Product Information for the User

Replagal 1 mg/ml Concentrate for Solution for Infusion

Agalsidase alfa

Read this entire leaflet carefully before you start taking the medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.

• If you have any questions, consult your doctor or pharmacist.

• This medicine has been prescribed for you only, and you must not give it to others, even if they have the same symptoms as you, as it may harm them.

• If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

The active ingredient of Replagal is agalsidase alfa (1 mg/ml). Agalsidase alfa is a form of the human α-galactosidase enzyme. It is produced by activating the α-galactosidase A gene of cells. The enzyme is then removed from the cells and converted into a sterile concentrate for perfusion solution.

Replagal is used to treat adult patients, as well as adolescents and children aged 7 years or older, with a confirmed diagnosis of Fabry disease. It is used as long-term enzyme replacement therapy when the enzyme level in the body is absent or lower than normal, as occurs in Fabry disease.

After 6 months of treatment, Replagal significantly reduced pain in patients compared to patients treated with placebo (inactive medication). Replagal reduced left ventricle mass in treated patients compared to patients treated with placebo. These results suggest that the symptoms of the disease are improving or that the disease is stabilizing

You should not be given 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

Consult your doctor or pharmacist before starting Replagal treatment.

If you notice any of these effects during or after a perfusion, you must inform your doctor immediately:

• high fever, chills, sweating, rapid heart rate

• vomiting

• dizziness

• urticaria (hives)

• swelling of the hands, feet, ankles, face, lips, mouth, or throat, which may cause difficulty swallowing or breathing.

Your doctor may temporarily stop the perfusion (5-10 minutes) until the symptoms disappear and then resume the perfusion.

Your doctor may also treat the symptoms with other medications (antihistamines or corticosteroids). In most cases, you can continue receiving Replagal even if these symptoms appear.

If you experience a severe allergic reaction (anaphylactic), Replagal administration will be stopped immediately and your doctor will need to start appropriate treatment.

If Replagal treatment causes your body to produce antibodies, this will not make Replagal ineffective and the antibodies may disappear over time.

If you have advanced kidney disease, you may find that Replagal treatment has a limited effect on your kidneys. Consult your doctor or pharmacist before starting to use Replagal.

Children

Experience in children aged 0 to 6 years is limited, and therefore no dosage can be recommended for this age group.

Use of Replagal with other medicines

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medicine.

Inform your doctor if you use any medicine containing chloroquine, amiodarone, benoquin, or gentamicin. There is a theoretical risk of decreased agalsidase alfa activity.

Pregnancy and breastfeeding

The very limited clinical data available on exposure to Replagal during pregnancy have not revealed adverse effects on the mother or newborn.

If you are pregnant, breastfeeding, think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before using this medicine.

Driving and operating machinery

You can drive and operate machinery while receiving Replagal.

This medication must be administered and supervised by personnel with the necessary training, who will also calculate the dose to be administered.

The recommended dose is an infusion of 0.2 mg per kilogram of body weight. This equates to approximately 14 mg or 4 vials (glass bottles) of Replagal for a person weighing around 70 kg.

Use in Children and Adolescents

For children and adolescents aged 7 to 18, a dose of 0.2 mg/kg every two weeks may be used.

Children and adolescents may be more likely than adults to experience a reaction related to the infusion. Consult with your doctor if you experience any adverse effects during the infusion.

Administration Form

Replagal must be diluted in a 9 mg/ml sodium chloride (0.9%) solution before administration.

After dilution, Replagal is administered through a vein, usually in the arm.

The infusion will be administered every two weeks.

Each time you receive treatment, it will take 40 minutes to administer Replagal through the vein. The treatment will be supervised by a doctor specializing in the treatment of Fabry's disease.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

If you experience a severe allergic reaction (anaphylactic), the administration of Replagal will be stopped immediately and your doctor will have to start an appropriate treatment.

Most of them are mild or moderate. Approximately 1 in 7 patients (very common reaction) may experience a reaction during or after the infusion of Replagal (infusion-related reaction). These reactions include chills, headache, nausea, fever, facial flushing, fatigue, decreased blood pressure, dizziness, sweating, difficulty breathing, itching, tremors, cough, and vomiting. However, some side effects can be severe and require treatment. Infusion-related reactions that affect the heart, including cardiac rhythm problems, myocardial ischemia, and heart failure, may occur in patients with Fabry disease affecting the cardiac structures (reactions with "unknown frequency" (cannot be estimated from available data)). Your doctor may temporarily stop the infusion (5-10 minutes) until the symptoms disappear and then start the infusion again. Your doctor may also treat the symptoms with other medications (antihistamines or corticosteroids). Most of the time, you can still receive Replagal even if these symptoms occur.

Other side effects list:

Very common: may affect more than 1 in 10 people

• general pain or discomfort

Common: may affect up to 1 in 10 people

• tingling, numbness, or pain in the fingers or toes, changes in food taste, excessive tearing, abnormal eyelid reflex, ringing in the ears, muscle twitching, prolonged sleep

• palpitations, increased heart rate, increased blood pressure

• cough, chest pain or tightness, hoarseness, throat pain or tightness, sticky secretions in the throat, nasal secretions, cold symptoms

• vomiting, abdominal pain or discomfort, diarrhea

• acne, redness, itching, or rashes on the skin, exanthema at the infusion site

• back or limb pain, muscle pain, joint pain, bone and muscle discomfort, swelling of the extremities or joints

• sensation of cold or heat, flu-like symptoms, nausea, feeling of fatigue

Rare: may affect up to 1 in 100 people

• severe allergic reaction (anaphylactic)

Children and adolescents

The side effects reported in children were generally similar to those reported in adults. However, infusion-related reactions (fever, difficulty breathing, chest pain) and worsening pain occurred more frequently.

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the national notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information about the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the label and the box after CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C).

Do not use Replagal if you observe changes in color or presence of foreign particles.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and the medication that you no longer need. This will help protect the environment.

Composition of Replagal

• The active ingredient is agalsidase alfa. Each ml of Replagal contains 1 mg of agalsidase alfa.

• The other components are: Sodium phosphate monobasic, monohydrate

Polysorbate 20

Sodium chloride

Sodium hydroxide

Water for injection

Appearance of the product and contents of the container

Replagal is a concentrate for solution for infusion. The medicinal product is available in vials containing 3.5 mg/3.5 ml of agalsidase alfa. There are containers of 1, 4 or 10 vials. Some container sizes may only be marketed.

Marketing Authorization Holder

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza

50–58 Baggot Street Lower

Dublin 2

D02 HW68

Ireland

Responsible for manufacturing

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

Last review date of this leaflet:

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu/. It also provides links to other websites on rare diseases and orphan drugs.

This information is intended solely for medical professionals or healthcare professionals:

Instructions for use, handling and disposal

The treatment with Replagal should be supervised by an experienced doctor in the care of patients with Fabry's disease or other hereditary metabolic disorders.

Replagal is administered at a dose of 0.2 mg/kg of body weight every other week, by intravenous infusion over 40 minutes.

1. Calculate the dose and the number of vials of Replagal needed.
2. Dilute the total volume of Replagal concentrate needed in 100 ml of a 9 mg/ml sodium chloride solution for infusion (0.9% w/v). Take precautions to ensure the sterility of the prepared solutions, as Replagal does not contain any preservative or bacteriostatic agent; an aseptic technique should be applied. Once diluted, the solution should be mixed gently, without shaking it.
3. The solution should be visually inspected to rule out the presence of particulate matter and color changes before administration.
4. The infusion solution will be administered over 40 minutes, using an intravenous line with a built-in filter. Since there are no preservatives, it is recommended to start the administration as soon as possible. However, the chemical and physical stability of the diluted solution has been demonstrated for 24 hours at 25 °C.
5. Do not use the same intravenous line for the infusion of Replagal and the concomitant infusion of other agents.
6. For single use only. The elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.