REPLAGAL 1 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Replagal 1 mg/ml concentrate for solution for infusion

Agalsidase alfa

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

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

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

• 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 or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What is Replagal and what is it used for

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

Replagal is used to treat adult patients, as well as adolescents and children from 7 years of age, with a confirmed diagnosis of Fabry disease. It is used as long-term enzyme replacement therapy when the level of enzymes 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 medicine). Replagal reduced left ventricular 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.

2. What you need to know before you are given Replagal

You should not be given Replagal

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

Warnings and precautions

Talk to your doctor or pharmacist before you start taking Replagal.

If you notice any of these effects during or after an infusion, you should tell your doctor immediately:

• high fever, chills, sweating, rapid heartbeat

• vomiting

• dizziness

• hives (rash)

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

Your doctor may temporarily stop the infusion (5-10 minutes) until the symptoms disappear and then restart the infusion. Your doctor may also treat the symptoms with other medicines (antihistamines or corticosteroids). Most of the time, you can still receive Replagal even if these symptoms occur.

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

If your body produces antibodies due to treatment with Replagal, this will not make Replagal less effective and the antibodies may disappear over time.

If you have advanced kidney disease, you may find that your treatment with Replagal has a limited effect on your kidneys. Talk to your doctor or pharmacist before you start taking Replagal.

Children

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

Using Replagal with other medicines

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

Tell your doctor if you are taking any medicine that contains chloroquine, amiodarone, benoquin, or gentamicin. There is a theoretical risk of decreased activity of agalsidase alfa.

Pregnancy and breastfeeding

The limited clinical data available on exposure to Replagal during pregnancy do not indicate any adverse effects on the mother or the newborn.

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

You can drive and use machines while you are receiving Replagal.

3. How Replagal is given

This medicine should be administered and supervised by trained personnel 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 corresponds to approximately 14 mg or 4 vials (glass bottles) of Replagal for a person weighing about 70 kg.

Use in children and adolescents

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

Children and adolescents may be more likely than adults to experience an infusion-related reaction. Talk to your doctor if you experience any side effects during the infusion.

Method of administration

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

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

The infusion will be given 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 disease.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

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

Most of them are mild or moderate. Approximately 1 in 7 patients (very common reaction) may have a reaction during or after the infusion of Replagal (infusion-related reaction). These reactions include chills, headache, nausea, fever, flushing of the face, fatigue, low blood pressure, instability, sweating, difficulty breathing, itching, tremors, cough, and vomiting. However, some side effects can be serious and may require treatment. Infusion-related reactions that affect the heart, including heart rhythm problems, myocardial ischemia, and heart failure, may occur in patients with Fabry disease that affects the heart (frequency not known). Your doctor may temporarily stop the infusion (5-10 minutes) until the symptoms disappear and then restart the infusion. Your doctor may also treat the symptoms with other medicines (antihistamines or corticosteroids). Most of the time, you can still receive Replagal even if these symptoms occur.

List of other side effects:

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 taste, eye watering, 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 rash on the skin, rash at the infusion site

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

• feeling of cold or heat, flu-like symptoms, nausea, feeling of lack of energy

Uncommon: may affect up to 1 in 100 people

• severe allergic reaction (anaphylactic type)

Children and adolescents

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

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. 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.

5. Storing Replagal

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 carton after EXP. The expiry date is the last day of the month stated.

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

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Replagal contains

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

• The other ingredients are: Sodium phosphate monobasic monohydrate

Polysorbate 20

Sodium chloride

Sodium hydroxide

Water for injections

Appearance and packaging

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

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

Date of last revision of this leaflet

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. It also provides links to other web sites on rare diseases and orphan medicines.

This information is intended only for healthcare professionals:

Instructions for use, handling, and disposal

Treatment with Replagal should be supervised by a doctor experienced in the care of patients with Fabry disease or other inherited metabolic disorders.

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

1. Calculate the dose and number of Replagal vials 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 must be used. Once diluted, the solution should be gently mixed, without shaking.
3. The solution should be visually inspected for particulate matter and color changes before administration.
4. The infusion solution will be administered over 40 minutes, using an intravenous line with an in-line filter. Since there are no preservatives, it is recommended to start 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. Disposal of unused medicine and all materials that have come into contact with it should be done in accordance with local regulations.