Consumer medicine information

Orfadin Capsules

Nitisinone

BRAND INFORMATION

Brand name

Orfadin

Active ingredient

Nitisinone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Orfadin Capsules.

What is in this leaflet

This leaflet answers some common questions about ORFADIN hard capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ORFADIN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ORFADIN is used for

ORFADIN contains a medicine called nitisinone which is used for the treatment of a disease called hereditary tyrosinaemia type 1 (HT-1). In this disease the body is unable to completely break down the amino acid tyrosine. Harmful substances can form and accumulate in the body.

ORFADIN blocks the breakdown of tyrosine and by doing so the harmful substances are not formed. However, tyrosine will remain in the body and therefore a special diet that is low in tyrosine and phenylalanine content must be followed when taking ORFADIN.

Nitisinone belongs to a group of medicines called 'other alimentary and metabolism products'.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

ORFADIN is not addictive.

ORFADIN is available only with a doctor's prescription.

Before you take ORFADIN

When you must not take it

Do not take ORFADIN if you have an allergy to:

  • any medicine containing nitisinone
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not breast-feed if you are taking this medicine.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor about your diet regimen. Your doctor will advise you on how to maintain a diet restricted in tyrosine and phenylalanine content.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking ORFADIN.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and ORFADIN may interfere with each other. These include:

  • warfarin, a medicine used to thin your blood
  • phenytoin, a medicine used to treat epilepsy
  • furosemide (frusemide), a diuretic

These medicines may be affected by ORFADIN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take ORFADIN capsules

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions , ask your doctor or pharmacist for help.

How much to take

The recommended starting dose is 1 mg/kg body weight/day divided in 2 doses administered orally. Your doctor will prescribe the correct dose for you.

Your doctor may change your total dose from twice a day to once a day if you weigh more than 20 kg and you have been taking ORFADIN twice daily for at least 4 weeks.

Your doctor will adjust your ORFADIN dose based on your response to ORFADIN and your test results.

How to take it

Take ORFADIN with food.

Swallow the capsule whole with a full glass of water. If you have problems with swallowing the capsules, you may open the capsule and mix the powder with a small amount of water or formula just before you take it, making sure that you take the entire amount.

When to take it

If you are taking ORFADIN twice daily, take your first dose in the morning and your second dose in the evening.

Your doctor will advise you on the correct time to take ORFADIN when moving you to once daily dose.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking ORFADIN for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ORFADIN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using ORFADIN

Things you must do

It is very important that you stay on the special diet, with low tyrosine and phenylalanine content that your doctor recommended. If you do not understand the instructions on your diet, ask your doctor for help.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ORFADIN.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking ORFADIN. Remind them if any new medicines are about to be started.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking ORFADIN. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked.

  • Your doctor will do regular blood and urine checks to ensure that you are on the right dose of ORFADIN and to make sure that there are no possible side effects causing blood disorders.
  • Your doctor will also check your liver regularly as the disease can affect the liver.
  • Your doctor will also check on your general development.

Things you must not do

Do not take ORFADIN to treat any other complaints unless your doctor tells you to.

Do not give ORFADIN to anyone else, even if they have the same condition as you.

Do not stop taking ORFADIN or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Do not breast-feed while taking ORFADIN.

Things to be careful of

ORFADIN is not known to cause dizziness or light headedness, but ORFADIN can affect your vision if you develop certain side effects. Be careful driving or operating machinery or doing other jobs until you know how ORFADIN affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ORFADIN.

This medicine helps most people with HT-1, but it may have some unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If you experience red eyes, or any of the following eye problems, tell your doctor immediately.

Your doctor will immediately check your eyes.

Eye problems could be a sign of inadequate dietary control.

  • different eye symptoms as listed below:
    - scarring or clouding of the cornea
    - inflammation in the cornea
    - inflammation in the eye
    - inflammation in the eyelid
    - sensitivity to light
    - eye pain

Tell your doctor or pharmacist if you notice any of the following symptoms, and they worry you:

  • rash
  • itching or irritating sensation of skin
  • redness and peeling of skin
  • headache
  • stomach pain
  • constipation

The above list includes the more common side effects of your medicine.

There may be other side effects affecting your liver and certain blood cell counts that your doctor will carefully monitor by doing regular blood and urine checks.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

After using ORFADIN

Storage

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

ORFADIN capsules should be stored in the box/bottle, in a refrigerator between 2°C - 8°C. Do not freeze. Alternatively, and for a period of 2 months only, ORFADIN capsules can also be stored in a cool dry place where the temperature stays below 25°C.

To help you remember, write the discard date in the space provided on the ORFADIN bottle when you stop refrigerating.

After this period, discard all ORFADIN capsules that have not been refrigerated.

Do not store ORFADIN or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car, especially on hot or cold days. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your doctor or pharmacist what to do with any medicine that is left over.

Product description

What it looks like

ORFADIN capsules are white, opaque, hard gelatin capsules, imprinted with "NTBC" and the strength "2 mg", "5 mg" "10 mg" or "20 mg" in black.

The capsules contain a white to off-white powder.

Ingredients

Each ORFADIN capsule contains either 2 mg, 5 mg, 10 mg, or 20 mg of nitisinone.

It also contains the following inactive ingredients:

  • pregelatinised maize starch
  • gelatin
  • titanium dioxide
  • printing ink: Capsugel Ink 10A1 Black (Proprietary Ingredient Number 109522) or
  • printing ink: Capsugel Ink 10A2 Black (Proprietary Ingredient Number 109521)

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

ORFADIN capsules are available in plastic bottles with child resistant closures.

Each bottle contains 60 capsules.

Supplier

ORFADIN is supplied in by:

A. Menarini Australia Pty. Ltd.
Level 8, 67 Albert Avenue
CHATSWOOD NSW 2067
Medical Information: 1800 644 542

Australian Registration Number:

ORFADIN 2 mg: AUST R 164163

ORFADIN 5 mg: AUST R 164173

ORFADIN 10 mg: AUST R 164174

ORFADIN 20 mg: AUST R 297735

ORFADIN® is a registered trademark of Swedish Orphan Biovitrum International AB, used under license by A. Menarini Australia Pty. Ltd.

This leaflet was revised September 2020.

For the most up to date version of this leaflet, please go to www.menarini.com.au/cmi

[vA14-0]

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Orfadin

Active ingredient

Nitisinone

Schedule

S4

 

1 Name of Medicine

Nitisinone.

2 Qualitative and Quantitative Composition

Capsules: Each capsule contains 2 mg, 5 mg, 10 mg or 20 mg nitisinone.
Oral suspension: 1 mL contains 4 mg of nitisinone.

Excipients with known effect.

The oral suspension contains glycerol and sodium benzoate (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsules: white, opaque, hard gelatin capsules imprinted with "NTBC 2 mg", "NTBC 5 mg", "NTBC 10 mg" or "NTBC 20 mg" in black ink; and contain a white to off white powder.
Oral suspension: white, slightly viscous, opaque suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Orfadin (nitisinone) is indicated for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

4.2 Dose and Method of Administration

Orfadin treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients.
Treatment of HT-1 should be initiated as early as possible to increase overall survival and avoid complications such as liver failure, liver cancer and renal disease. Adjunct to the Orfadin treatment, a diet deficient in phenylalanine and tyrosine is mandatory. The patient should be provided with clear instructions on the restricted diet and on the importance of adherence to the restricted diet. The patient's compliance to the diet should be checked regularly by monitoring of phenylalanine and plasma tyrosine levels.

Starting dose.

The recommended initial dose is 1 mg/kg body weight/day divided in 2 doses administered orally. The dose of Orfadin should be adjusted individually.

Dose adjustment.

Regular monitoring, should include urine succinylacetone, liver function test values and alpha-fetoprotein levels (see Section 4.4 Special Warnings and Precautions for Use). If urine succinylacetone is still detectable one month after the start of Orfadin treatment, the Orfadin dose should be increased to 1.5 mg/kg body weight/day divided in 2 doses. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of all biochemical parameters. This dose should be considered as a maximal dose for all patients.
If the biochemical response is satisfactory, the dose should be adjusted only according to body weight gain.
However, in addition to the tests above, during the initiation of therapy, a switch from twice daily to once daily dosing or if there is a deterioration, it may be necessary to follow more closely all available biochemical parameters (i.e. plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
In patients who weigh 20 kg or more, and who have undetectable plasma and urine succinylacetone concentrations after a minimum of 4 weeks on a stable twice a day dosage of Orfadin, the total daily dose of Orfadin may be given once daily (i.e. 1 to 2 mg/kg once daily).
However, due to the limited data in patients with body weight < 20 kg, it is recommended to divide the total daily dose into two daily administrations in this patient population.
Orfadin capsules and oral suspension should be administered with food, (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Method of administration.

Capsules.

Orfadin is available in 2 mg, 5 mg, 10 mg and 20 mg capsules. In the case of paediatric patients, the capsules may be opened and the content suspended in a small amount of water or formula diet immediately before intake.
Orfadin is also available as a 4 mg/mL oral suspension for paediatric and adult patients who may have difficulty in swallowing capsules.

Oral suspension.

The suspension is administered in the patient's mouth with an oral syringe without dilution. Three oral syringes (1 mL, 3 mL and 5 mL) are included in the pack to measure the dose in mL in accordance with the prescribed dose. It is recommended that the healthcare professional advises the patient or caregiver how to use the oral syringes to ensure that the correct volume is administered and that the prescription is given in mL.
The oral syringes are graduated in 0.01 mL, 0.1 mL and 0.2 mL increments respectively. Table 1 shows the dose conversion (mg/mL) for the three oral syringes sizes.

Important information about instructions for use.

Re-dispersing is required before each use by vigorous shaking.
Before re-dispersion, the medicinal product may appear as a solid cake with a slightly opalescent supernatant.
The dose should be withdrawn and administered immediately after re-dispersion.
It is important to carefully follow the instructions given below for preparation and administration of the dose, in order to ensure the dosing accuracy.

How to prepare a new bottle of Orfadin suspension before first time use.

Before taking the first dose, the bottle should be shaken vigorously since during long-term storage the particles will form a solid cake at the bottom of the bottle.
1. The bottle should be removed from the refrigerator and the date it should be discarded should be noted on the bottle label, which is 2 months after it is first opened.
2. Before measuring the first dose, the unopened bottle should be shaken vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed.
3. The child-resistant screw cap should be removed by pushing it down firmly and turning it anti-clockwise.
4. The open bottle should be placed upright on a table, and the plastic adaptor pushed firmly into the neck of the bottle as far as possible. The adaptor must be left in place throughout the use of this bottle of medicine. The bottle should be closed with the child resistant screw cap.
For subsequent dosing, follow the instructions below on 'How to prepare a dose of medicine'.

How to prepare a dose of medicine.

1. The bottle should be shaken vigorously for at least 5 seconds.
2. Immediately thereafter, the bottle should be opened by removing the child-resistant screw cap.
3. The plunger inside the oral syringe should be pushed fully down.
4. The bottle should be kept in an upright position and the oral syringe inserted firmly into the hole of the adaptor, at the top of the bottle.
5. The bottle should be carefully turned upside down with the oral syringe in place.
6. In order to withdraw the prescribed dose (mL), the plunger should be pulled down slowly until the top edge of the black ring is exactly level with the line marking the dose. If any air bubbles are observed inside the filled oral syringe, the plunger should be pushed back up until the air bubbles are expelled. Then the plunger should be pulled down again until the top edge of the black ring is exactly level with the line marking the dose.
7. The bottle should be turned to an upright position again, and the oral syringe disconnected by gently twisting it out of the bottle adaptor.
8. The dose should be administered in the mouth immediately (without dilution) in order to avoid caking in the oral syringe. The oral syringe should be emptied slowly to allow swallowing; rapid squirting of the medicine may cause choking.
9. The child-resistant screw cap should be immediately screwed onto the bottle. The bottle adaptor should not be removed.
10. The opened bottle of medicine may be stored at a temperature below 25°C or in the refrigerator (2-8°C) and must be discarded 2 months after opening. The date it should be discarded should be noted on the bottle label.
Clean the oral syringe immediately with water. Separate barrel and plunger and rinse both with water. Shake off excess water and leave the disassembled oral syringe to dry until reassemble for next dosing occasion.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Mothers receiving nitisinone must not breastfeed (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

High plasma tyrosine concentrations and associated adverse effects.

There is a predictable increase in plasma tyrosine concentrations if nitisinone is administered without a diet restricted in tyrosine and phenylalanine content. Inadequate restriction of tyrosine and phenylalanine intake can result in elevations in plasma tyrosine. Plasma tyrosine levels should be kept below 500 micromole/L in order to avoid toxic effects to the eyes (corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin (painful hyperkeratotic plaques on the soles and palms) and nervous system (variable degrees of mental retardation and developmental delay). In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels > 500 micromole/L, both symptomatic and asymptomatic keratopathies have been observed in patients after receiving treatment with nitisinone.

Diet compliance and monitoring of plasma tyrosine levels.

To avoid side effects that can occur due to high plasma tyrosine levels as described above, it is important to establish that the patient adheres to the dietary regimen and to monitor plasma tyrosine concentrations regularly. A more restricted tyrosine and phenylalanine diet should be implemented if the plasma tyrosine level goes above 500 micromole/L. It is not recommended to lower the plasma tyrosine concentration by reducing or discontinuing nitisinone, since the metabolic defect may result in deterioration of the patient's clinical condition.

General development.

Cognitive and developmental disturbances have been observed in the patient population. Ongoing analysis has not yet identified whether these are caused by the disease itself, the medication or other contributing factors. In the view of the limited data on the long-term effects of nitisinone treatment, it is essential that all patients treated with nitisinone undergo regular and systematic developmental assessment, including neurocognitive development.

Eye monitoring.

It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment, and thereafter regularly. A patient displaying visual disorders during treatment with nitisinone should without delay be examined by an ophthalmologist.

Liver monitoring.

The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended also to monitor serum alpha-fetoprotein concentration. Increase in serum alpha-fetoprotein concentration may be a sign of inadequate treatment. Patients with increasing alpha-fetoprotein or signs of nodules in the liver should always be evaluated for hepatic malignancy.
Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasm, and liver failure requiring liver transplantation. Regular monitoring of these complications by hepatic imaging (ultrasound, computerised tomography, and magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. Patients with increasing alpha-fetoprotein levels or development of liver nodules during treatment with nitisinone should be evaluated for hepatic malignancy.

Platelet and white blood cell (WBC) monitoring.

It is recommended that platelet and WBC counts are monitored regularly, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation.
Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.

Cytochrome P450.

Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treated patients who are concomitantly treated with medicinal products primarily metabolized through CYP2C9, especially those with a narrow therapeutic window, should be monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excipients with known effect - oral suspension.

Glycerol.

Each mL contains 500 mg glycerol. A dose of 20 mL oral suspension (10 g glycerol) or more may cause headache, stomach upset and diarrhoea. Consider switching patients who are unable to tolerate the oral suspension to Orfadin capsules.

Sodium.

Each mL contains 0.7 mg (0.03 millimole) of sodium. Consider switching patients on a sodium restricted diet to Orfadin capsules.

Sodium benzoate.

Each mL contains 1 mg sodium benzoate. Increase in bilirubin following its displacement from albumin, caused by benzoic acid and its salts, may increase jaundice in pre-term and full-term jaundiced neonates and develop into kernicterus (unconjugated bilirubin deposits in the brain tissue). A close monitoring of the plasma levels of bilirubin in the newborn patient is therefore of great importance. Bilirubin levels should be measured before start of treatment: in case of markedly elevated plasma levels of bilirubin, especially in premature patients with risk factors as acidosis and low albumin level, treatment with an appropriately weighed portion of Orfadin capsules should be considered instead of the oral suspension until the unconjugated bilirubin plasma levels are normalised.

Use in adult population.

There is very limited data in the adult population and no information on the treatment of the elderly.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Nitisinone is metabolised in vitro by CYP3A4 and dose-adjustment may therefore be needed when nitisinone is co-administered with inhibitors or inducers of this enzyme.
Based on data from a clinical interaction study, nitisinone is a moderate inhibitor of CYP2C9, a weak inducer of CYP2E1 and a weak inhibitor of OAT1 and OAT3, whereas nitisinone did not inhibit CYP2D6. Nitisinone treatment may therefore result in increased plasma concentrations of co-medications metabolized primarily via CYP2C9, such as warfarin and phenytoin (see Section 4.4 Special Warnings and Precautions for Use).
The following AUC ratios were observed for the probe drugs used in the clinical interaction study, when administered alone and together with nitisinone. See Table 2.
Based on in vitro studies, nitisinone is not expected to inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism or induce CYP1A2, 2B6, or 3A4/5. Nitisinone is not expected to inhibit P-gp, BCRP, OATP1B1, OATP1B3 or OCT2-mediated transport.
Food does not influence the bioavailability (AUC) of Orfadin oral suspension, but intake together with food decreases the absorption rate, as shown in a study in healthy volunteers, and consequently leads to lower fluctuations in serum concentrations within a dosage interval. Cmax after administration with food was 81.5% of Cmax in fasting subjects. Tmax increased from 0.5 h in fasting subjects to 8 h when the suspension was given with food.
No formal food interactions studies have been performed with Orfadin capsules. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment with Orfadin capsules is initiated with food, this should be maintained on a routine basis.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Prolonged mating period and increased postimplantation loss were observed following treatment of female mice prior to mating through early embryogenesis at 50 mg/kg/day orally (2 times the maximum clinical dose based on body surface area). No effects were observed at 5 mg/kg/day (less than the maximum clinical dose based on body surface area).
(Category B3)
There are no adequate data from the use of nitisinone in pregnant women. Nitisinone should not be used during pregnancy unless clearly necessary. Nitisinone crosses the human placenta.
Gestation length was increased in pregnant mice given nitisinone at oral doses from 50 mg/kg/day (2 times the maximum clinical dose based on body surface area).
In pregnant mice and rabbits, embryotoxicity (decreased fetal weights, increased early intrauterine deaths and increased postimplantation loss) and fetal abnormalities (incomplete skeletal ossification in mice, umbilical hernia, gastroschisis, reduced or absent lung, increased skeletal malformations and variations in rabbits) were observed at oral nitisinone doses from 5 mg/kg/day during organogenesis (less than the maximum clinical dose based on body surface area). In a preliminary study in pregnant rats, embryotoxicity (increased stillbirths, reduced live births, birthweights and survival after birth) and fetal abnormalities (increased skeletal variants) were observed at maternally toxic oral doses from 50 mg/kg/day (4 times the maximum clinical dose based on body surface area).
 It is not known whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk (see below). Therefore, mothers receiving nitisinone must not breastfeed, since a risk to the suckling child cannot be excluded (see Section 4.3 Contraindications).
Maternal treatment of mice at oral doses from 5 mg/kg/day (less than the maximum clinical dose based on body surface area) during organogenesis through weaning was associated with reduced pup survival, weight gain and developmental delays. In rats, lactational exposure of naive pups to nitisinone from treated dams given 100 mg/kg/day orally was associated with reduced pup weight and the development of corneal opacities (9 times the maximum clinical dose based on body surface area).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.
Adverse reactions involving the eyes (see Section 4.8 Adverse Effects (Undesirable Effects)) can affect the vision. If the vision is affected the patient should not drive or use machines until the event has subsided.

4.8 Adverse Effects (Undesirable Effects)

Orfadin was studied in one open label, uncontrolled main study of 207 patients with HT-1, from ages 0 to 21.7 years at enrolment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, biochemical and enzyme markers. Median duration of treatment was 22.2 months (range 0.1 to 80 months). A complementary analysis was performed on 250 patients.
Additional adverse events, regardless of causality assessment, reported in the complementary analysis of 250 patients, are presented in Table 3.
The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and absolute frequency. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10) or uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders.

Common: thrombocytopenia, leucopenia, granulocytopenia.
Uncommon: leucocytosis.

Eye disorders.

Common: conjunctivitis, corneal opacity, keratitis, photophobia, eye pain.
Uncommon: blepharitis.

Skin and subcutaneous tissue disorders.

Uncommon: exfoliative dermatitis, erythematous rash, pruritus.

Investigations.

Very common: elevated tyrosine levels.

Description of selected adverse reactions.

Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been associated with eye-related adverse reactions, such as e.g. corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinaemia by lowering tyrosine levels (see Section 4.4 Special Warnings and Precautions for Use).
In clinical studies, granulocytopenia was only uncommonly severe (< 0.5 x 109/L) and not associated with infections. Adverse reactions affecting the MedDRA system organ class 'Blood and lymphatic system disorders' subsided during continued nitisinone treatment.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
No case of overdose has been reported. Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. Elevated tyrosine levels have been associated with toxicity to eyes, skin, and the nervous system. Restriction of tyrosine and phenylalanine in the diet should limit toxicity associated with this type of tyrosinaemia. No information about specific treatment of overdose is available.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other alimentary tract and metabolism products. ATC code: A16A X04.

Mechanism of action.

The biochemical defect in hereditary tyrosinaemia type 1 (HT-1) is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.

Pharmacodynamic effects.

Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG - synthase activity and urine 5-ALA, decreased urinary excretion of succinylacetone, increased plasma tyrosine concentration and increased urinary excretion of phenolic acids. Available data from a clinical study indicates that in more than 90% of the patients urine succinylacetone was normalised during the first week of treatment. Succinylacetone should not be detectable in urine or plasma when the nitisinone dose is properly adjusted.

Clinical trials.

Effects on overall survival.

When compared to data for historical controls treatment with nitisinone together with dietary restriction results in a better survival probability in all HT-1 phenotypes than dietary restriction alone. This is seen in Tables 4, 5 and 6 from the main analysis, complementary analysis and the historical control group.
Data from a study used as a historical control (van Spronsen et al 1994) showed the following survival probability when treated with dietary restriction alone:
Treatment with nitisinone was also found to result in reduced risk for the development of hepatocellular carcinoma compared to historical data on treatment with dietary restriction alone. It was found that the early initiation of treatment resulted in a further reduced risk for the development of hepatocellular carcinoma.
An open-label study to evaluate the PK, efficacy and safety of once daily dosing compared to twice daily dosing was performed in 18 patients with HT-1. While 19 patients were initially enrolled in the study, one enrolled patient did not take the IMP due to withdrawal of consent. All study patients were on a stable Orfadin daily dosage (0.4 - 1.6 mg/kg/day) during both study dosing regimens. After at least 4 weeks of twice a day dosing with Orfadin, both the urine and/or blood succinylacetone concentrations were below the limit of quantification. Patients were switched to once a day dosing with the same total daily dose of Orfadin and blood and/or urine succinylacetone concentrations remained undetectable when measured following at least 4 weeks treatment with once a day dosing. There was insufficient data to support a once daily dosing regimen in patients with body weight < 20 kg.

5.2 Pharmacokinetic Properties

Formal absorption, distribution, metabolism and elimination studies have not been performed with nitisinone. In 10 healthy male volunteers, after administration of a single dose of nitisinone capsules (1 mg/kg body weight) the terminal half-life (median) of nitisinone in plasma was 52.0 hours (ranging from 39 to 86 hours). A population pharmacokinetic analysis has been conducted on a group of 207 HT-1 patients. The clearance and half-life were determined to be 0.0956 L/kg body weight/day and 52.1 hours respectively. In a small study in 6 children with HT-1 the mean terminal half-life was 25 hours compared with 21 hours in one adult with HT-1. The mean volume of distribution was 0.3 L/kg in 3 children with HT-1 and 0.07 L/kg in one adult with HT-1.
The single-dose pharmacokinetics of nitisinone have been studied for both Orfadin capsules and Orfadin oral suspension in healthy adult subjects.

Absorption.

The pharmacokinetic characteristics following single oral administration of Orfadin 30 mg under fasting conditions are shown in Table 7. Compared to Orfadin capsule, the median Tmax occurred about 3 hours earlier with Orfadin oral suspension.
In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP3A4 mediated metabolism.
In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromole concentration.
Patients with a diagnosis of HT-1 verified by the presence of succinylacetone in the urine or plasma. The median age of patients at enrolment was 9 months (range birth to 21.7 years, see Table 8).

Biochemical effects of nitisinone treatment.

The efficacy of nitisinone as an inhibitor of 4-hydroxy-phenylpyruvate dioxygenase was inferred by the effects of treatment on the following biochemical parameters: urine succinylacetone, plasma succinylacetone and erythrocyte porphobilinogen synthase (PBG) activity. For all 186 patients for whom data are available, the excretion of succinylacetone in urine was reduced to a level below the reference limit, which represents the sensitivity of the analytical procedure. The median time to normalisation was 0.3 months. For most patients for whom data are available (150/172=87%) the plasma concentration of succinylacetone decreased to a level below the reference. The median time to normalisation was 3.9 months. For all 180 patients for whom data are available, the porphobilinogen synthase activity of erythrocytes increased to within reference limits. The median time to normalisation was 0.3 months. The differences in these indices compared to the start of nitisinone treatment were statistically significant (p < 0.001).

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence of genotoxic potential for nitisinone in vitro and in vivo. Nitisinone was not mutagenic in the bacterial reverse mutation test but was genotoxic in the mouse lymphoma cell forward mutation test in vitro. In vivo nitisinone was weakly positive in the mouse bone marrow micronucleus test but negative in the mouse liver unscheduled DNA synthesis (UDS) test.

Carcinogenicity.

At oral doses up to 100 mg/kg/day, nitisinone did not show carcinogenic potential in a 26 week carcinogenicity study in transgenic mice (TgrasH2).

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Pregelatinised maize starch.

Capsule shell.

Gelatin, titanium dioxide.
Printing ink - either Capsugel Ink 10A1 Black or Capsugel Ink 10A2 Black (containing iron oxide black, shellac, propylene glycol, ammonium hydroxide).

Oral suspension.

Hypromellose, glycerol, polysorbate 80, sodium benzoate, citric acid monohydrate, sodium citrate, strawberry 501440 T (aroma), purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Capsules.

Store at 2°C to 8°C (Refrigerate. Do not freeze).
During the shelf life, Orfadin capsules can also be stored within the bottle at a temperature below 25°C for a maximum of 2 months. The discard date (when stored below 25°C) should be calculated and the "Discard after_" section on the product label should be filled in at the start of the 2 months as a record. After this time, discard all capsules that have not been refrigerated.

Oral suspension.

Store unopened bottle at 2°C to 8°C (Refrigerate. Do not freeze). Store upright.
After opening the oral suspension, keep the bottle in its box in a cool place where the temperature stays below 25°C for a single period of 2 months. Oral suspension must be discarded 2 months after opening. The date it should be discarded should be noted on the bottle label.

6.5 Nature and Contents of Container

Capsules.

High density polyethylene (HDPE) bottle with a tamper proof low density polyethylene (LDPE) cap, containing 60 capsules.

Oral suspension.

100 mL brown glass (type III) bottle with a white, child resistant HDPE screw cap with tamper-evident seal. Each bottle contains 90 mL oral suspension. Each pack contains one bottle, one LDPE bottle adapter and 3 polypropylene (PP) oral syringes (1 mL, 3 mL and 5 mL).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name: nitisinone; 2-(2-nitro -4-trifluoromethylbenzoyl) cyclohexane-1,3 -dione.

Chemical structure.


Molecular formula: C14H10F3NO5.
Molecular weight: 329.23.

CAS number.

104206-65-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes