Orfadin

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



 2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Orfadin 2 mg hard capsules 
Orfadin 5 mg hard capsules 
Orfadin 10 mg hard capsules 
Orfadin 20 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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.  
 
 
3. PHARMACEUTICAL FORM 
 
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. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of 
HT-1 patients. 
 
Posology 
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). 
 
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 
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 



 3 

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).  
 
Special populations 
There are no specific dose recommendations for elderly or patients that have renal or hepatic 
impairment. 
 
Paediatric population 
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. 
 
Method of administration 
The capsule may be opened and the content suspended in a small amount of water or formula diet 
immediately before intake. 
 
Orfadin is also available as a 4 mg/ml oral suspension for paediatric patients who have difficulties 
swallowing capsules. 
 
It is recommended that if nitisinone treatment is initiated with food, this should be maintained on a 
routine basis, see section 4.5. 
 
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 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. 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. 
 
Liver monitoring 
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, as a few cases of reversible 
thrombocytopenia and leucopenia were observed during clinical evaluation. 
 



 4 

Monitoring visits should be performed every 6 months; shorter intervals between visits are 
recommended in case of adverse events. 
 
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). 
 
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). 
 
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 with 
food, this should be maintained on a routine basis, 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. 
 
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 



 5 

to elevated tyrosine levels are therefore common. 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 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 frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
MedDRA system organ class Frequency Adverse reaction 
Blood and lymphatic system 
disorders 

Common  Thrombocytopenia, 
leucopenia, granulocytopenia 

Uncommon  Leukocytosis 
Eye disorders Common  Conjunctivitis, corneal 

opacity, keratitis, 
photophobia, eye pain 

Uncommon Blepharitis 
Skin and subcutaneous tissue 
disorders 

Uncommon  Exfoliative dermatitis, 
erythematous rash, pruritus 

Investigations Very common  Elevated tyrosine levels 
 
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. 
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, 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 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 national reporting system 
listed in Appendix V. 
 
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. 
 
 



 6 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract 
and metabolism products, ATC code: A16A X04. 
 
Mechanism of action 
The biochemical defect in hereditary tyrosinemia type 1 (HT-1) is a deficiency of fumarylacetoacetate 
hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive 
inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate 
hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in 
patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate 
and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic 
metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin 
synthesis pathway leading to the accumulation of 5-aminolevulinate.  
 
Pharmacodynamic effects 
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. 
 
Clinical efficacy and safety 
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. 

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 following 
survival 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 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. 
 



 7 

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: 
 

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% 
(95; 100) 

94%  
(90; 98) 

91%  
(81; 100) 

Start age 
≤ 24 
months 

193 114 61 8 99%  
(98; 100) 

99%  
(97; 100) 

99%  
(94; 100) 

Start age 
> 24 
months 

57 41 25 8 92%  
(84; 100) 

82%  
(70; 95) 

75%  
(56; 95) 

 
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. 
 
5.2 Pharmacokinetic properties 
 
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. 
 
5.3 Preclinical safety data 
 
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). 



 8 

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). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
Starch, pregelatinised (maize) 
 
Capsule shell 
gelatin 
titanium dioxide (E 171) 
 
Printing ink 
black iron oxide (E 172) 
shellac 
propylene glycol 
ammonium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
During the shelf life, the patient may store the capsules for a single period of 2 months (for 2 mg 
capsules) or 3 months (for 5 mg, 10 mg and 20 mg capsules) at a temperature not above 25°C, after 
which the medicinal product must be discarded. 
 
6.4 Special precautions for storage  
 
Store in a refrigerator (2°C – 8°C). 
 
6.5 Nature and contents of container 
 
HDPE bottle with a tamper-proof closure of LDPE, containing 60 capsules.  
Each pack contains 1 bottle. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



 9 

7. MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/04/303/001 
EU/1/04/303/002 
EU/1/04/303/003 
EU/1/04/303/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 February 2005 
Date of latest renewal: 19 January 2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



 10 

1. NAME OF THE MEDICINAL PRODUCT 
 
Orfadin 4 mg/ml oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 ml contains 4 mg of nitisinone.  
 
Excipients with known effect: 
Each ml contains: 
sodium 0.7 mg (0.03 mmol) 
glycerol 500 mg 
sodium benzoate 1 mg 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral suspension. 
White, slightly viscous opaque suspension. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of 
HT-1 patients. 
 
Posology 
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). 
 
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 
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. 
 



 11 

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).  
 
Special populations 
There are no specific dose recommendations for elderly or patients that have renal or hepatic 
impairment. 
 
Paediatric population 
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. 
 
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: 
 

 

1-ml oral 
syringe 
(0.01 ml 

graduation) 

Dose Orfadin 
mg ml 
1.00 0.25 
1.25 0.31 
1.50 0.38 
1.75 0.44 
2.00 0.50 
2.25 0.56 
2.50 0.63 
2.75 0.69 
3.00 0.75 
3.25 0.81 
3.50 0.88 
3.75 0.94 
4.00 1.00 

3-ml oral 
syringe  
(0.1 ml 

graduation) 

Dose Orfadin 
mg ml 
4.5 1.1 
5.0 1.3 
5.5 1.4 
6.0 1.5 
6.5 1.6 
7.0 1.8 
7.5 1.9 
8.0 2.0 
8.5 2.1 
9.0 2.3 
9.5 2.4 

10.0 2.5 
10.5 2.6 
11.0 2.8 
11.5 2.9 
12.0 3.0 

 

5-ml oral 
syringe  
(0.2 ml 

graduation) 

Dose Orfadin 
mg ml 
13.0 3.2 
14.0 3.6 
15.0 3.8 
16.0 4.0 
17.0 4.2 
18.0 4.6 
19.0 4.8 
20.0 5.0 

 

 
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. 



 12 

 
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 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. 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. 
 
Liver monitoring 
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, as a few cases of reversible 
thrombocytopenia and leucopenia were observed during clinical evaluation. 
 
Monitoring visits should be performed every 6 months; shorter intervals between visits are 
recommended in case of adverse events. 
 
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 



 13 

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. 
 
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. 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 a clinical trial and post-marketing use. Frequency is defined as very common (≥1/10), 



 14 

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 Adverse reaction 
Blood and lymphatic system 
disorders 

Common  Thrombocytopenia, 
leucopenia, granulocytopenia 

Uncommon  Leukocytosis 
Eye disorders Common  Conjunctivitis, corneal 

opacity, keratitis, 
photophobia, eye pain 

Uncommon Blepharitis 
Skin and subcutaneous tissue 
disorders 

Uncommon  Exfoliative dermatitis, 
erythematous rash, pruritus 

Investigations Very common  Elevated tyrosine levels 
 
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. 
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, 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 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 national reporting system 
listed in Appendix V. 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract 
and metabolism products, ATC code: A16A X04. 
 
Mechanism of action 
The biochemical defect in hereditary tyrosinemia type 1 (HT-1) is a deficiency of fumarylacetoacetate 
hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive 



 15 

inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate 
hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in 
patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate 
and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic 
metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin 
synthesis pathway leading to the accumulation of 5-aminolevulinate.  
 
Pharmacodynamic effects 
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. 
 
Clinical efficacy and safety 
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. 

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 following 
survival 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 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: 
 

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% 
(95; 100) 

94%  
(90; 98) 

91%  
(81; 100) 

Start age 
≤ 24 
months 

193 114 61 8 99%  
(98; 100) 

99%  
(97; 100) 

99%  
(94; 100) 

Start age 
> 24 
months 

57 41 25 8 92%  
(84; 100) 

82%  
(70; 95) 

75%  
(56; 95) 

 



 16 

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. 
 
5.2 Pharmacokinetic properties 
 
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. 
 
5.3 Preclinical safety data 
 
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). 
 
 



 17 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Hydroxypropylmethylcellulose 
Glycerol 
Polysorbate 80 
Sodium benzoate (E211) 
Citric acid monohydrate  
Sodium citrate  
Strawberry aroma (artificial) 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
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. 
 
6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container  
 
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). 
 
6.6 Special precautions for disposal and other handling 
 
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. 
 



 18 

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. 
 

        
  Figure A.               Figure B.       Figure C. 
 

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 
 

            
 Figure D.       Figure E.    Figure F. 
 

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. 



 19 

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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/04/303/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 February 2005 
Date of latest renewal: 19 January 2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



 20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURERS RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTION REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 21 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
2 mg, 5 mg, 10 mg and 20 mg hard capsules: 
Apotek Produktion & Laboratorier AB 
Prismavägen 2 
SE-141 75 Kungens Kurva 
Sweden 
 
4 mg/ml oral suspension: 
Apotek Produktion & Laboratorier AB 
Celsiusgatan 43 
SE-212 14 Malmö 
Sweden 
 
Apotek Produktion & Laboratorier AB 
Prismavägen 2 
SE-141 75 Kungens Kurva 
Sweden 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 



 22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 24 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orfadin 2 mg hard capsules 
Orfadin 5 mg hard capsules 
Orfadin 10 mg hard capsules 
Orfadin 20 mg hard capsules 
Nitisinone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 2 mg nitisinone 
Each capsule contains 5 mg nitisinone 
Each capsule contains 10 mg nitisinone 
Each capsule contains 20 mg nitisinone 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 



 25 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
SE-112 76  Stockholm 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/303/001 
EU/1/04/303/002 
EU/1/04/303/003 
EU/1/04/303/004 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orfadin 2 mg 
Orfadin 5 mg 
Orfadin 10 mg 
Orfadin 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 



 26 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Orfadin 2 mg hard capsules 
Orfadin 5 mg hard capsules 
Orfadin 10 mg hard capsules 
Orfadin 20 mg hard capsules 
Nitisinone 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
 
 
4. EXPIRY DATE 
 
EXP  
 
 
5. SPECIAL STORAGE CONDITIONS 
 
2 mg: Store in a refrigerator. The product can be stored for a single period of 2 months at a 
temperature not above 25°C, after which it must be discarded. 
Date when removed from refrigerator:  
 
5 mg, 10 mg, 20 mg: Store in a refrigerator. The product can be stored for a single period of 3 months 
at a temperature not above 25°C, after which it must be discarded. 
Date when removed from refrigerator:  
 
 
6. BATCH NUMBER 
 
Lot 
 
 
7. CONTENTS BY UNIT 
 
60 capsules 
 



 27 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orfadin 4 mg/ml oral suspension 
Nitisinone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 ml contains 4 mg nitisinone. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Oral suspension 
1 bottle of 90 ml, 1 bottle adaptor, 3 oral syringes (1 ml, 3 ml, 5 ml). 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet carefully before use. 
Oral use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store upright. 
 
 



 28 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/04/303/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orfadin 4 mg/ml 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 



 29 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orfadin 4 mg/ml oral suspension 
Nitisinone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 ml contains 4 mg nitisinone. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Oral suspension 
90 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet carefully before use. 
Oral use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze.  
Store upright. 
The product can be stored for a single period of 2 months at a temperature not above 25°C, after which 
it must be discarded. 
Date when removed from refrigerator: 
 



 30 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/303/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 



 31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 32 

Package leaflet: Information for the user  
 

Orfadin 2 mg hard capsules 
Orfadin 5 mg hard capsules  
Orfadin 10 mg hard capsules 
Orfadin 20 mg hard capsules 

nitisinone 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Orfadin is and what it is used for 
2. What you need to know before you take Orfadin 
3. How to take Orfadin 
4. Possible side effects 
5. How to store Orfadin 
6. Contents of the pack and other information 
 
 
1. What Orfadin is and what it is used for 
 
The active ingredient of Orfadin is nitisinone. This medicine is used for treatment of a rare disease 
called hereditary tyrosinemia type 1 in adults, adolescents and children (in any age range).  
 
In this disease your body is unable to completely break down the amino acid tyrosine (amino acids are 
building blocks of our proteins), forming harmful substances. These substances are accumulated in 
your body. Orfadin blocks the breakdown of tyrosine and the harmful substances are not formed.  
 
You must follow a special diet while you are taking this medicine, because tyrosine will remain in 
your body. This special diet is based on low tyrosine and phenylalanine (another amino acid) content. 
 
 
2. What you need to know before you take Orfadin 
 
Do not take Orfadin 
- if you are allergic to nitisinone or any of the other ingredients of this medicine (listed in 

section 6). 
 
Do not breast-feed while taking this medicine, see section “Pregnancy and breast-feeding”. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Orfadin. 
- Your eyes will be checked by an ophthalmologist before and regularly during nitisinone 

treatment. If you get red eyes or any other signs of effects on the eyes, contact your doctor 
immediately for an eye examination. Eye problems could be a sign of inadequate dietary control 
(see section 4). 

 
During the treatment, blood samples will be drawn in order for your doctor to check whether the 
treatment is adequate and to make sure that there are no possible side effects causing blood disorders. 



 33 

 
Your liver will be checked at regular intervals because the disease affects the liver. 
 
Follow-up by your doctor should be performed every 6 months. If you experience any side effects, 
shorter intervals are recommended. 
 
Other medicines and Orfadin 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
Orfadin may interfere with the effect of other medicines, such as: 
- Medicines for epilepsy (such as phenytoin) 
- Medicines against blood clotting (such as warfarin) 
 
Orfadin with food 
If you start treatment by taking it with food, it is recommended that you carry on taking it with food 
throughout your course of treatment. 
 
Pregnancy and breast-feeding 
The safety of this medicine has not been studied in pregnant and breast-feeding women.  
Please contact your doctor if you plan to become pregnant. If you become pregnant you should contact 
your doctor immediately. 
Do not breast-feed while taking this medicine, see section “Do not take Orfadin”. 
 
Driving and using machines 
This medicine has minor influence on the ability to drive and use machines. However, if you 
experience side effects affecting your vision you should not drive or use machines until your vision is 
back to normal (see section 4“Possible side effects”).  
 
 
3. How to take Orfadin 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Treatment with this medicine should be started and supervised by a doctor experienced in the 
treatment of the disease (hereditary tyrosinemia type 1). 
 
The recommended total daily dose is 1 mg/kg body weight administered orally. Your doctor will 
adjust the dose 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. 
 
If you have problems with swallowing the capsules, you may open the capsule and mix the powder 
with a small amount of water or formula diet just before you take it. 
 
If you take more Orfadin than you should 
If you have taken more of this medicine than you should, contact your doctor or pharmacist as soon as 
possible.  
 
If you forget to take Orfadin 
Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, contact your 
doctor or pharmacist. 
 
If you stop taking Orfadin 
If you have the impression that the medicine is not working properly, talk to your doctor. Do not 
change the dose or stop the treatment without talking to your doctor. 



 34 

 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If you notice any side effects relating to the eyes, talk to your doctor immediately to have an eye 
examination. Treatment with nitisinone leads to higher levels of tyrosine in the blood which can cause 
eye related symptoms. Common eye related side effects (may affect more than 1 in 10 people) caused 
by higher tyrosine levels are inflammation in the eye (conjunctivitis), opacity and inflammation in the 
cornea (keratitis), sensitivity to light (photophobia) and eye pain. Inflammation of the eyelid 
(blepharitis) is an uncommon side effect (may affect up to 1 in 100 people). 
 
Other common side effects 
- Reduced number of platelets (thrombocytopenia) and white blood cells (leukopenia), shortage of 

certain white blood cells (granulocytopenia). 
 
Other uncommon side effects  
- increased number of white blood cells (leucocytosis),  
- itching (pruritus), skin inflammation (exfoliative dermatitis), rash. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Orfadin 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and the carton after “EXP”.  
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
The medicine can be stored for a single period of 2 months (for 2 mg capsules) or 3 months (for 5 mg, 
10 mg and 20 mg capsules) at a temperature not above 25°C, after which it must be discarded. 
 
Do not forget to mark the date on the bottle, when removed from the refrigerator. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Orfadin contains 
- The active substance is nitisinone.  
 Orfadin 2 mg: Each capsule contains 2 mg nitisinone. 
 Orfadin 5 mg: Each capsule contains 5 mg nitisinone. 
 Orfadin 10 mg: Each capsule contains 10 mg nitisinone. 
 Orfadin 20 mg: Each capsule contains 20 mg nitisinone. 
 



 35 

- The other ingredients are 
 Capsule content:  
 starch, pregelatinised (maize). 
 Capsule shell:  
 gelatine  
 titanium dioxide (E 171). 
 Printing ink:  
 iron oxide (E 172)  
 shellac  
 propylene glycol 
 ammonium hydroxide 
 
What Orfadin looks like and contents of the pack  
The hard capsules are white, opaque, imprinted with “NTBC” and the strength “2 mg”, “5 mg”, 
“10 mg” or “20 mg”, in black. The capsule contains a white to off-white powder. 
 
The capsules are packaged in plastic bottles with tamper-proof closures. Each bottle contains 
60 capsules. 
 
Marketing Authorisation Holder 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
Manufacturer 
Apotek Produktion & Laboratorier AB 
Prismavägen 2 
SE-141 75 Kungens Kurva 
Sweden 
 
 
This leaflet was last revised in  
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 



 36 

Package leaflet: Information for the user 
 

Orfadin 4 mg/ml oral suspension 
nitisinone 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.  
 
What is in this leaflet 
 
1. What Orfadin is and what it is used for 
2. What you need to know before you take Orfadin 
3. How to take Orfadin 
4. Possible side effects 
5. How to store Orfadin 
6. Contents of the pack and other information 
 
 
1. What Orfadin is and what it is used for 
 
The active ingredient of Orfadin is nitisinone. This medicine is used for treatment of a rare disease 
called hereditary tyrosinemia type 1 in adults, adolescents and children (in any age range).  
 
In this disease your body is unable to completely break down the amino acid tyrosine (amino acids are 
building blocks of our proteins), forming harmful substances. These substances are accumulated in 
your body. Orfadin blocks the breakdown of tyrosine and the harmful substances are not formed.  
 
You must follow a special diet while you are taking this medicine, because tyrosine will remain in 
your body. This special diet is based on low tyrosine and phenylalanine (another amino acid) content. 
 
 
2. What you need to know before you take Orfadin 
 
Do not take Orfadin 
- if you are allergic to nitisinone or any of the other ingredients of this medicine (listed in 

section 6). 
 
Do not breast-feed while taking this medicine, see section “Pregnancy and breast-feeding”. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Orfadin. 
- Your eyes will be checked by an ophthalmologist before and regularly during nitisinone 

treatment. If you get red eyes or any other signs of effects on the eyes, contact your doctor 
immediately for an eye examination. Eye problems could be a sign of inadequate dietary control 
(see section 4). 

 
During the treatment, blood samples will be drawn in order for your doctor to check whether the 
treatment is adequate and to make sure that there are no possible side effects causing blood disorders. 
 
Your liver will be checked at regular intervals because the disease affects the liver. 
 



 37 

Follow-up by your doctor should be performed every 6 months. If you experience any side effects, 
shorter intervals are recommended. 
 
Other medicines and Orfadin 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
Orfadin may interfere with the effect of other medicines, such as: 
- Medicines for epilepsy (such as phenytoin) 
- Medicines against blood clotting (such as warfarin) 
 
Orfadin with food 
It is recommended that the oral suspension is taken with food. 
 
Pregnancy and breast-feeding 
The safety of this medicine has not been studied in pregnant and breast-feeding women.  
Please contact your doctor if you plan to become pregnant. If you become pregnant you should contact 
your doctor immediately. 
Do not breast-feed while taking this medicine, see section “Do not take Orfadin”. 
 
Driving and using machines 
This medicine has minor influence on the ability to drive and use machines. However, if you 
experience side effects affecting your vision you should not drive or use machines until your vision is 
back to normal (see section 4“Possible side effects”). 
 
Orfadin contains sodium, glycerol and sodium benzoate 
This medicinal product contains 0.7 mg (0.03 mmol) sodium per ml. 
A dose of 20 ml oral suspension (10 g glycerol) or more may cause headache, stomach upset and 
diarrhoea. 
Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in pre-term and full-term 
jaundiced neonates and develop into kernicterus (brain damage due to deposits of bilirubin in the 
brain). The newborn baby’s blood levels of bilirubin (a substance that causes the yellowing of the skin 
in high levels) will be closely monitored. If the levels are markedly higher than they should be, 
especially in prematures babies with risk factors as acidosis (too low pH in the blood) and low albumin 
level (a protein in the blood) treatment with Orfadin capsules will be considered instead of the oral 
suspension until the bilirubin plasma levels are normalised. 
 
 
3. How to take Orfadin 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Follow the instructions given below for dose preparation and administration carefully, in order 
to ensure that the correct dose is administered. 
 
Treatment with this medicine should be started and supervised by a doctor experienced in the 
treatment of the disease (hereditary tyrosinemia type 1). 
 
The recommended total daily dose is 1 mg/kg body weight administered orally. Your doctor will 
adjust the dose 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. 
 
The oral suspension is taken with a oral syringe directly in the mouth without dilution. 
Orfadin must not be injected. Do not attach a needle to the syringe. 
 



 38 

How to prepare the dose to be administered 
The dose that your doctor prescribes you should be given in ml of suspension and not in mg. This is 
because the oral syringe which is used to withdraw the correct dose from the bottle is marked in ml. If 
your prescription is in mg, contact your pharmacist or doctor for advice. 
 
The pack contains a bottle of medicine with a cap, a bottle adaptor and three oral syringes (1 ml, 3 ml 
and 5 ml). Always use one of the oral syringes provided to take the medicine. 

• The 1-ml oral syringe (the smallest oral syringe) is marked from 0.1 ml to 1 ml with minor 
0.01-ml graduations. It is used for measuring doses of less than or up to 1 ml. 

• The 3 ml oral syringe (the middle sized oral syringe), is marked from 1 ml to 3 ml with minor 
0.1-ml graduations. It is used for measuring doses of more than 1 ml and up to 3 ml. 

• The 5 ml oral syringe (the largest oral syringe), is marked from 1 ml to 5 ml with minor 
0.2-ml graduations. It is used for measuring doses of more than 3 ml.  

 
It is important that you use the correct oral syringe when taking the medicine. Your doctor, pharmacist 
or nurse will advise which oral syringe to use depending on the dose that has been prescribed. 
 
How to prepare a new bottle of medicine for first time use: 
 
Before you take the first dose, shake the bottle vigorously since during long-term storage the particles 
will form a solid cake at the bottom of the bottle. Follow the instructions below: 
 

        
  Figure A.              Figure B.       Figure C. 
 

1. Remove the bottle from the refrigerator. Note the date when the bottle is removed from the 
refrigerator on the bottle label. 

2. Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the 
bottle is completely dispersed (figure A). 

3. Remove the child resistant screw cap by pushing it down firmly and turning it anti-clockwise 
(figure B).  

4. Place the open bottle upright on a table. Push the plastic adapter firmly into the neck of the 
bottle as far as you can (figure C) and close the bottle 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 
 

            
 Figure D.       Figur E.           Figure F. 



 39 

 
1. Shake the bottle vigorously for at least 5 seconds (figure D).  
2. Immediately thereafter, open the bottle by removing the child resistant screw cap. 
3. Push the plunger inside the oral syringe fully down. 
4. Keep the bottle in an upright position and insert the oral syringe firmly into the hole at the top 

of the bottle (figure E). 
5. Carefully turn the bottle upside down with the oral syringe in place (Figure F). 
6. In order to withdraw the prescribed dose (ml), pull the plunger slowly down 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, push the plunger back up until the air bubbles are 
expelled. Then pull the plunger down again until the top edge of the black ring is exactly level 
with the line marking the dose. 

7. Turn the bottle to an upright position again. Disconnect the oral syringe 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 must be emptied slowly to allow swallowing; rapid 
squirting of the medicine may cause choking. 

9. Replace the child resistant screw cap directly after use. The bottle adapter should not be 
removed. 

10. The bottle may be stored at room temperature (not above 25°C). 
 

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. 

 
If you take more Orfadin than you should 
If you have taken more of this medicine than you should, contact your doctor or pharmacist as soon as 
possible.  
 
If you forget to take Orfadin 
Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, contact your 
doctor or pharmacist. 
 
If you stop taking Orfadin 
If you have the impression that the medicine is not working properly, talk to your doctor. Do not 
change the dose or stop the treatment without talking to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If you notice any side effects relating to the eyes, talk to your doctor immediately to have an eye 
examination. Treatment with nitisinone leads to higher levels of tyrosine in the blood which can cause 
eye related symptoms. Common eye related side effects (may affect more than 1 in 10 people) caused 
by higher tyrosine levels are inflammation in the eye (conjunctivitis), opacity and inflammation in the 
cornea (keratitis), sensitivity to light (photophobia) and eye pain. Inflammation of the eyelid 
(blepharitis) is an uncommon side effect (may affect up to 1 in 100 people). 
 
Other common side effects 
- Reduced number of platelets (thrombocytopenia) and white blood cells (leukopenia), shortage of 

certain white blood cells (granulocytopenia). 
 



 40 

Other uncommon side effects  
- increased number of white blood cells (leucocytosis),  
- itching (pruritus), skin inflammation (exfoliative dermatitis), rash. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Orfadin 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C).  
Do not freeze. 
Store the bottle upright. 
 
After first opening, the medicine can be stored for a single period of 2 months at a temperature not 
above 25°C, after which it must be discarded. 
 
Do not forget to mark the date on the bottle, when removed from the refrigerator. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Orfadin contains  
- The active substance is nitisinone. Each ml contains 4 mg nitisinone. 
- The other ingredients are hydroxypropylmethylcellulose, glycerol (see section 2), polysorbate 

80, sodium benzoate (E211) (see section 2), citric acid monohydrate, sodium citrate (see 
section 2), strawberry aroma (artificial) and purified water. 

 
What Orfadin looks like and contents of the pack 
The oral suspension is a white, slightly thicker opaque suspension.  Before shaking the bottle, it may 
look like a solid cake in the bottom and a slightly opalescent liquid. It is provided in a 100 ml brown 
glass bottle with a white, child resistant screw cap. Each bottle contains 90 ml supension. 
Each pack contains one bottle, one bottle adapter and three oral syringes. 
 
Marketing Authorisation Holder 
Swedish Orphan Biovitrum International AB 
SE-112 76 Stockholm 
Sweden 
 
Manufacturer  
Apotek Produktion & Laboratorier AB 
Celsiusgatan 43 
SE-212 14 Malmö 
Sweden 
 



 41 

Apotek Produktion & Laboratorier AB 
Prismavägen 2 
SE-141 75 Kungens Kurva 
Sweden 
 
 
This leaflet was last revised in  
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET