Orfadin 4mg/ml Oral Suspension

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).

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 ml, 3 ml and 5 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 0.01 ml, 0.1 ml and 0.2 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.

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).

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.

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.

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.

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.

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.

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.

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.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16A X04.

Mechanism of action

Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second step in the tyrosine metabolism. By inhibiting the normal catabolism of tyrosine in patients with HT-1 and AKU, nitisinone prevents the accumulation of harmful metabolites downstream of 4-hydroxyphenylpyruvate dioxygenase.

The biochemical defect in HT-1 is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. These intermediates are otherwise converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.

The biochemical defect in AKU is a deficiency of homogentisate 1,2 dioxygenase, the third enzyme of the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the harmful metabolite homogentisic acid (HGA), which otherwise leads to ochronosis of joints and cartilage and thereby the development of the clinical features of the disease.

Pharmacodynamic effects

In patients with HT-1, nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte porphobilinogen synthase activity and urine 5-aminolevulinate, 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.

In patients with AKU, nitisinone treatment reduces the accumulation of HGA. Available data from a clinical study shows a 99.7 % reduction of urinary HGA, and a 98.8 % reduction of serum HGA, following nitisinone treatment compared to untreated control patients after 12 months of treatment.

Clinical efficacy and safety in HT-1

The clinical study was open-labelled and uncontrolled. The dosing frequency in the study was twice daily. Survival probabilities after 2, 4 and 6 years of treatment with nitisinone are summarized in the table below.

Data from a study used as a historical control (van Spronsen et al., 1994) showed the following survival probability.

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.

The 2-, 4-, and 6-year probability of no occurrence of HCC during nitisinone treatment for patients aged 24 months or younger at the start of treatment and for those older than 24 months at the start of treatment is shown in the following table:

In an international survey of patients with HT-1 on treatment with dietary restriction alone, it was found that HCC had been diagnosed in 18% of all patients aged 2 years and above.

A study to evaluate the PK, efficacy and safety of once daily dosing compared to twice daily dosing was performed in 19 patients with HT-1. There were no clinically important differences in AEs or other safety assessments between once and twice daily dosing. No patient had detectable succinylacetone (SA) levels at the end of the once-daily treatment period. The study indicates that once daily administration is safe and efficacious across all ages of patients. Data is, however, limited in patients with body weight <20 kg.

Clinical efficacy and safety in AKU

The efficacy and safety of 10 mg once daily nitisinone in the treatment of adult patients with AKU have been demonstrated in a randomized, evaluator blinded, no- treatment controlled, parallel-group 48-months study in 138 patients (69 treated with nitisinone). The primary endpoint was the effect on urinary HGA levels; a 99.7% reduction following nitisinone treatment compared to untreated control patients was seen after 12 months.Treatment with nitisinone was shown to have a statistically significant positive effect on cAKUSSI, eye pigmentation, ear pigmentation, osteopenia of the hip, and number of spinal regions with pain compared to the untreated control. cAKUSSI is a composite score including eye and ear pigmentation, kidney and prostate stones, aortic stenosis, osteopenia, bone fractures, tendon/ligament/muscle ruptures, kyphosis, scoliosis, joint replacements, and other manifestations of AKU. Thus, the lowered HGA levels in nitisinone-treated patients resulted in a reduction of the ochronotic process and reduced clinical manifestations, supporting a decreased disease progression.

Ocular events such as keratopathy and eye pain, infections, headache and weight gain were reported with a higher incidence in nitisinone-treated than in untreated patients. Keratopathy led to temporary or permanent treatment discontinuation in 14% of nitisinone-treated patients but was reversible upon withdrawal of nitisinone.

No data is available for patients > 70 years.

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 54 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 vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP3A4 mediated metabolism.

Based on data from a clinical interaction study with 80 mg nitisinone at steady-state, nitisinone caused a 2.3-fold increase in AUC_∞ of the CYP2C9 substrate tolbutamide, which is indicative of a moderate inhibition of CYP2C9. Nitisinone caused an approximate 30% decrease in chlorzoxazone AUC_∞ , indicative of a weak induction of CYP2E1. Nitisinone does not inhibit CYP2D6 since metoprolol AUC_∞ was not affected by the administration of nitisinone. Furosemide AUC_∞ was increased 1.7-fold, indicating a weak inhibition of OAT1/OAT3 (see sections 4.4 and 4.5).

Based on in vitro studies, nitisinone is not expected to inhibit CYP1A2, 2C19 or 3A4-mediated metabolism or to induce CYP1A2, 2B6 or 3A4/5. Nitisinone is not expected to inhibit P-gp, BCRP or OCT2-mediated transport. Nitisinone plasma concentration reached in clinical setting is not expected to inhibit OATP1B1, OATP1B3 mediated transport.

Nitisinone has shown embryo-foetal toxicity in the mouse and rabbit at clinically relevant dose levels. In the rabbit, nitisinone induced a dose-related increase in malformations (umbilical hernia and gastroschisis) from a dose level 2.5-fold higher than the maximum recommended human dose (2 mg/kg/day).

A pre- and postnatal development study in the mouse showed statistically significantly reduced pup survival and pup growth during the weaning period at dose levels 125- and 25-fold higher, respectively, than the maximum recommended human dose, with a trend toward a negative effect on pup survival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reduced mean pup weight and corneal lesions.

No mutagenic but a weak clastogenic activity was observed in in vitro studies. There was no evidence of in vivo genotoxicity (mouse micronucleus assay and mouse liver unscheduled DNA synthesis assay). Nitisinone did not show carcinogenic potential in a 26-week carcinogenicity study in transgenic mice (TgrasH2).

Hydroxypropylmethylcellulose

Glycerol

Polysorbate 80

Sodium benzoate (E211)

Citric acid monohydrate

Sodium citrate

Strawberry aroma (artificial)

Purified water

Not applicable.

2 years.

After first opening, the in-use stability is a single period of 2 months at a temperature not above 25° C, after which it must be discarded.

Store in a refrigerator (2° C – 8° C). Do not freeze.

Store upright.

For storage conditions after first opening of the medicinal product, see section 6.3.

100 ml brown glass bottle (type III) with a white child-resistant HDPE screw cap with sealing and tamper evidence. 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).

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.

Three oral syringes (1 ml, 3 ml and 5 ml) are provided for accurate measurement of the prescribed dose. It is recommended that the healthcare professional advises the patient or carer giver how to use the oral syringes to ensure that the correct volume is administered.

How to prepare a new bottle of medicine for 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 when the bottle is removed from the refrigerator should be noted on the bottle label.

2. The bottle should be shaken vigourously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed (Figure A).

3. The child-resistant screw cap should be removed by pushing it down firmly and turning it anti-clockwise (Figure B).

4. The open bottle should be placed upright on a table, and the plastic adapter pushed firmly into the neck of the bottle as far as possible (Figure C). The bottle should be closed with the child resistant screw cap.

For subsequent dosing see the instructions below 'How to prepare a dose of medicine'

How to prepare a dose of medicine

1. The bottle should be shaken vigourously for at least 5 seconds (Figure D).

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 (Figure E).

5. The bottle should be turned carefully upside down with the oral syringe in place (Figure F).

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 (Figure F). 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.

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 replaced directly after use. The bottle adapter should not be removed.

10. The bottle may be stored at a temperature not above 25° C or in the refrigerator.

Cleaning

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.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.