4.1. Therapeutic indications

Hereditary tyrosinemia type 1 (HT-1)

Orfadin is indicated for the treatment of adult and paediatric (in any age range) patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Alkaptonuria (AKU)

Orfadin is indicated for the treatment of adult patients with alkaptonuria (AKU).

4.2. Posology and method of administration

Posology

HT-1:

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 required and should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).

Starting dose HT-1

The recommended initial daily dose in the paediatric and adult population is 1 mg/kg body weight administered orally. The dose of nitisinone should be adjusted individually. It is recommended to administer the dose 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.

Dose adjustment HT-1

During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels (see section 4.4). 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. 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, 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).

AKU:

Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of AKU patients.

The recommended dose in the adult AKU population is 10 mg once daily.

Special populations

There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.

Paediatric population

HT-1: The dose recommendation in mg/kg body weight is the same in children and adults.

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.

AKU: The safety and efficacy of Orfadin in children aged 0 to 18 years with AKU have not been established. No data are available.

Method of administration

The suspension is administered in the patient's mouth with an oral syringe without dilution. A 1.5 ml, 3 ml and 6 ml oral syringes are included in the pack to measure the dose in ml in accordance with the prescribed posology. The oral syringes are graduated in 0.05 ml, 0.1 ml and 0.25 ml steps respectively. The table below shows the dose conversion (mg/ml) for the three oral syringes sizes.

Dose conversion tables respectively for the three oral syringe 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 in section 6.6 for preparation and administration of the dose, in order to ensure the dosing accuracy.

It is recommended that the healthcare professional advises the patient or care giver how to use the oral syringes to ensure that the correct volume is administered and that the prescription is given in ml.

Orfadin is also available in 2 mg, 5 mg, 10 mg and 20 mg capsules, if considered more suitable for the patient.

It is recommended that the oral suspension is taken with food, see section 4.5.

Precautions to be taken before handling or administering the medicinal product

No needle, intravenous tubing or any other device for parenteral administration should be attached to the oral syringe.

Orfadin is for oral use only.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Mothers receiving nitisinone must not breast-feed (see sections 4.6 and 5.3).

4.4. Special warnings and precautions for use

Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.

Monitoring of plasma tyrosine levels

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

HT:1: It should be established that the patient is adhering to his/her dietary regimen and the plasma tyrosine concentration should be measured. A more restricted tyrosine and phenylalanine diet should be implemented in case the plasma tyrosine level is above 500 micromol/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.

AKU: In patients who develop keratopathies, plasma tyrosine levels should be monitored. A diet restricted in tyrosine and phenylalanine should be implemented to keep the plasma tyrosine level below 500 micromol/l. In addition, nitisinone should be temporarily discontinued and may be reintroduced when the symptoms have been resolved.

Liver monitoring

HT-1: The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended to also monitor serum alpha-fetoprotein concentrations. 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) monitoring

It is recommended that platelet and WBC counts are monitored regularly for both HT-1 and AKU patients, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation of HT-1.

Concomitant use with other medicinal products

Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treatment may therefore result in increased plasma concentrations of co-administered medicinal products metabolized primarily via CYP2C9. Nitisinone-treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolized through CYP2C9, such as warfarin and phenytoin, should be carefully monitored. Dose-adjustment of these co-administered medicinal products may be needed (see section 4.5).

Excipients with known effect:

Glycerol

Each ml contains 500 mg. A dose of 20 ml oral suspension (10 g glycerol) or more may cause headache, stomach upset and diarrhoea.

Sodium

Each ml contains 0.7 mg (0.03 mmol).

Sodium benzoate

Each ml contains 1 mg. 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 an Orfadin capsule should be considered instead of the oral suspension until the unconjugated bilirubin plasma levels are normalised.

4.5. Interaction with other medicinal products and other forms of interaction

Nitisinone is metabolised in vitro by CYP 3A4 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 with 80 mg nitisinone at steady-state, nitisinone is a moderate inhibitor of CYP2C9 (2.3-fold increase in tolbutamide AUC), therefore nitisinone treatment may result in increased plasma concentrations of co-administered medicinal products metabolized primarily via CYP2C9 (see section 4.4).

Nitisinone is a weak inducer of CYP2E1 (30% decrease in chlorzoxazone AUC) and a weak inhibitor of OAT1 and OAT3 (1.7-fold increase in AUC of furosemide), whereas nitisinone did not inhibit CYP2D6 (see section 5.2).

Food does not influence the bioavailability of nitisinone oral suspension, but intake together with food decreases the absorption rate and consequently leads to lower fluctuations in serum concentrations within a dosage interval. Therefore, it is recommended that the oral suspension is taken with food, see section 4.2.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Orfadin should not be used during pregnancy unless the clinical condition of the woman requires treatment with nitisinone. Nitisinone crosses the human placenta.

Breast-feeding

It is unknown whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk. Therefore, mothers receiving nitisinone must not breast-feed, since a risk to the suckling child cannot be excluded (see sections 4.3 and 5.3).

Fertility

There are no data on nitisinone affecting fertility.

4.7. Effects on ability to drive and use machines

Orfadin has minor influence on the ability to drive and use machines. Adverse reactions involving the eyes (see section 4.8) can affect the vision. If the vision is affected the patient should not drive or use machines until the event has subsided.

4.8. Undesirable effects

Summary of the safety profile

By its mode of action, nitisinone increases tyrosine levels in all nitisinone-treated patients. Eye-related adverse reactions, such as conjunctivitis, corneal opacity, keratitis, photophobia, and eye pain, related to elevated tyrosine levels are therefore common in both HT-1 and AKU patients. In the HT-1 population other common adverse reactions include thrombocytopenia, leucopenia, and granulocytopenia.

Exfoliative dermatitis may occur uncommonly.

Tabulated list of adverse reactions

The adverse reactions listed below by MedDRA system organ class and absolute frequency, are based on data from clinical trials in patients with HT-1 and AKU and post-marketing use in HT-1. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system organ class

Frequency in HT- 1

Frequency in AKU1

Adverse reaction

Infections and infestations

Common

Bronchitis, pneumonia

Blood and lymphatic system disorders

Common

Thrombocytopenia, leucopenia, granulocytopenia

Uncommon

Leukocytosis

Eye disorders

Common

Conjunctivitis, corneal opacity, keratitis, photophobia

Very common2

Keratopathy

Common

Very common2

Eye pain

Uncommon

Blepharitis

Skin and subcutaneous tissue disorders

Uncommon

Exfoliative dermatitis, erythematous rash

Uncommon

Common

Pruritus, rash

Investigations

Very common

Very common

Elevated tyrosine levels

1The frequency is based on one clinical study in AKU.

2Elevated tyrosine levels are associated with eye-related adverse reaction. Patients in the AKU study did not have a diet restricted in tyrosine and phenylalanine.

Description of selected adverse reactions

Nitisinone treatment leads to elevated tyrosine levels. Elevated levels of tyrosine have been associated with eye-related adverse reactions, such as e.g. corneal opacities and hyperkeratotic lesions in HT-1 and AKU patients. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia by lowering tyrosine levels (see section 4.4).

In clinical studies of HT-1, granulocytopenia was only uncommonly severe (<0.5x109/L) and not associated with infections. Adverse reactions affecting the MedDRA system organ class 'Blood and lymphatic system disorders' subsided during continued nitisinone treatment.

Paediatric population

The safety profile in HT-1 is mainly based on the paediatric population since nitisinone treatment should be started as soon as the diagnosis of hereditary tyrosinemia type 1 (HT-1) has been established. From clinical study and post- marketing data there are no indications that the safety profile is different in different subsets of the paediatric population or different from the safety profile in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 tyrosinemia. No information about specific treatment of overdose is available.