Consumer medicine information

Nityr

Nitisinone

BRAND INFORMATION

Brand name

Nityr

Active ingredient

Nitisinone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nityr.

What is in this leaflet

This leaflet answers some common questions about NITYR tablets.

It does not contain all of the available information. Some of the information it contains may not apply to you. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. In deciding to give you NITYR, your doctor has weighed the risks of you taking NITYR against the expected benefits it will have for you.

Always follow the instructions that your doctor and pharmacist give you about NITYR.

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

What NITYR are used for

NITYR contains the medicine Nitisinone. Nitisinone belongs to a group of medicines called ‘other alimentary and metabolism products’.

NITYR is used for the treatment of a disease called hereditary tyrosinaemia type 1. In this disease the body is unable to completely break down the amino acid tyrosine. Harmful substances will be formed and accumulated in the body.

NITYR block 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 (with low tyrosine and phenylalanine content) must be followed when taking NITYR.

Your doctor may have prescribed this medicine for another use. If you want more information, ask your doctor.

NITYR is not addictive.

NITYR is only available on a doctor's prescription

Before you take NITYR

You should not take NITYR if:

  • you are allergic to Nitisinone or any of the ingredients listed under 'Product Description' at the end of this leaflet. Signs of allergic reactions may include itchy skin, rash, shortness of breath and swelling of the face or tongue.
  • you are breastfeeding
  • the packaging shows signs of tampering.
  • the expiry date on the pack has passed.

Before you start to take NITYR

You must tell your doctor if:

You are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of taking NITYR during pregnancy.

  • The use of NITYR during breast feeding has not been investigated. Ask your doctor for advice about breast feeding.
  • Hypersensitive to the active substance or to any of the excipients

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

Taking other medicines

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

If you are unsure about any medicine you are taking you should check with your doctor or pharmacist. They will have more information on medicines to be careful with or avoid while taking NITYR.

How to take NITYR

It is important to follow the directions that your doctor has given to you.

How much to take

Your doctor will tell you how many tablets to take each day.

Take NITYR only as prescribed by your doctor and follow his or her directions carefully. They may differ from the information contained in this leaflet.

When to take it

The usual daily dose is 1 mg/kg body weight per day divided in morning and evening administrations.

Take your first dose in the morning. Take your second dose in the evening.

Swallow the tablets whole with a full glass of water.

NITYR may be taken with or without food.

If you have problems with swallowing the tablets, tablets may be disintegrated in water inside an oral syringe or crushed between two spoons and mixed with applesauce. Your doctor will tell you if and how you can disintegrate or crush NITYR and how many tablets you should use.

Instructions for this process are provided at the end of this leaflet.

How long to take it

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

If you forget to take it

Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

Telephone your doctor or Poisons Information Centre (13 11 26) if you think that you have taken more than you should.

While you are taking NITYR

Things you must do

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

Make sure that all of your doctors and pharmacists know about your use of NITYR. Remind them if any new medicines are about to be started.

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

Be sure to keep all of your doctor’s appointments so your progress can be checked.

  • Your Doctor will test your blood to check if the amounts of NITYR given are enough 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 use NITYR to treat any complaint other than that directed by your doctor. It may not be safe to use NITYR for another complaint.

Do not give NITYR to someone else even if their symptoms are the same. It may not be safe for another person to use NITYR.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how this medicine affects you.

Side effects

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

Like other medicines NITYR can cause some side effects. Most are likely to be minor and temporary. However, some may be serious and need medical attention.

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

Tell your doctor immediately if you notice any of the following:

  • different eye symptoms as listed below:
    - opacity in the cornea
    - inflammation in the cornea
    - inflammation in the eye
    - inflammation in the eyelid
    - sensitivity to light
    - eye pain
    - rash, itching or other skin disorders
    - headache, abdominal pain, constipation, diarrhoea

There may be other side effects that your doctor will carefully monitor by taking blood samples. These are:

  • reduced number of platelets and white blood cells
  • shortage of certain white blood cells (granulocytopenia)
  • increased number of white blood cells

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell. Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using NITYR

Storage

  • Keep NITYR in their bottle until it is time to take your dose. If you take them out of their container, they may not keep well.
  • Keep NITYR in a dry place at room temperature below 25°C. Store the tablets in the original bottle. Protect from light.
  • Do not leave it in the car on hot or cold days. Heat and dampness can destroy some medicines.
  • Keep NITYR where children cannot reach it.

Do not use after the expiry date which is stated on the carton and bottle label after “EXP’’.

Disposal

If your doctor tells you to stop taking NITYR, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

NITYR are white to beige, round, flat tablets, which may display light yellow to brown speckles, marked with “L” on one side and the strength “2”, “5” or “10” on the other side.

NITYR are available in plastic square bottles with a childresistant tamper-evident closure. Each bottle contains 60 tablets. Each pack (carton) contains 1 bottle.

AUST R 288126, 288127, 288128

Active Ingredient:

Each NITYR (nitisinone) tablet contains 2 mg, 5 mg or 10 mg nitisinone.

Other Ingredients:

Glyceryl dibehenate
Lactose monohydrate.

Manufacturer

NITYR™ is supplied in Australia by:

Orpharma Pty Ltd
Level 1,
530 Little Collins St
Melbourne VIC 3000

This leaflet was prepared in September, 2024.

Instructions for administration of the product

The following instructions explain how to take NITYR tablets using an oral syringe if you are unable to swallow the tablet/s.

PLEASE READ ALL THE INSTRUCTIONS CAREFULLY BEFORE YOU START TAKING NITYR TABLETS USING AN ORAL SYRINGE.

  • Only 1 or 2 NITYR tablets can be prepared in an oral syringe at one time.
  • Use a 5 mL oral syringe with a cap to prepare NITYR tablets in an oral syringe. Ask your pharmacist for your oral syringe. You may need more than one 5 mL oral syringe if you take more than 2 NITYR tablets for your prescribed dose.
  • Clean your hands well before preparing NITYR tablets using an oral syringe.

How to prepare and take 1 NITYR and 2 NITYR tablets using a 5 mL oral syringe:

  1. Remove the plunger and cap from the 5-mL oral syringe, insert one OR two tablets according to your doctor’s advice and replace the plunger.

  1. Draw up 2.6 mL for one tablet OR 5 mL for two tablets of room temperature water.

  1. Cap the oral syringe and leave it for at least 60 minutes.

  1. After 60 minutes, turn the oral syringe up and down for at least 30 seconds.

  1. Inspect the syringe to ensure the tablet/s has/have disintegrated before administration to the patient. Administer immediately, but only if the tablet/s has/have fully disintegrated.
  2. If the tablet/s is/are not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablet/s has/have disintegrated prior to administration to the patient. Do not administer unless the tablet/s has/have fully disintegrated.
  3. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablet. Discard after 24 hours.
  4. Uncap the oral syringe and administer the suspension in the patient’s mouth. To facilitate full administration, avoid pressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.

  1. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake it well for 10 seconds to suspend any remaining particles.

  1. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully pressing the plunger and ensuring the syringe is empty and no particles are left in the tip of the syringe.

  1. After use, remove the plunger from the oral syringe barrel. Rinse the oral syringe with water after each use and let it dry. Do not replace the plunger into the barrel of the oral syringe until ready to use again to allow it to dry. Do not throw away the oral syringe.

How to prepare and take more than 2 NITYR tablets using an oral syringe:

If more than two NITYR tablets are needed for the prescribed dose, prepare and take the prescribed dose following the instructions in “How to prepare and take 1 NITYR and 2 NITYR tablets using a 5 mL oral syringe”. You may need an extra oral syringe.

The following instructions explain how to crush NITYR tablets in applesauce if you are unable to swallow the tablet/s.

How to prepare and take NITYR tablets mixed in applesauce:

  1. Measure around one teaspoon of applesauce and transfer it into a clean glass.
  2. Take out two metal teaspoons. Position one NITYR tablet between two metal teaspoons and apply light pressure on the top spoon. The two teaspoons should overlap each other. Always crush one tablet at a time.
  3. Press and rotate the two teaspoons against each other repeatedly until the whole tablet is crushed into a fine powder.
  4. Carefully transfer the resulting powder to the applesauce in the glass. Make sure all the powder is transferred and no powder is left on the teaspoon.
  5. If more than one tablet is needed, repeat the procedure starting in Step 2 and collect all the resulting powder together in the glass.
  6. Mix the powder into the applesauce until all the powder is dispersed.
  7. Give the entire NITYR tablet-applesauce mixture to the patient’s mouth using a teaspoon. The mixture should be given immediately. If this is not possible, the mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the powder to the applesauce. Discard any mixture after 2 hours.
  8. To make sure that there is no leftover applesauce mixture in the glass, add another teaspoon of applesauce to the glass and mix. Ensure any remaining applesauce is mixed well with the extra applesauce.
  9. Give the additional NITYR tablet-applesauce mixture immediately to the patient’s mouth using a spoon.

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Nityr

Active ingredient

Nitisinone

Schedule

S4

 

1 Name of Medicine

Nitisinone.

2 Qualitative and Quantitative Composition

Each tablet contains 2 mg, 5 mg or 10 mg nitisinone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nityr tablets are white to beige, round, flat tablets, which may display light yellow to brown speckles, marked with the strength "2", "5" or "10" on one side and "L" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Nityr tablets (nitisinone) are indicated for the treatment of patients with hereditary tyrosinaemia type 1 in combination with dietary restriction of tyrosine and phenylalanine.

4.2 Dose and Method of Administration

Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients. Treatment of all genotypes of the disease 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 nitisinone 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 plasma tyrosine levels.
The dose of nitisinone should be adjusted individually.
The recommended initial dose is 1 mg/kg body weight/day divided in 2 doses administered orally.
Nityr tablets may be taken with or without food.
For infants, tablets may be crushed between two spoons and mixed with apple sauce for administration. Administration of Nityr tablets with other liquids or foods has not been studied and is not recommended. Tablets may also be disintegrated in water inside an oral syringe by following the instruction described below. Do not administer the suspension using a baby bottle.

Preparation and administration of Nityr tablets with water in an oral syringe.

A 5 mL oral syringe with a cap will be provided by a pharmacist.
Follow the instructions below for one or two intact tablets, depending on the number of tablets needed to achieve the patient's individual dosage.
Do not prepare more than two tablets at once within the same oral syringe.
If patient's dosage requires more than two tablets, follow the steps below using multiple oral syringes to achieve the required dose.

One tablet.

1. Remove the plunger from the 5 mL oral syringe and insert a single, intact tablet.
2. Replace the plunger and draw up 2.6 mL of room temperature water.
3. Cap the oral syringe and leave it for at least 60 minutes.
4. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablet has disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablet. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension in the patient's mouth. To facilitate full administration, avoid pressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake it well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient's mouth, this time fully pressing the plunger and ensuring the syringe is empty and no particles are left in the tip of the syringe. If particles are still present in the syringe, repeat steps 9-10.

Two tablets.

1. Remove the plunger from the 5 mL oral syringe and insert two intact tablets.
2. Replace the plunger and draw up 5 mL of room temperature water.
3. Cap the oral syringe and leave it for at least 60 minutes.
4. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablets have disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablets are not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablets have disintegrated prior to administration to the patient. Do not administer unless the tablets have fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake it well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient's mouth, this time fully depressing the plunger and ensuring the syringe is empty and no particles are left in the tip of the syringe. If particles are still present in the syringe, repeat steps 9-10.

Disposal.

In Australia, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation and administration of Nityr tablets mixed in applesauce.

For patients who can swallow semi-solid food, Nityr tablets can be crushed and mixed with applesauce.
1. Measure around one teaspoon of applesauce and transfer it into a clean container (e.g. clean glass).
2. Always crush one tablet at a time. Position the tablet between two metal teaspoons and apply light pressure on the top spoon. The two teaspoons should overlap each other to form a fine powder.
3. Press and rotate the two teaspoons against each other repeatedly until all of the tablet is in a fine powder.
4. Carefully transfer the resulting powder to the applesauce container ensuring all the powder is transferred, and no powder residue remains on the teaspoons.
5. If more than one tablet is needed, repeat the procedure starting from Step 2 and collect all the resulting powder together in the applesauce container.
6. Mix the powder into the applesauce until the powder is well dispersed.
7. Administer the entire Nityr tablets-applesauce mixture to the patient's mouth using a teaspoon. Administer immediately. However, if this is not possible, the mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the crushed tablets to the applesauce. Discard any mixture that has not been given within 2 hours.
8. To assure that any leftover applesauce mixture from the container is recovered, add around one teaspoon of applesauce to the same container and mix the fresh applesauce with the remaining mixture.
9. Administer the additional Nityr tablets applesauce mixture immediately to the patient's mouth using a teaspoon.

Dose adjustment.

During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels if urine succinylacetone is still detectable one month after the start of nitisinone treatment, the nitisinone 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 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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Mothers receiving nitisinone should not breast-feed.

4.4 Special Warnings and Precautions for Use

High plasma tyrosine concentrations.

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 micromol/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).

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 reduction or discontinuation of 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. On-going analysis has yet not 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 neuro-cognitive development.

Eye monitoring.

It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment. 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.

Platelet and white blood cell (WBC) monitor.

It is recommended that platelet and white cell 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.

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

No formal interaction studies with other medicinal products have been conducted.
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 in vitro studies, nitisinone is not expected to inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism.
No formal food interactions studies have been performed. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment 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 post-implantation loss were observed following treatment of female mice prior to mating through early embryogenesis at 50 mg/kg/day per oral (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.
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 intra-uterine deaths and increased post-implantation 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, birth weights 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 should not breast-feed, since a risk to the suckling child cannot be excluded.
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 naïve 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.

4.8 Adverse Effects (Undesirable Effects)

Nitisinone 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.
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, computerized 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.
Additional adverse events, regardless of causality assessment, reported in the complementary analysis of 250 patients, are presented in Table 1.
The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and absolute frequency. Frequencies are defined as common (≥ 1/100, < 1/10) or uncommon (≥ 1/1,000, < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders.

Common: thrombocytopenia, leucopenia, granulocytopenia.

Eye disorders.

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

Skin and subcutaneous tissue disorders.

Uncommon: exfoliative dermatitis, rash, pruritus.
Other adverse reactions, reported in less than 1% of the patients, included encephalopathy, diarrhoea, septicaemia and bronchitis.
Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinaemia.

Reporting of suspected adverse reactions.

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 advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26).
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 and metabolism products. ATC code: A16AX04.

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.

5.2 Pharmacokinetic Properties

Formal absorption, distribution, metabolism and elimination studies have not been performed with nitisinone. In 23 healthy adult volunteers, after administration of a single dose of Nityr tablets (10 mg) the terminal half-life (median) of nitisinone in plasma was 60.4 hours, and the median time to maximal plasma concentrations (Tmax) was 3.5 hours (range 1.0-4.0 hours).
Administration of Nityr tablets with food resulted in delayed absorption of nitisinone compared to administration whilst fasting, with a median Tmax of 6 h (range 2.0-10.0 h) in fed conditions, compared to 3 h (range 2.0-8.0 h) in fasting conditions. No clinically significant effect of food was seen on nitisinone AUC0-72h, Cmax, or t1/2.
Population pharmacokinetic analysis of nitisinone 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.
In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP3A4-mediated metabolism.
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 2).

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 normalization 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 normalization 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 normalization was 0.3 months. The differences in these indices compared to the start of nitisinone treatment were statistically significant (p < 0.001).

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 3, 4 and 5 from the main analysis, complementary analysis and the historical control group.
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 normalized during the first week of treatment. Succinylacetone should not be detectable in urine or plasma when the nitisinone dose is properly adjusted.
Treatment with nitisinone was also found to result in reduced risk for the development of hepatocellular carcinoma (2.3 to 3.7-fold) 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 (13.5-fold when initiated prior to the age of 12 months).

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.

The carcinogenic potential of nitisinone has not been studied in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glyceryl dibehenate and lactose monohydrate.

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

Store below 25°C.
Store in the original bottle. Protect from light.

6.5 Nature and Contents of Container

Nityr tablets are packed in High-density polyethylene (HDPE) square bottles with a child resistant tamper-evident Polypropylene (PP) screw cap. Each bottle contains 60 tablets.

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

Nitisinone, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione.
Molecular formula: C14H10F3NO5.
Molecular weight: 329.23.

Chemical structure.


CAS number.

104206-65-7.
The active substance is a weak acid and it is highly soluble in the pH range 4.5 - 7.2 according to the Biopharmaceutics classification system. Partition coefficient for nitisinone in octanol/water at pH 6.5 is 0.432.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes