NITISINONE MDK 5mg capsules medication leaflet

Nitisinone MDK 2 mg hard capsules

Nitisinone MDK 5 mg hard capsules

Nitisinone MDK 10 mg hard capsules

Nitisinone MDK 20 mg hard capsules

Nitisinone MDK 2 mg hard capsule

Each hard capsule contains 2 mg nitisinone.

Nitisinone MDK 5 mg hard capsule

Each hard capsule contains 5 mg nitisinone.

Nitisinone MDK 10 mg hard capsule

Each hard capsule contains 10 mg nitisinone.

Nitisinone MDK 20 mg hard capsule

Each hard capsule contains 20 mg nitisinone.

For the full list of excipients, see section 6.1.

Hard capsule.

The capsules contain a white to off white powder.

Nitisinone MDK 2 mg hard capsule

White, opaque capsules of 15.7 mm imprinted with black ink “2 mg” on the cap and “Nitisinone” on thebody.

Nitisinone MDK 5 mg hard capsule

White, opaque capsules of 15.7 mm imprinted with black ink “5 mg” on the cap and “Nitisinone” on thebody.

Nitisinone MDK 10 mg hard capsule

White, opaque capsules of 15.7 mm imprinted with black ink “10 mg” on the cap and “Nitisinone” onthe body.

Nitisinone MDK 20 mg hard capsule

White, opaque capsules of 15.7 mm imprinted with black ink “20 mg” on the cap and “Nitisinone” onthe body.

Treatment of adult and paediatric (in any age range) patients with confirmed diagnosis of hereditarytyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

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).

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.

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 to1.5 mg/kg body weight/day. A dose of 2 mg/kg body weight/day may be needed based on theevaluation of all biochemical parameters. This dose should be considered as a maximal dose for allpatients.

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).

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

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.

Oral use.

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

Other pharmaceutical forms are available for paediatric patients who have difficulties swallowingcapsules.

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. It should beestablished that the patient is adhering to his/her dietary regimen and the plasma tyrosineconcentration should be measured. A more restricted tyrosine and phenylalanine diet should beimplemented 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.

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, as a few cases of reversiblethrombocytopenia and leucopenia were observed during clinical evaluation.

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

Nitisinone treated patients who are concomitantly treated with medicinal products with a narrowtherapeutic window metabolised through CYP2C9, such as warfarin and phenytoin, should becarefully monitored. Dose adjustment of these co-administered medicinal products may be needed (seesection 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 metabolisedprimarily 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 Nitisinone MDK hard capsules.

However, nitisinone has been co-administered with food during the generation of efficacy and safetydata. Therefore, it is recommended that if nitisinone treatment with Nitisinone MDK hard capsules isinitiated with food, 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. Animal studies have shownreproductive toxicity (see section 5.3). The potential risk for humans is unknown. Nitisinone MDKshould 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.

Nitisinone has minor influence on the ability to drive and use machines. Adverse reactions involvingthe eyes (see section 4.8) can affect the vision. If the vision is affected, the patient should not drive oruse machines 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. Other common adverse reactions includethrombocytopenia, leucopenia, and granulocytopenia. Exfoliative dermatitis may occur uncommonly.

The adverse reactions listed below by MedDRA system organ class and absolute frequency, are basedon data from a clinical trial and post-marketing use. 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system organ class Frequency Adverse reaction

Blood and lymphatic system Common Thrombocytopenia, leucopenia,disorders granulocytopenia

Uncommon Leukocytosis

Eye disorders Common Conjunctivitis, corneal opacity,keratitis, photophobia, eye pain

Uncommon Blepharitis

Skin and subcutaneous tissue Uncommon Exfoliative dermatitis,disorders erythematous rash, pruritus

Investigations Very common Elevated tyrosine levels

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.

Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this typeof tyrosinemia by lowering tyrosine levels (see section 4.4).

In clinical studies, granulocytopenia was only uncommonly severe (<0.5x109/L) and not associatedwith infections. Adverse reactions within the MedDRA system organ class ‘Blood and lymphaticsystem disorders’ subsided during continued nitisinone treatment.

The safety profile is mainly based on the paediatric population since nitisinone treatment should bestarted as soon as the diagnosis of HT-1 has been established. From clinical study and post-marketingdata there are no indications that the safety profile is different in different subsets of the paediatricpopulation or different from the safety profile in adult patients.

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: A16AX04.

The biochemical defect in HT-1 is a deficiency of fumarylacetoacetate hydrolase, which is the finalenzyme of the tyrosine catabolic pathway. Nitisinone is a competitive inhibitor of4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase inthe tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1,nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate andfumarylacetoacetate. In patients with HT1, these intermediates are converted to the toxic metabolitessuccinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathwayleading to the accumulation of 5-aminolevulinate.

Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyteporphobilinogen synthase activity and urine 5-aminolevulinate, decreased urinary excretion ofsuccinylacetone, increased plasma tyrosine concentration and increased urinary excretion of phenolicacids. Available data from a clinical study indicates that in more than 90% of the patients urinesuccinylacetone was normalized during the first week of treatment. Succinylacetone should not bedetectable in urine or plasma when the nitisinone dose is properly adjusted.

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%confidence interval) at

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

Start age 57 41 25 8 92% 82% 75%> 24 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.

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). 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 and52.1 hours respectively.

In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shownlimited CYP 3A4-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 significant reduced pupsurvival and pup growth during the weaning period at dose levels 125- and 25-fold higher,respectively, the maximum recommended human dose, with a trend toward a negative effect on pupsurvival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reduced meanpup 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).

Pregelatinised starch (maize)

Gelatin

Titanium dioxide (E171)

Black iron oxide (E172)

Shellac

Not applicable.

Nitisinone MDK 2 mg, 5 mg and 10 mg hard capsules2 years

Nitisinone MDK 20 mg hard capsules3 years.

Store in a refrigerator (2°C - 8°C).

Alternatively, the capsules may be stored for a single period of 2 months, at a temperature not above25°C, after which the medicinal product must be discarded.

If capsule is opened

If the capsule is opened and the content suspended in a small amount of water or formula diet (seesection 4.2), the suspended powder must be consumed immediately.

Store in a refrigerator (2°C - 8°C). Store in the original bottle in order to protect from light.

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

HDPE plastic bottle with LDPE plastic cap containing 60 hard capsules.

Each carton pack contains one bottle.

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

MendeliKABS Europe Limited

Unit 3D, North Point House

North Point Business Park

New Mallow Road

Cork, T23 AT2P, Ireland

EU/1/17/1217/001

EU/1/17/1217/002

EU/1/17/1217/003

EU/1/17/1217/004

Date of first authorisation: 24 August 2017

Date of latest renewal:

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

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