Drugs List

Therapeutic Indications

Uses

Alkaptonuria
Hereditary tyrosinaemia type 1

Administration

Capsule
The capsule may be opened immediately before intake and the contents suspended in a small amount of water or formula diet.

If nitisinone treatment using capsules is initiated with food, it is recommended that this should be maintained on a routine basis.

Oral suspension
Oral suspension should be taken with food.

Contraindications

Breastfeeding

Precautions and Warnings

Children under 18 years
Children weighing less than 20kg
Leucopenia
Pregnancy
Thrombocytopenia

Advise visual disturbances may affect ability to drive or operate machinery
Treatment to be initiated and supervised by a specialist
Perform slit-lamp eye examination before initiation and at least annually
Monitor hepatic function regularly
Monitor serum alpha-fetoprotein concentrations regularly in HT-1
Monitor urine succinylacetone regularly in hereditary tyrosinemia type 1
Perform regular white blood cell and platelet counts
Advise patient to report new visual problems and symptoms
Refer immediately visual disturbances to a specialist
Not licensed for all indications in all age groups
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Dietary restrictions should be maintained

Before initiating treatment it is generally recommended that a slit-lamp examination of the eyes is performed and thereafter regularly, at least once a year. If the patient is displaying visual disorders during treatment with nitisinone then the patient should be examined by an ophthalmologist without delay.

In HT-1, plasma tyrosine concentration should be monitored in order to ensure that the patient is adhering to their dietary regimen. If the plasma tyrosine concentration is above 500 micromol per litre then a more restricted tyrosine and phenylalanine diet should be implemented. It is not advisable 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.

In AKU patients who develop keratopathies, plasma tyrosine levels should be monitored. A restricted diet in tyrosine and phenylalanine should be implemented to keep the plasma tyrosine level below 500 micromol per litre. Nitisinone should be temporarily discontinued and can be reintroduced once the symptoms have been resolved.

In HT-1 treatment, it is important to regularly monitor urine succinylacetone, the liver function by liver function tests and liver imaging. Serum alpha-fetoprotein concentration should also be monitored and if an increase is detected it may be a sign of inadequate treatment. If increases are detected or there are signs of nodules in the liver then hepatic malignancy should be excluded.

During 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 (PGB)-synthase activity) in addition to the tests above.

Monitoring visits should be performed every 6 months or sooner in the case of adverse events.

Pregnancy and Lactation

Pregnancy

Use nitisinone with caution during pregnancy.

Animal studies performed have shown adverse postnatal effects via exposure of nitisinone in milk. The potential risk for humans is unknown as there is no adequate data from the use of nitisinone in pregnant women. Nitisinone should not therefore be used during pregnancy unless clearly necessary.

Lactation

Nitisinone is contraindicated during breastfeeding.

It is recommended that women receiving nitisinone should not breastfeed as it has not been established whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk.

Side Effects

Blepharitis
Conjunctivitis
Corneal opacities
Erythematous rash
Exfoliative dermatitis
Eye pain
Granulocytopenia
Hyperkeratosis
Keratitis
Leucocytosis
Leucopenia
Photophobia
Pruritus
Thrombocytopenia

Presentation

Oral formulations containing nitisinone.

Drugs List

Therapeutic Indications

Uses

Alkaptonuria
Hereditary tyrosinaemia type 1

Dosage

Initiate treatment as early as possible to increase overall survival and to avoid complications such as liver failure, liver cancer and renal disease. When initiated prior to the age of 12 months a 13.5 fold reduced risk for the development of hepatocellular carcinoma has been seen.

Adjust the dose of nitisinone according to the individual and based on the evaluation of all available parameters.

It is important that adjunct to the treatment with nitisinone, that the patient also has a diet deficient in phenylalanine and tyrosine. Plasma amino acids should be monitored.

Adults

Children

Additional Dosage Information

Administration

Capsule
The capsule may be opened immediately before intake and the contents suspended in a small amount of water or formula diet.

If nitisinone treatment using capsules is initiated with food, it is recommended that this should be maintained on a routine basis.

Oral suspension
Oral suspension should be taken with food.

Contraindications

Breastfeeding

Precautions and Warnings

Children under 18 years
Children weighing less than 20kg
Leucopenia
Pregnancy
Thrombocytopenia

Advise visual disturbances may affect ability to drive or operate machinery
Treatment to be initiated and supervised by a specialist
Perform slit-lamp eye examination before initiation and at least annually
Monitor hepatic function regularly
Monitor serum alpha-fetoprotein concentrations regularly in HT-1
Monitor urine succinylacetone regularly in hereditary tyrosinemia type 1
Perform regular white blood cell and platelet counts
Advise patient to report new visual problems and symptoms
Refer immediately visual disturbances to a specialist
Not licensed for all indications in all age groups
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Dietary restrictions should be maintained

Before initiating treatment it is generally recommended that a slit-lamp examination of the eyes is performed and thereafter regularly, at least once a year. If the patient is displaying visual disorders during treatment with nitisinone then the patient should be examined by an ophthalmologist without delay.

In HT-1, plasma tyrosine concentration should be monitored in order to ensure that the patient is adhering to their dietary regimen. If the plasma tyrosine concentration is above 500 micromol per litre then a more restricted tyrosine and phenylalanine diet should be implemented. It is not advisable 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.

In AKU patients who develop keratopathies, plasma tyrosine levels should be monitored. A restricted diet in tyrosine and phenylalanine should be implemented to keep the plasma tyrosine level below 500 micromol per litre. Nitisinone should be temporarily discontinued and can be reintroduced once the symptoms have been resolved.

In HT-1 treatment, it is important to regularly monitor urine succinylacetone, the liver function by liver function tests and liver imaging. Serum alpha-fetoprotein concentration should also be monitored and if an increase is detected it may be a sign of inadequate treatment. If increases are detected or there are signs of nodules in the liver then hepatic malignancy should be excluded.

During 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 (PGB)-synthase activity) in addition to the tests above.

Monitoring visits should be performed every 6 months or sooner in the case of adverse events.

Pregnancy and Lactation

Pregnancy

Use nitisinone with caution during pregnancy.

Animal studies performed have shown adverse postnatal effects via exposure of nitisinone in milk. The potential risk for humans is unknown as there is no adequate data from the use of nitisinone in pregnant women. Nitisinone should not therefore be used during pregnancy unless clearly necessary.

Lactation

Nitisinone is contraindicated during breastfeeding.

It is recommended that women receiving nitisinone should not breastfeed as it has not been established whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk.

Counselling

The importance of adhering to a diet deficient in phenylalanine and tyrosine should be explained.

Patient should be advised to inform their physician immediately if they experience visual disturbances during treatment.

Advise patient that adverse reactions of nitisinone involving the eyes can affect vision. If vision is affected the patient should be advised not to drive or use machines until the event has subsided.

Advise the patient not to take St John's wort concurrently.

Advise the patient that grapefruit products may increase the plasma level of nitisinone.

Side Effects

Blepharitis
Conjunctivitis
Corneal opacities
Erythematous rash
Exfoliative dermatitis
Eye pain
Granulocytopenia
Hyperkeratosis
Keratitis
Leucocytosis
Leucopenia
Photophobia
Pruritus
Thrombocytopenia

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: October 2015

Reference Sources

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Summary of Product Characteristics: Orfadin 2 mg, 5 mg, 10 mg and 20 mg hard capsules. Swedish Orphan Biovitrum Ltd. Revised October 2020.

Summary of Product Characteristics: Orfadin 4 mg/ml oral suspension. Swedish Orphan Biovitrum Ltd. Revised October 2020.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 14 January 2019