Orfadin

Patient Information Leaflet: Information for the User

Orfadin 2 mg hard capsules, 5 mg hard capsules, 10 mg hard capsules, 20 mg hard capsules

nitisinone
Please read 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 questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What Orfadin is and what it is used for

Orfadin contains the active substance nitisinone. Orfadin is used to treat:

• a rare disease called hereditary tyrosinaemia type 1 in adults, adolescents and children (of any age group)
• a rare disease called alkaptonuria (AKU) in adults

If you suffer from these disorders, your body is unable to fully break down the amino acid tyrosine
(amino acids are the building blocks of proteins), leading to the formation of harmful substances that accumulate in the body. Orfadin blocks the breakdown of tyrosine, thereby preventing the formation of these harmful substances.
For the treatment of hereditary tyrosinaemia type 1, since tyrosine will remain in the body, you must follow a specific diet low in tyrosine and phenylalanine (another amino acid) while taking this medicine.
For the treatment of AKU, your doctor may advise you to follow a special diet.

2. What you should know before taking Orfadin

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 breast-feed during treatment with this medicine; see section
“Pregnancy and breast-feeding”.
Warnings and precautions
Talk to your doctor or pharmacist before taking Orfadin.

• Your eyes will be examined by an ophthalmologist before starting treatment with nitisinone and regularly during treatment. If your eyes become red or you notice any other eye problems, contact your doctor immediately for an eye examination. Eye disorders could be a sign of inadequate dietary control (see section 4).

During treatment, blood samples will be taken so that your doctor can monitor whether the treatment is appropriate and ensure that there are no unwanted effects that could cause changes in blood composition.
If you are receiving Orfadin for the treatment of hereditary tyrosinaemia type 1, you will undergo regular liver monitoring, as the disease affects the liver.
Your doctor should perform check-ups every 6 months. If any adverse effects occur, shorter intervals between check-ups are recommended.
Other medicines and Orfadin
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Orfadin may interfere with the effect of other medicines, such as:

• Medicines for epilepsy (such as phenytoin)
• Anticoagulant medicines (such as warfarin)

Orfadin with food
If you start treatment taking Orfadin with food, it is recommended to continue taking it with food throughout the duration of treatment.
Pregnancy and breast-feeding
The safety of this medicine in pregnant or breast-feeding women has not been studied.
If you are planning a pregnancy, consult your doctor. If you become pregnant, you must contact your doctor immediately.
You must not breast-feed while taking this medicine; see section “Do not take Orfadin”.
Driving and using machines
This medicine has a minor influence on the ability to drive and use machines. However, if you experience adverse reactions affecting your vision, do not drive or operate machinery until you have recovered normal visual function (see section 4 “Possible side effects”).

3. How to take Orfadin

Take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
For hereditary tyrosinemia type 1, treatment with this medicine must be initiated and monitored by a physician experienced in the management of this disease.
For hereditary tyrosinemia type 1, the recommended total daily dose is 1 mg/kg body weight, administered orally. Your doctor will adjust the dose individually.
It is recommended to take the dose once daily. Data in patients with body weight <20 kg are limited; therefore, in this patient population, it is recommended to divide the total daily dose into two daily administrations.
For AKU, the recommended dose is 10 mg once daily.
If you have difficulty swallowing the capsules, you may open them and mix the powder with a small amount of water or a liquid meal substitute immediately before administration.

If you take more Orfadin than you should
If you take more medicine than prescribed, contact your doctor or pharmacist as soon as possible.

If you forget to take Orfadin
Do not take a double dose to make up for the missed dose. If you miss a dose, contact your doctor or pharmacist.

If you stop taking Orfadin
If you feel that the medicine is not working as expected, inform your doctor. Do not change the dose or stop treatment without consulting your doctor.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If you notice any eye- or vision-related side effects, consult your doctor immediately for an ophthalmological examination. Treatment with nitisinone leads to higher levels of tyrosine in the blood, which may cause symptoms affecting the eyes. In patients with hereditary tyrosinaemia type 1, commonly reported eye-related side effects (which may affect more than 1 in 100 people) caused by elevated tyrosine levels include ocular inflammation (conjunctivitis), corneal opacity and inflammation (keratitis), light sensitivity (photophobia), and eye pain. Inflammation of the eyelids (blepharitis) is an uncommon side effect (may affect up to 1 in 100 people).
In patients with AKU, eye irritation (keratopathy) and eye pain are very commonly reported side effects (may affect more than 1 in 10 people).

Other side effects reported in patients with hereditary tyrosinaemia type 1 are listed below:
Other common side effects

• Reduced number of platelets (thrombocytopenia) and white blood cells (leucopenia), decrease in certain specific white blood cells (granulocytopenia).

Other uncommon side effects

• Increased number of white blood cells (leucocytosis).
• Itching, skin inflammation (exfoliative dermatitis), skin rashes.

Other side effects reported in patients with AKU are listed below:
Other common side effects

• bronchitis
• pneumonia
• itching, skin rash

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via 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 Orfadin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton after "EXP" and "Scad.", respectively. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
This medicine may be stored for a single period of 2 months (for 2 mg capsules) or 3 months (for 5 mg, 10 mg and 20 mg capsules) at a temperature not exceeding 25°C, after which it must be disposed of.
Once removed from the refrigerator, remember to record the date on the vial.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Pack contents and other information

What Orfadin contains

• The active substance is nitisinone. Orfadin 2 mg: each capsule contains 2 mg of nitisinone. Orfadin 5 mg: each capsule contains 5 mg of nitisinone. Orfadin 10 mg: each capsule contains 10 mg of nitisinone. Orfadin 20 mg: each capsule contains 20 mg of nitisinone.
• The other components are: Capsule contents: starch, pregelatinized (from maize). Capsule shell: gelatin, titanium dioxide (E 171). Printed ink: iron oxide (E 172), lacquer, propylene glycol, ammonium hydroxide.

Description of the appearance of Orfadin and pack contents
The hard capsules are opaque white, marked with the black print “NTBC” and the dosage strength “2 mg”, “5 mg”, “10 mg” or “20 mg”. The capsules contain a white or almost white powder.
The capsules are packed in plastic bottles with tamper-evident closures. Each bottle contains 60 capsules.
Marketing Authorization Holder
Swedish Orphan Biovitrum International AB
SE-112 76 Stockholm
Sweden
Manufacturer
Apotek Produktion & Laboratorier AB
Prismavägen 2
SE-141 75 Kungens Kurva
Sweden
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 their therapeutic treatments are provided.

Package leaflet: Information for the user

Orfadin 4 mg/ml oral suspension

nitisinone
Please read this 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What Orfadin is and what it is used for

Orfadin contains the active substance nitisinone. Orfadin is used to treat:

• a rare disease called hereditary tyrosinaemia type 1 in adults, adolescents and children (of any age)
• a rare disease called alkaptonuria (AKU) in adults

If you suffer from these disorders, your body is unable to fully break down the amino acid tyrosine (amino acids are the building blocks of proteins), leading to the formation of harmful substances that accumulate in the body. Orfadin blocks the breakdown of tyrosine, thereby preventing the formation of these harmful substances.

For the treatment of hereditary tyrosinaemia type 1, since tyrosine will remain in the body, you must follow a specific diet low in tyrosine and phenylalanine (another amino acid) while taking this medicine.

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

2. What you should know before taking Orfadin

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 breast-feed during treatment with this medicine; see section
"Pregnancy and breast-feeding".
Warnings and precautions
Talk to your doctor or pharmacist before taking Orfadin.

• Your eyes will be examined by an ophthalmologist before starting treatment with nitisinone and regularly during treatment. If your eyes become red or you notice any other eye effects, contact your doctor immediately for an eye examination. Eye problems could be a sign of inadequate dietary control (see section 4).
  During treatment, blood samples will be taken so that your doctor can monitor whether the treatment is appropriate and ensure that there are no unwanted effects that could cause changes in blood composition.
  If you are receiving Orfadin for the treatment of hereditary tyrosinemia type 1, you will undergo regular liver monitoring, as the disease affects the liver.
  Your doctor should perform check-ups every 6 months. If any adverse effects occur, shorter intervals between check-ups are recommended.
  Other medicines and Orfadin
  Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
  Orfadin may interfere with the effect of other medicines, such as:

• Medicines for epilepsy (such as phenytoin)

• Anticoagulant medicines (such as warfarin)

Orfadin with food
It is recommended to take the oral suspension with food.
Pregnancy and breast-feeding
The safety of this medicine in pregnant or breast-feeding women has not been studied.
If you are planning a pregnancy, consult your doctor. If you become pregnant, you must contact your doctor immediately.
You must not breast-feed during treatment with this medicine; see section "Do not take Orfadin".
Driving and using machines
This medicine has a minor influence on the ability to drive and use machines. However, if you experience adverse reactions affecting your vision, do not drive or use machines until your normal vision has returned (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 (10 g of glycerol) or higher of the oral suspension may cause headache, gastrointestinal disturbances and diarrhoea.
Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in premature and full-term infants with jaundice and may lead to nuclear jaundice (brain damage due to deposition of bilirubin in the brain). Bilirubin levels (a substance which at high levels causes yellowing of the skin) in the blood of newborns will be closely monitored. If these levels are considerably higher than normal, especially in premature infants with risk factors such as acidosis (blood pH too low) and low albumin levels (a protein present in the blood), treatment with Orfadin capsules instead of the oral suspension may be considered until bilirubin plasma levels return to normal.

3. How to take Orfadin

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
To ensure the correct dose is administered, strictly follow the instructions below for preparing and administering the dose.
For hereditary tyrosinemia type 1, treatment with this medicine must be initiated and monitored by a doctor experienced in managing the disease.
For hereditary tyrosinemia type 1, the recommended total daily dose is 1 mg/kg body weight, administered orally. Your doctor will adjust the dose individually.
It is recommended to administer the dose once daily. Data in patients with body weight <20 kg are limited; therefore, in this patient population, it is recommended to divide the total daily dose into two daily administrations.
For AKU, the recommended dose is 10 mg once daily.
The oral suspension is administered using an oral syringe directly into the mouth, without dilution.
Orfadin must 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 must be administered in ml of suspension, not in mg, as the oral syringe used to draw the correct dose from the bottle is marked in ml. If your prescription is in mg, consult your pharmacist or doctor for guidance.
The package contains a medicine bottle with a cap, an adapter, and three oral syringes (1 ml, 3 ml, and 5 ml). Always use one of the provided oral syringes to take the medicine.

• The 1 ml oral syringe (the smallest oral syringe) is marked from 0.1 ml to 1 ml with minor graduations of 0.01 ml. It is used to measure doses less than or up to 1 ml.
• The 3 ml oral syringe (the medium-sized oral syringe) is marked from 1 ml to 3 ml with minor graduations of 0.1 ml. It is used to measure doses greater than 1 ml and up to 3 ml.
• The 5 ml oral syringe (the largest oral syringe) is marked from 1 ml to 5 ml with minor graduations of 0.2 ml. It is used to measure doses greater than 3 ml.

It is important to use the correct oral syringe when taking the medicine. Your doctor, pharmacist, or nurse will tell you which oral syringe to use based on the dose prescribed for you.

How to prepare a new medicine bottle for first use:
Before taking the first dose, the bottle must be shaken vigorously because, during prolonged storage, particles may form a solid aggregate at the bottom. Follow the instructions below:

Figure A. Figure B. Figure C.

1. Remove the bottle from the refrigerator. Record on the bottle label the date the bottle was removed from the refrigerator.
2. Shake the bottle vigorously for at least 20 seconds until the solid aggregate at the bottom of the bottle is completely dispersed (Figure A).
3. Remove the child-resistant screw cap by pressing down firmly and turning it counterclockwise (Figure B).
4. Place the open bottle upright on a table. Firmly push the plastic adapter as far as possible onto the neck (Figure C). Close the bottle with the child-resistant screw cap.

For subsequent dosing, follow the instructions below: “How to prepare a dose of medicine.”

How to prepare a dose of medicine

Figure D. Figure E. Figure F.

1. Shake the bottle vigorously for at least 5 seconds (Figure D).
2. Immediately after, open the bottle by removing the child-resistant screw cap.
3. Fully press the plunger into the oral syringe.
4. Hold the bottle upright and firmly insert the oral syringe into the opening of the adapter at the top of the bottle (Figure E).
5. Carefully invert the bottle, keeping the oral syringe in place (Figure F).
6. To draw the prescribed dose (ml), slowly pull the plunger until the top edge of the black ring aligns exactly with the dose mark (Figure F). If air bubbles are visible in the filled oral syringe, push the plunger back up to expel the air bubbles. Then pull the plunger again until the black ring aligns exactly with the dose mark.
7. Return the bottle to an upright position. Detach the oral syringe by gently rotating and removing it from the bottle.
8. The dose must be administered immediately into the mouth (without dilution) to prevent aggregation in the oral syringe. The oral syringe must be emptied slowly to allow for safe swallowing; rapid administration of the medicine may cause choking.
9. Immediately replace the child-resistant screw cap after use. Do not remove the bottle adapter.
10. The bottle may be stored at room temperature (not exceeding 25°C).

Cleaning:
Clean the oral syringe immediately with water. Separate the barrel and plunger and rinse both parts with water. Shake off excess water and allow the disassembled oral syringe to dry before reassembling for the next dose.

If you take more Orfadin than you should
If you take more medicine than prescribed, contact your doctor or pharmacist as soon as possible.

If you forget to take Orfadin
Do not take a double dose to make up for a missed dose. If you miss a dose, contact your doctor or pharmacist.

If you stop taking Orfadin
If you feel the medicine is not working as expected, inform your doctor. Do not change the dose or stop treatment without informing your doctor.

If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you notice any eye- or vision-related side effects, consult your doctor immediately for an ophthalmological examination. Treatment with nitisinone leads to higher levels of tyrosine in the blood, which may cause symptoms affecting the eyes. In patients with hereditary tyrosinemia type 1, eye-related side effects commonly reported (affecting more than 1 in 100 people) due to increased tyrosine levels include ocular inflammation (conjunctivitis), corneal opacity and inflammation (keratitis), light sensitivity (photophobia), and eye pain. Inflammation of the eyelids (blepharitis) is an uncommon side effect (may affect up to 1 in 100 people).
In patients with AKU, ocular irritation (keratopathy) and eye pain are very commonly reported side effects (may affect more than 1 in 10 people).

Other side effects reported in patients with hereditary tyrosinemia type 1 are listed below:
Other common side effects

• Reduced number of platelets (thrombocytopenia) and white blood cells (leukopenia), decrease in certain specific white blood cells (granulocytopenia).

Other uncommon side effects

• Increased number of white blood cells (leukocytosis).
• Itching, skin inflammation (exfoliative dermatitis), skin rashes.

Other side effects reported in patients with AKU are listed below:
Other common side effects

• bronchitis
• pneumonia
• itching, skin rash

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Orfadin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton after "EXP" and "Scad.", respectively. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial in an upright position.
After first opening, this medicine may be stored for a single period of 2 months and at a temperature not exceeding 25°C, after which it must be disposed of.
Once removed from the refrigerator, remember to record the date on the vial.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Orfadin contains

• The active substance is nitisinone. Each ml contains 4 mg of nitisinone.
• The other components are hypromellose, glycerol (see section 2), polysorbate 80, sodium benzoate (E211) (see section 2), monohydrate citric acid, sodium citrate (see section 2), artificial strawberry flavour, and purified water.

Description of the appearance of Orfadin and package contents
The oral suspension is a white, opaque, slightly viscous suspension. Before shaking,
Orfadin oral suspension may appear as a solid agglomerate at the bottom of the bottle and a
slightly opalescent liquid.
The suspension is contained in a 100 ml dark glass bottle with a white child-resistant screw cap. Each bottle contains 90 ml of suspension.
Each package contains one bottle, one adapter, and three 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

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 their therapeutic treatments are provided.