ORFADIN 5mg capsules medication leaflet

Orfadin 2 mg hard capsules

Orfadin 5 mg hard capsules

Orfadin 10 mg hard capsules

Orfadin 20 mg hard capsules

Each capsule contains 2 mg nitisinone.

Each capsule contains 5 mg nitisinone.

Each capsule contains 10 mg nitisinone.

Each capsule contains 20 mg nitisinone.

For the full list of excipients, see section 6.1.

Hard capsule.

White, opaque capsules (6x16 mm) imprinted “NTBC 2mg” in black on the body of the capsule.

White, opaque capsules (6x16 mm) imprinted “NTBC 5mg” in black on the body of the capsule.

White, opaque capsules (6x16 mm) imprinted “NTBC 10mg” in black on the body of the capsule.

White, opaque capsules (6x16 mm) imprinted “NTBC 20mg” in black on the body of the capsule.

The capsules contain a white to off white powder.

Hereditary tyrosinemia type 1 (HT-1)

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

Alkaptonuria (AKU)

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

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 overallsurvival and avoid complications such as liver failure, liver cancer and renal disease. Adjunct to thenitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and should be followedby 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 weightadministered orally. The dose of nitisinone should be adjusted individually. It is recommended toadminister 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 patientpopulation.

Dose adjustment HT-1

During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test valuesand alpha-fetoprotein levels (see section 4.4). If urine succinylacetone is still detectable one monthafter the start of nitisinone treatment, the nitisinone dose should be increased to 1.5 mg/kg bodyweight/day. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of allbiochemical 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 weightgain.

However, in addition to the tests above, during the initiation of therapy, switch from twice daily toonce daily dosing or if there is a deterioration, it may be necessary to follow more closely all availablebiochemical parameters (i.e. plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyteporphobilinogen (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.

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

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 thetotal 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 beenestablished. No data are available.

The capsule may be opened and the content suspended in a small amount of water or formula dietimmediately before intake.

Orfadin is also available as a 4 mg/ml oral suspension for paediatric and other patients who havedifficulties swallowing capsules.

It is recommended that if nitisinone treatment is initiated with food, this should be maintained on aroutine basis, see section 4.5.

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 arerecommended 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 nitisinonetreatment and thereafter regularly, at least once a year. A patient displaying visual disorders duringtreatment 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 plasmatyrosine concentration should be measured. A more restricted tyrosine and phenylalanine diet shouldbe implemented in case the plasma tyrosine level is above 500 micromol/l. It is not recommended tolower the plasma tyrosine concentration by reduction or discontinuation of nitisinone, since themetabolic defect may result in deterioration of the patient’s clinical condition.

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

HT-1: The liver function should be monitored regularly by liver function tests and liver imaging. It isrecommended to also monitor serum alpha-fetoprotein concentrations. Increase in serumalpha-fetoprotein concentration may be a sign of inadequate treatment. Patients with increasingalpha-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 AKUpatients, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinicalevaluation of HT-1.

Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treatment may therefore result in increasedplasma concentrations of co-administered medicinal products metabolized primarily via CYP2C9.

Nitisinone-treated patients who are concomitantly treated with medicinal products with a narrowtherapeutic window metabolized through CYP2C9, such as warfarin and phenytoin, should becarefully monitored. Dose-adjustment of these co-administered medicinal products may be needed(see section 4.5).

Nitisinone is metabolised in vitro by CYP 3A4 and dose-adjustment may therefore be needed whennitisinone 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 amoderate inhibitor of CYP2C9 (2.3-fold increase in tolbutamide AUC), therefore nitisinone treatmentmay result in increased plasma concentrations of co-administered medicinal products metabolizedprimarily via CYP2C9 (see section 4.4).

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

CYP2D6 (see section 5.2).

No formal food interactions studies have been performed with Orfadin hard 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 hard capsules is initiated withfood, this should be maintained on a routine basis, see section 4.2.

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

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

There are no data on nitisinone affecting fertility.

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

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

The adverse reactions listed below by MedDRA system organ class and absolute frequency, are basedon 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 theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

MedDRA system organ Frequency in HT-1 Frequency in AKU1 Adverse reactionclass

Infections and Common Bronchitis, pneumoniainfestations

Blood and lymphatic Common Thrombocytopenia,system disorders leucopenia, granulocytopenia

Uncommon Leukocytosis

Eye disorders Common Conjunctivitis, cornealopacity, keratitis,photophobia

Very common2 Keratopathy

Common Very common2 Eye pain

Uncommon Blepharitis

MedDRA system organ Frequency in HT-1 Frequency in AKU1 Adverse reactionclass

Skin and subcutaneous Uncommon Exfoliative dermatitis,tissue disorders erythematous rash

Uncommon Common Pruritus, rash

Investigations Very common Very common Elevated tyrosine levels1The frequency is based on one clinical study in AKU.2Elevated tyrosine levels are associated with eye-related adverse reaction. Patients in the AKU studydid not have a diet restricted in tyrosine and phenylalanine.

Nitisinone treatment leads to elevated tyrosine levels. Elevated levels of tyrosine have been associatedwith eye-related adverse reactions, such as e.g. corneal opacities and hyperkeratotic lesions in HT-1and AKU patients. Restriction of tyrosine and phenylalanine in the diet should limit the toxicityassociated 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 notassociated with infections. Adverse reactions affecting the MedDRA system organ class ‘Blood andlymphatic system disorders’ subsided during continued nitisinone treatment.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine andphenylalanine will result in elevated tyrosine levels. Elevated tyrosine levels have been associatedwith toxicity to eyes, skin, and the nervous system. Restriction of tyrosine and phenylalanine in thediet should limit toxicity associated with this type of tyrosinemia. No information about specifictreatment of overdose is available.

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

Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second step in thetyrosine 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-hydroxyphenylpyruvatedioxygenase.

The biochemical defect in HT-1 is a deficiency of fumarylacetoacetate hydrolase, which is the finalenzyme of the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxicintermediates maleylacetoacetate and fumarylacetoacetate. These intermediates are otherwiseconverted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibitsthe 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 ofthe tyrosine catabolic pathway. Nitisinone prevents the accumulation of the harmful metabolitehomogentisic acid (HGA), which otherwise leads to ochronosis of joints and cartilage and thereby thedevelopment of the clinical features of the disease.

In patients with HT-1, nitisinone treatment leads to normalised porphyrin metabolism with normalerythrocyte porphobilinogen synthase activity and urine 5-aminolevulinate, decreased urinaryexcretion of succinylacetone, increased plasma tyrosine concentration and increased urinary excretionof phenolic acids. Available data from a clinical study indicates that in more than 90% of the patientsurine succinylacetone was normalized during the first week of treatment. Succinylacetone should notbe 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 aclinical 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 twicedaily. Survival probabilities after 2, 4 and 6 years of treatment with nitisinone are summarized in thetable below.

NTBC study (N=250)

Age at start of treatment 2 years 4 years 6 years≤ 2 months 93% 93% 93%≤ 6 months 93% 93% 93%> 6 months 96% 95% 95%

Overall 94% 94% 94%

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

Age at onset of symptoms 1 year 2 years< 2 months 38% 29%> 2-6 months 74% 74%> 6 months 96% 96%

Treatment with nitisinone was also found to result in reduced risk for the development ofhepatocellular carcinoma compared to historical data on treatment with dietary restriction alone. It wasfound that the early initiation of treatment resulted in a further reduced risk for the development ofhepatocellular carcinoma.

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

NTBC study (N=250)

Number of patients at Probability of no HCC (95% confidenceinterval) atstart 2 years 4 years 6 years 2 years 4 years 6 years

All patients 250 155 86 15 98% 94% 91%(95; 100) (90; 98) (81; 100)

Start age ≤ 24 193 114 61 8 99% 99% 99%months (98; 100) (97; 100) (94; 100)

Start age > 24 57 41 25 8 92% 82% 75%months (84; 100) (70; 95) (56; 95)

In an international survey of patients with HT-1 on treatment with dietary restriction alone, it wasfound 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 dosingwas performed in 19 patients with HT-1. There were no clinically important differences in AEs orother safety assessments between once and twice daily dosing. No patient had detectablesuccinylacetone (SA) levels at the end of the once-daily treatment period. The study indicates thatonce daily administration is safe and efficacious across all ages of patients. Data is, however, limitedin 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 AKUhave been demonstrated in a randomized, evaluator-blinded, no-treatment controlled, parallel-group48-months study in 138 patients (69 treated with nitisinone). The primary endpoint was the effect onurinary HGA levels; a 99.7% reduction following nitisinone treatment compared to untreated controlpatients was seen after 12 months. Treatment with nitisinone was shown to have a statisticallysignificant positive effect on cAKUSSI, eye pigmentation, ear pigmentation, osteopenia of the hip, andnumber of spinal regions with pain compared to the untreated control. cAKUSSI is a composite scoreincluding eye and ear pigmentation, kidney and prostate stones, aortic stenosis, osteopenia, bonefractures, tendon/ligament/muscle ruptures, kyphosis, scoliosis, joint replacements, and othermanifestations of AKU. Thus, the lowered HGA levels in nitisinone-treated patients resulted in areduction of the ochronotic process and reduced clinical manifestations, supporting a decreaseddisease progression.

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

No data is available for patients > 70 years.

Formal absorption, distribution, metabolism and elimination studies have not been performed withnitisinone. 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 (rangingfrom 39 to 86 hours). A population pharmacokinetic analysis has been conducted on a group of207 HT-1 patients. The clearance and half-life were determined to be 0.0956 l/kg body weight/day and52.1 hours respectively.

In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shownlimited CYP3A4-mediated metabolism.

Based on data from a clinical interaction study with 80 mg nitisinone at steady-state, nitisinone causeda 2.3-fold increase in AUC∞ of the CYP2C9 substrate tolbutamide, which is indicative of a moderateinhibition 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-mediatedmetabolism 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 expectedto 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 andgastroschisis) 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 pupsurvival 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 onpup survival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reducedmean pup weight and corneal lesions.

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

Starch, pregelatinised (maize)

Capsule shellgelatintitanium dioxide (E 171)

Printing inkblack iron oxide (E 172)shellacpropylene glycolammonium hydroxide

Not applicable.

2 years.

During the shelf life, the patient may store the capsules for a single period of 2 months (for 2 mgcapsules) or 3 months (for 5 mg, 10 mg and 20 mg capsules) at a temperature not above 25°C, afterwhich the medicinal product must be discarded.

Store in a refrigerator (2°C - 8°C).

HDPE bottle with a tamper-proof closure of LDPE, containing 60 capsules.

Each pack contains 1 bottle.

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

Swedish Orphan Biovitrum International AB

SE-112 76 Stockholm

Sweden

EU/1/04/303/001

EU/1/04/303/002

EU/1/04/303/003

EU/1/04/303/004

Date of first authorisation: 21 February 2005

Date of latest renewal: 19 January 2010

22/10/2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.