve the symptoms of the disease.

- if you are allergic to velmanase alfa or any of the other ingredients of this medicine (listed in section 6).

Talk to your doctor before Lamzede is used.

If you are treated with Lamzede, you may experience a side effect during or immediately following the drip (infusion) used to give the medicine (see section 4). This is known as an infusion-related reaction and can sometimes be severe.

- Infusion-related reactions include dizziness, headache, nausea, low blood pressure, tiredness and fever. If you experience an infusion-related reaction, you must tell your doctor immediately.

- If you have an infusion-related reaction you may be given additional medicines to treat or help prevent future reactions. These medicines may include medicines used to treat allergies (antihistamines), medicines used to treat fever (antipyretics) and medicines to control inflammation (corticosteroids).

- If the infusion-related reaction is severe, your doctor will stop the infusion immediately and start giving you appropriate medical treatment.

- If the infusion-related reactions are severe and/or there is a loss of effect from this medicine, your doctor will perform a blood test to check for antibodies that might affect the outcome of your treatment.

- Most of the time you can still be given Lamzede even if you experience an infusion-related reaction.

Tell your doctor if you are taking, have recently taken or might take any other medicines.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is used.

Lamzede should be used during pregnancy only when medically necessary. It is not known whether velmanase alfa passes into breast milk. Lamzede can be used during breast-feeding.

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

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

This medicine is only to be used under the supervision of a doctor experienced in the treatment of alpha-mannosidosis or other similar diseases and should only be given by a healthcare professional.

The recommended dose of Lamzede is 1 mg/kg of body weight given once every week.

Lamzede may be given to children and adolescents at the same dose and frequency as in adults. There is no experience with patients younger than 6 years of age.

Lamzede is supplied in a vial as a powder for infusion which will be made up with water for injections before being given.

Once it has been made up, the medicine will be given by infusion pump (drip) into a vein over a period of at least 50 minutes under your doctor’s supervision.

If you have any further questions on the use of this medicine, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects occur during the infusion or shortly after (“infusion-related reaction”, see section 2 Warnings and precautions).

While under treatment with Lamzede, you may experience some of the following reactions:

Common side effects (may affect up to 1 in 10 people)

- loss of consciousness (fainting, which may be preceded by feeling dizzy, lightheaded or confused)

- acute renal insufficiency (kidney problems which can be recognised from fluid retention, swelling in legs, ankles or feet, drowsiness, shortness of breath or fatigue)

- hypersensitivity and serious allergic reaction (symptoms including localised or diffuse skin itching, dizziness, difficulty breathing, chest pain, gastrointestinal symptoms such as nausea, vomiting, diarrhea or intestinal pain, swelling of the throat, face, lips or tongue)

Very common side effects (may affect more than 1 in 10 people)

- diarrhoea

- weight increase

- fever/increased body temperature

Common side effects (may affect up to 1 in 10 people)

- low heart beat (bradycardia)

- psychotic behaviour (mental illness with hallucinations, difficulty in thinking clearly and understanding reality, anxiety), initial difficulty in sleeping

- confused state, fainting, tremor, dizziness, headache

- intestinal (abdominal) pain, irritation of the stomach caused by digestive acids (reflux gastritis), nausea, vomiting

- pain at the site the infusion is given, chills, feeling hot, malaise, tiredness (fatigue)

- skin rashes (urticaria), increased sweating (hyperhidrosis)

- nosebleed

- joint pain, back pain, joint stiffness, muscle pain, pain in extremity (hands, feet)

- eye irritation, eyelid swelling (eyelid oedema), eye redness

- increased appetite

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and the carton after ‘EXP’. The expiry date refers to the last day of that month.

Store and transport refrigerated (2°C - 8°C).

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

After reconstitution, the medicine should be used immediately. If not used immediately, the reconstituted solution may be stored up to 24 hours at 2°C to 8°C.

This medicine must not be used if the reconstituted solution contains opaque particles or is discoloured.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

- The active substance is velmanase alfa.

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).

- The other ingredients are: disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, mannitol and glycine.

Lamzede is a white to off-white powder for solution for infusion, supplied in a glass vial. Each carton contains 1, 5 or 10 vials.

Not all pack sizes may be marketed.

Chiesi Farmaceutici S.p.A. Via Palermo 26/A

43122 Parma Italy

Chiesi Farmaceutici S.p.A. Via San Leonardo, 96 43122 Parma

Italy

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

This medicine has been authorised under ‘exceptional circumstances’. This means that because of the rarity of this disease it has been impossible to get complete information on this medicine.

The European Medicines Agency will review any new information on this medicine every year and this leaflet will be updated as necessary.

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only.

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 to reconstitute. If the number of calculated vials includes a fraction, it should be rounded up to the next whole number.

- Approximately 30 minutes prior to reconstitution, the required number of vials should be removed from the refrigerator. The vials should reach ambient temperature (between 15°C and 25°C) prior to reconstitution.

Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of the wall of each vial. Each mL of reconstituted solution contains 2 mg of velmanase alfa. Only the volume 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 be administered.

b) The powder should be reconstituted in the vial by a slow drop-wise addition of the water for injections down the inside of the vial and not directly onto the lyophilised powder. Forcefully ejecting the water for injections from the syringe onto the powder should be avoided to minimise 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 the dissolution process. The vial should not be inverted, swirled, or shaken.

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

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

e) The reconstituted solution should be administered using an infusion set equipped with a pump and 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 administrated over a minimum of 50 minutes. For patients weighing less than 18 kg, and receiving less than 9 mL reconstituted solution, the infusion rate should be calculated so that the infusion time is

≥50 minutes. The maximum infusion rate is 25 mL/hour. The infusion time can be calculated from the following table:

f) When the last syringe is empty, the dosage syringe is replaced with a 20 mL syringe filled with sodium chloride 9 mg/mL (0.9%) solution for injection. A volume of 10 mL sodium chloride solution should be administered through the infusion system to infuse the remaining fraction of Lamzede in the line to the patient.

Disposal

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

CONCLUSIONS ON THE GRANTING OF THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES PRESENTED BY THE EUROPEAN MEDICINES AGENCY