Package Leaflet: Information for the User

Orfadin 2 mg Hard Capsules

Orfadin 5 mg Hard Capsules

Orfadin 10 mg Hard Capsules

Orfadin 20 mg Hard Capsules

nitisinona

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

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

- If you have any questions, ask your doctor, pharmacist or nurse.

- This medicine has been prescribed for you only. Do not pass it on to others even if they have the same symptoms as you, as it may harm them.

- If you experience any side effects, talk to your doctor, pharmacist or nurse. See section 4.

1. What Orfadin is and what it is used for

2. What you need to know before you start taking Orfadin

3. How to take Orfadin

4. Possible side effects

5. Storage of Orfadin

6. Contents of the pack and additional information

Orfadin contains the active ingredient nitisinona. Orfadin is used to treat:

• an uncommon disease called hereditary tyrosinemia type 1 in adults, adolescents, and children (of any age group).
• an uncommon disease called alcaptonuria (AKU) in adults

In these diseases, your body cannot fully break down the amino acid tyrosine (amino acids are the fundamental elements of proteins), forming toxic substances. These substances accumulate in your body. Orfadin blocks the breakdown of tyrosine, and toxic substances are not formed.

For the treatment of hereditary tyrosinemia type 1, you must follow a special diet while taking this medication, because tyrosine will still be in your body. This diet is based on a low content of tyrosine and phenylalanine (another amino acid).

For the treatment of AKU, your doctor may advise you to follow a special diet.

Do not take Orfadin

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

Do not breastfeed while taking this medicine (see section “Pregnancy and breastfeeding”).

Warnings and precautions

Consult your doctor or pharmacist before starting to take Orfadin.

• Your ophthalmologist will examine your eyes before treatment and regularly during treatment with nitisinone. If you notice redness of the eyes or any other eye effect, contact your doctor immediately for an eye examination. Eye problems (see section 4) may be a sign of inadequate dietary control.

Blood samples will be taken during treatment to control whether the treatment is adequate and to ensure that there are no blood-related side effects.

If you are taking Orfadin for the treatment of hereditary tyrosinemia type 1, you will have regular liver checks because the disease affects the liver.

Your doctor should follow up with you every 6 months. If you experience any side effects, it is recommended to use shorter intervals.

Other medicines and Orfadin

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

Orfadin may interfere with the effect of other medicines, such as:

- epilepsy medicines (such as phenytoin)

- blood clotting medicines (such as warfarin)

Use of Orfadin with food

It is recommended to take the oral suspension with food.

Pregnancy and breastfeeding

The safety of this medicine has not been studied in pregnant women and breastfeeding women.

Consult your doctor if you plan to become pregnant. If you become pregnant, you should consult your doctor immediately.

Do not breastfeed while taking this medicine (see section “Do not take Orfadin”).

Driving and operating machines

The influence of this medicine on the ability to drive and use machines is small. However, if you experience side effects that affect your vision, you should not drive or use machines until your vision has returned to normal (see section 4 “Possible side effects”).

Orfadin contains sodium, glycerol, and sodium benzoate

This medicine contains 0.7 mg (0.03 mmol) of sodium per ml.

A dose of 20 ml of oral suspension (10 g of glycerol) or more may cause headache, stomach discomfort, and diarrhea.

Sodium benzoate may increase jaundice (yellow coloration of the skin and eyes) in premature or full-term newborns and may lead to kernicterus (brain damage caused by bilirubin deposits in the brain). In newborns, blood bilirubin levels (a substance that causes yellow coloration of the skin at high concentrations) should be strictly controlled. If levels are markedly higher than they should be, especially in premature babies with risk factors such as acidosis (low blood pH) or low albumin concentration, consider using Orfadin capsules instead of the oral suspension until bilirubin plasma levels have normalized.

Follow exactly the medication administration instructions provided by your doctor. If you are unsure, ask your doctor or pharmacist.

Follow carefully the instructions provided below on preparation and administration of the dose to ensure that the correct dose is administered.

For hereditary tyrosinemia type 1, treatment with this medication should be initiated and supervised by a doctor experienced in the treatment of the disease (hereditary tyrosinemia type 1).

For hereditary tyrosinemia type 1, the recommended daily dose is 1 mg/kg of body weight administered orally. Your doctor will adjust the dose individually.

It is recommended to administer the dose once a day. However, due to limited data in patients with a body weight of less than 20 kg, the dose may need to be adjusted.

For AKU, the recommended dose is 10 mg once a day.

The oral suspension should be administered directly in the mouth without dilution using the oral syringe.

Orfadin should not be injected. Do not attach a needle to the syringe.

How to prepare the dose to be administered

The dose prescribed by your doctor should be administered in ml of suspension and not in mg. This is because the oral syringe to be used to extract the correct dose from the bottle is marked in ml.If your prescription is in mg, contact your doctor or pharmacist for advice.

The packaging contains a medication bottle with a child-resistant cap, a bottle adapter, and three oral syringes (1 ml, 3 ml, and 5 ml). Always use these oral syringes to take the medication.

•The 1 ml oral syringe (the smallest) is graduated between 0.1 ml and 1 ml with small marks of 0.01 ml. It is used to measure doses up to 1 ml.

•The 3 ml oral syringe (the medium) is graduated between 1 ml and 3 ml with small marks of 0.1 ml. It is used to measure doses from 1 ml to 3 ml.

•The 5 ml oral syringe (the largest) is graduated between 1 ml and 5 ml with small marks of 0.2 ml. It is used to measure doses from 3 ml.

It is essential to use the correct oral syringe to take the medication. Your doctor, pharmacist, or nurse will indicate how to use the oral syringe according to the prescribed dose.

How to prepare a new medication bottle for the first time use:

Before taking the first dose, the bottle should be shaken vigorously, as during prolonged storage, particles form a solid precipitate at the bottom of the bottle. Follow the instructions described below:

Figure A. Figure B. Figure C.

1. Remove the bottle from the refrigerator and note the date on the bottle label.
2. Shake the bottle vigorously for at least 20 seconds until the solid precipitate at the bottom of the bottle is completely dispersed (Figure A).
3. Remove the child-resistant cap; to do this, press it down firmly and turn it counterclockwise (Figure B).

Place the bottle upright on the table. Push the plastic adapter as far as possible into the neck of the bottle (Figure C) and close the bottle with the child-resistant cap.

For subsequent doses, refer to the instructions "How to prepare a medication dose" below.

How to prepare a medication dose

Figure D. Figure E. Figure F.

1. Shake the bottle vigorously for at least 5 seconds (Figure D).
2. Immediately, remove the child-resistant cap and open the bottle.
3. Push the plunger of the oral syringe as far as possible.
4. Hold the bottle upright and insert the oral syringe firmly into the opening of the adapter located at the top of the bottle (Figure E).
5. Invert the bottle carefully without extracting the oral syringe (Figure F).
6. To obtain the prescribed dose (ml), pull the plungerslowlydownward until the top edge of the black ring is exactly level with the line indicating the dose (Figure F). If you observe any air bubbles inside the oral syringe, push the plunger back up until the bubbles come out. Then, pull the plunger down again until the top edge of the black ring is exactly level with the line indicating the dose.
7. Place the bottle upright again. Gently turn the oral syringe to extract it from the bottle.
8. The dose should be administered immediately in the mouth (without dilution) to prevent a precipitate from forming in the oral syringe. The oral syringe should be emptiedslowlyto allow the patient to swallow the product; if the medication comes out in a fast stream, it may cause choking.
9. Immediately place the child-resistant cap back on. The bottle adapter should not be removed.
10. The bottle can be stored at room temperature (not exceeding 25 °C).

Cleaning:

Cleanimmediatelythe oral syringe with water. Separate the plunger from the barrel of the syringe and rinse both with water. Shake off any excess water and let the oral syringe dry disassembled until it needs to be reassembled for a new administration.

If you take more Orfadin than you should

If you have taken more of this medication than you should, inform your doctor or pharmacist immediately.

If you forget to take Orfadin

Do not take a double dose to compensate for the missed doses. If you have forgotten to take a dose, inform your doctor or pharmacist.

If you interrupt treatment with Orfadin

If you think the medication is not working properly, inform your doctor. Do not change the dose or discontinue treatment without first consulting your doctor.

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

Like all medications, this medication may cause adverse effects, although not everyone will experience them.

If you notice any adverse effects related to the eyes, inform your doctor immediately so that they can perform an ophthalmological examination. Treatment with nitisinone increases blood tyrosine levels, which can cause eye-related symptoms. In patients with hereditary tyrosinemia type 1, frequent eye adverse effects (affecting more than 1 in 100 people) due to higher tyrosine levels include conjunctivitis, corneal opacity and inflammation (keratitis), light sensitivity (photophobia), and eye pain. Blepharitis is a rare adverse effect (affecting up to 1 in 100 people).

In patients with AKU, eye irritation (keratopathy) and eye pain are frequently reported adverse effects (affecting more than 1 in 10 people).

Below are other adverse effects reported in patients with hereditary tyrosinemia type 1:

Other frequent adverse effects

• Decreased platelet count (thrombocytopenia) and white blood cell count (leucopenia), reduced counts of certain types of white blood cells (granulocytopenia).

Other rare adverse effects

- Increased white blood cell count (leucocytosis),

- Itching (pruritus), skin inflammation (dermatitis exfoliativa), and rash.

Below are other adverse effects reported in patients with AKU:

Other frequent adverse effects

• Bronchitis,
• Pneumonia,
• Itching (pruritus), rash.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national notification system included in the Appendix V . By reporting adverse effects, you can contribute to providing more information about the safety of this medication.

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

Do not use this medication after the expiration date that appears on the bottle and the box after “EXP”. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2 °C and 8 °C). Do not freeze.

Keep the bottle in an upright position.

After the first opening, the medication can be stored for a single period of 2 months at a temperature not exceeding 25 °C, after which it must be discarded.

Do not forget to note on the bottle the date when you took it out of the refrigerator.

Medicines should not be thrown down the drains or in the trash. Ask your pharmacist how to dispose of the packaging and the medications that you no longer need. In this way, you will help to protect the environment.

Composition of Orfadin

-The active ingredient is nitisinona. Each ml contains 4 mg of nitisinona.

-The other components are hypromellose, glycerol (see section 2), polisorbate 80, sodium benzoate (E211) (see section 2), citric acid monohydrate, sodium citrate (see section 2), strawberry artificial flavor, and purified water.

Appearance of the product and contents of the container

The oral suspension is a white, opaque, and slightly viscous suspension. Before shaking the bottle, it may appear as a solid cake at the bottom with a slightly opalescent supernatant.

It is presented in a 100 ml amber-colored bottle with a white child-resistant cap.

Each bottle contains 90 ml of oral suspension.

Each package contains a bottle, a bottle adapter, and 3 oral syringes.

Marketing Authorization Holder

Swedish Orphan Biovitrum International AB

SE-112 76 Stockholm

Sweden

Manufacturer

Apotek Produktion & Laboratorier AB

Celsiusgatan 43

SE-212 14 Malmö

Sweden

Apotek Produktion & Laboratorier AB

Prismavägen 2

SE-141 75 Kungens Kurva

Sweden

Last review date of this leaflet: 04/2024.

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu/.There are also links to other websites on rare diseases and orphan medicines.