Replagal

Package leaflet: Information for the user

Replagal 1 mg/ml concentrate for solution for infusion

agalsidase alfa
Read this entire leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Replagal is and what it is used for
2. What you need to know before receiving Replagal
3. How Replagal is administered
4. Possible side effects
5. How to store Replagal
6. Contents of the pack and other information

1. What Replagal is and what it is used for

The active substance in Replagal is agalsidase alfa (1 mg/ml). Agalsidase alfa is a form of the human enzyme α-galactosidase, produced by activating the gene for α-galactosidase A at the cellular level. The enzyme is then extracted from the cells and processed into a sterile concentrate for infusion solution.
Replagal is used for the treatment of adult, adolescent, and pediatric patients over 7 years of age with a confirmed diagnosis of Fabry disease. It is administered as a long-term enzyme replacement therapy when enzyme levels in the body are absent or below normal, as occurs in Fabry disease.
After 6 months of treatment, patients treated with Replagal showed a significant reduction in pain compared to patients treated with placebo (a dummy medicine). Replagal reduced left ventricular mass compared to placebo. These results indicate an improvement in disease symptoms or stabilization of the disease.

2. What you need to know before receiving Replagal

Do not receive Replagal

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

Warnings and precautions
Talk to your doctor or pharmacist before using Replagal.
If you notice any of the following symptoms during or after an infusion, you must inform your doctor immediately:

• high fever, chills, sweating, rapid heartbeat;
• vomiting;
• feeling of emptiness in the head;
• hives;
• swelling of the hands, feet, ankles, face, lips, mouth or throat, causing difficulty in swallowing or breathing.

Your doctor may decide to temporarily interrupt the infusion (5–10 minutes), resuming it once symptoms have subsided.
Your doctor may also treat the symptoms with other medicines (antihistamines or corticosteroids).
In most cases, you will still be able to continue receiving Replagal despite the occurrence of these symptoms.
In case of a severe allergic reaction (anaphylactic type), administration of Replagal will be immediately stopped and your doctor will initiate appropriate therapy.
Treatment with Replagal may cause your body to produce antibodies. However, this does not prevent the medicine from working and the antibodies may disappear over time.
If you have advanced kidney disease, the effect of Replagal treatment on your kidneys may be limited. Talk to your doctor or pharmacist before using Replagal.

Children
Experience in children aged 0 to 6 years is limited; therefore, no dosing regimen can be recommended for this age group.

Other medicines and Replagal
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Inform your doctor if you are taking medicines containing chloroquine, amiodarone, benoquin or gentamicin. There is a theoretical risk of reduced activity of agalsidase alfa.

Pregnancy and breastfeeding
Very limited clinical data on pregnancies exposed to Replagal have not shown adverse effects on the mother or newborn.
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
During treatment with Replagal, you may drive and operate machinery.

Replagal contains sodium
This medicine contains 14.2 mg of sodium (the main component of table salt) per vial. This corresponds to 0.7% of the maximum daily recommended dietary intake for an adult.

Record-keeping
To improve traceability of biological medicines, healthcare professionals are required to clearly record the name and batch number of the administered product. Please consult your doctor for any questions.

3. How Replagal is administered

This medicine must be administered by and under the supervision of specially trained personnel, who will also calculate the required dose. While remaining under medical supervision, Replagal may be self-administered (by you or by your caregiver) after adequate training provided by your treating physician and/or nurse. Self-administration must occur in the presence of a responsible adult.

The recommended dose is an infusion of 0.2 mg per kg of body weight, corresponding to approximately 14 mg or 4 vials (glass bottles) of Replagal for a person of average weight (70 kg).

Use in children and adolescents
In children and adolescents aged between 7 and 18 years, a dose of 0.2 mg/kg administered every other week may be used.
Children and adolescents may be more likely than adults to develop infusion-related reactions. Inform your doctor if any adverse effects occur during the infusion.

Method of administration
Before use, Replagal must be diluted with 0.9% sodium chloride solution (9 mg/ml). After dilution, Replagal will be administered into a vein, usually in the arm.
Infusions are given every two weeks.
Each intravenous administration of Replagal will last at least 40 minutes. The infusion must be performed under the supervision of a physician specialized in the treatment of Fabry disease.
For self-administration, the prescribed dose and infusion rate must not be changed without the approval of your treating physician.

If you use more Replagal than you should
If you think you have used more Replagal than you should have, contact your doctor.

If you use less Replagal than you should
If you think you have used less Replagal than you should have, contact your doctor.

If you forget to use Replagal
If you have missed an infusion of Replagal, contact your doctor.

If you stop using Replagal
Do not stop treatment with Replagal without first consulting your doctor. If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you develop a severe allergic reaction (anaphylactic type), administration of Replagal will be immediately stopped and your doctor will initiate appropriate treatment.
Most side effects are mild to moderate in intensity. More than 1 in 10 people (frequency "very common") may develop adverse reactions during or after Replagal infusion (infusion-related reactions), including chills, headache, nausea, fever, fatigue, restlessness, breathing difficulties, tremor, cough and vomiting. However, some of these effects may be severe and require appropriate treatment. In patients with Fabry disease affecting cardiac structures, infusion-related reactions with cardiac effects may occur, including myocardial ischemia and heart failure (frequency "not known" (the frequency cannot be determined from the available data)). Your doctor may temporarily interrupt the infusion (5–10 minutes) until symptoms resolve and then resume it. Your doctor may also treat symptoms with other medicines (antihistamines or corticosteroids). In most cases, you will be able to continue taking Replagal despite these symptoms.

Other side effects
Very common: may affect more than 1 in 10 people

• swelling of tissues (e.g. legs, arms)
• tingling, numbness or pain in fingers or toes
• ringing in the ear
• palpitations
• sore throat
• abdominal pain, diarrhoea
• skin rash
• back pain or limb pain, muscle pain, joint pain
• chest pain, cold-like symptoms, fever, malaise

Common: may affect up to 1 in 10 people

• altered taste, prolonged sleep
• tearing
• increased ringing in the ear
• increased heart rate, heart rhythm disorders
• increased blood pressure, decreased blood pressure, facial flushing (reddening)
• hoarseness or throat tightness, runny nose
• abdominal discomfort
• acne, red, itchy or blotchy skin, excessive sweating
• muscle and bone discomfort, swelling of extremities or joints
• hypersensitivity
• chest tightness, increased feeling of lack of energy, sensation of cold or heat, flu-like symptoms, discomfort

Uncommon: may affect up to 1 in 100 people

• severe allergic reaction (anaphylactic type)
• abnormal eyelid reflex
• increased heart rate
• low oxygen levels in the blood and thick secretions in the throat
• altered sense of smell
• fluid accumulation under the skin may lead to swelling of body parts, mottled discoloration of the skin, e.g. of the leg
• sensation of heaviness
• skin rash at injection site

Children and adolescents

The side effects observed in children have generally been similar to those in adults. However, children have experienced infusion-related reactions (fever, breathing difficulties, chest pain) and more intense pain more frequently.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please contact your doctor or pharmacist. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Replagal

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after Exp. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not use Replagal if you notice the presence of foreign particles or any change in colour.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Replagal contains

• The active substance is agalsidase alfa. Each ml of Replagal contains 1 mg of agalsidase alfa.
• The other components are: monosodium phosphate monohydrate, polysorbate 20, sodium chloride, sodium hydroxide, water for injections.

Replagal contains sodium. See section 2.

Description of the appearance of Replagal and package contents

Replagal is a concentrate for solution for infusion supplied in vials containing 3.5 mg/3.5 ml of agalsidase alfa. Pack sizes of 1, 4 or 10 vials are available. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Takeda Pharmaceuticals International AG Ireland Branch
Block 2 Miesian Plaza
50–58 Baggot Street Lower
Dublin 2
D02 HW68
Ireland

Manufacturer
Takeda Pharmaceuticals International AG Ireland Branch
Block 2 Miesian Plaza
50–58 Baggot Street Lower
Dublin 2
D02 HW68
Ireland

Shire Pharmaceuticals Ireland Limited
Block 2 & 3 Miesian Plaza
50–58 Baggot Street Lower
Dublin 2
Ireland

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Takeda Belgium NV Takeda, UAB
Tel/Tél: +32 2 464 06 11 Tel: +370 521 09 070
[email protected] [email protected]

България Luxembourg/Luxemburg
Такеда България ЕООД Takeda Belgium NV
Тел.: +359 2 958 27 36 Tel/Tél: +32 2 464 06 11
[email protected] [email protected]

Česká republika Magyarország
Takeda Pharmaceuticals Czech Republic s.r.o. Takeda Pharma Kft.
Tel: +420 234 722 722 Tel: +36 1 270 7030
[email protected] [email protected]

Danmark Malta
Takeda Pharma A/S Τakeda HELLAS S.A.
Tlf: +45 46 77 10 10 Tel: +30 210 6387800
[email protected] [email protected]

Deutschland Nederland
Takeda GmbH Takeda Nederland B.V.
Tel: +49 (0)800 825 3325 Tel: +31 20 203 5492
[email protected] [email protected]

Eesti Norge
Takeda Pharma AS Takeda AS
Tel: +372 6177 669 Tlf: +47 800 800 30
[email protected] [email protected]

Ελλάδα Österreich
Τakeda ΕΛΛΑΣ Α.Ε. Takeda Pharma Ges.m.b.H.
Tηλ: +30 210 6387800 Tel: +43 (0) 800-20 80 50
[email protected] [email protected]

España Polska
Takeda Farmacéutica España S.A Takeda Pharma Sp. z o.o.
Tel: +34 917 90 42 22 Tel: +48223062447
[email protected] [email protected]

France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tél. + 33 1 40 67 33 00 Tel: + 351 21 120 1457
[email protected] [email protected]

Hrvatska România
Takeda Pharmaceuticals Croatia d.o.o. Takeda Pharmaceuticals SRL
Tel: +385 1 377 88 96 Tel: +40 21 335 03 91
[email protected] [email protected]

Ireland Slovenija
Takeda Products Ireland Ltd Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: 1800 937 970 Tel: + 386 (0) 59 082 480
[email protected] [email protected]

Ísland Slovenská republika
Vistor hf. Takeda Pharmaceuticals Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 (2) 20 602 600
[email protected] [email protected]

Italia Suomi/Finland
Takeda Italia S.p.A. Takeda Oy
Tel: +39 06 502601 Puh/Tel: 0800 774 051
[email protected] [email protected]

Κύπρος Sverige
Τakeda ΕΛΛΑΣ Α.Ε. Takeda Pharma AB
Τηλ: +30 210 6387800 Tel: 020 795 079
[email protected] [email protected]

Latvija United Kingdom (Northern Ireland)
Takeda Latvia SIA Takeda UK Ltd
Tel: +371 67840082 Tel: +44 (0) 2830 640 902
[email protected] [email protected]

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.

The following information is intended exclusively for healthcare professionals:

Instructions for use, handling and disposal

Replagal must be administered under the supervision of a physician experienced in the treatment of Fabry disease or other inherited metabolic disorders.
Replagal is administered every other week at a dose of 0.2 mg/kg body weight by intravenous infusion over 40 minutes.

1. Calculate the required dose and the number of Replagal vials needed.
2. Dilute the total required volume of Replagal concentrate in 100 ml of 0.9% (9 mg/ml) sodium chloride solution for intravenous infusion. Since Replagal does not contain preservatives or bacteriostatic agents, utmost care must be taken to maintain the sterility of the solution: aseptic techniques must therefore be used. After dilution, the solution should be gently mixed, but not shaken.
3. Prior to administration, the solution should be inspected visually for the presence of foreign particles or discoloration.
4. Administer the solution over a 40-minute period using an intravenous infusion set with an in-line filter. Since the solution contains no preservatives, administration should be initiated as soon as possible. However, from a physico-chemical standpoint, the diluted solution is stable for 24 hours at 25 °C.
5. Do not administer Replagal in the same infusion line with other medicinal products.
6. The solution is for single use only. Any unused product and waste materials arising from this medicinal product must be disposed of in accordance with local legal requirements.