ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Orfadin 2 mg hard capsules
2.
Each capsule contains 2 mg nitisinone.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
White, opaque capsules imprinted “NTBC 2mg” in black on the body of the capsule.
The capsules contain a white to off white powder.
4.
Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in
combination with dietary restriction of tyrosine and phenylalanine.
Posology
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of
HT-1 patients. Treatment of all genotypes of the disease should be initiated as early as possible to
increase overall survival and avoid complications such as liver failure, liver cancer and renal disease.
Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and
should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).
The dose of nitisinone should be adjusted individually.
The recommended initial dose in the paediatric and adult population is 1 mg/kg body weight/day
divided in 2 doses administered orally.
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 divided in 2 doses. 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 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
2
There are no specific dose recommendations for elderly or patients that have renal or hepatic
impairment.
Paediatric population
The safety and effect of nitisinone have been studied in the paediatric population. The dose
recommendation in mg/kg body weight is the same in children and adults.
Method of administration
The capsule may be opened and the content suspended in a small amount of water or formula diet
immediately before intake.
Hypersensitivity to the active substance or to any of the excipients.
Mothers receiving nitisinone
must not breast-feed (see sections 4.6 and 5.3).
Monitoring of plasma tyrosine levels
It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone
treatment. 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 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 also to monitor serum alpha-fetoprotein concentration. 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 white cell counts are monitored regularly, as a few cases of
reversible trombocytopenia 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.
No formal interaction studies with other medicinal products have been conducted.
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
in vitro
studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-
mediated metabolism.
No formal food interactions studies have been performed. However, nitisinone has been co-
administered with food during the generation of efficacy and safety data. Therefore, it is recommended
that if nitisinone treatment is initiated with food, this should be maintained on a routine basis.
3
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. Nitisinone
should not be used during pregnancy unless clearly necessary.
Lactation
It is not known 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).
No studies on the effects on the ability to drive and use machines have been performed.
If the patient experiences adverse reactions affecting the vision, the ability to drive and use machines
should be considered.
The adverse reactions considered at least possibly related to treatment are listed below, by body
system, organ class, and absolute frequency. 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.
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
Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been
associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine
in the diet should limit the toxicity associated with this type of tyrosinemia (see section 4.4).
No case of overdose has been reported. 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract
and metabolism products, ATC code: A16A X04.
4
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.
Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG-
synthase activity and urine 5-ALA, 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.
Effects on overall survival
When compared to data for historical controls, it can be seen that treatment with nitisinone together
with dietary restriction results in a better survival probability in all HT-1 phenotypes. This is seen in
the following table:
Age at start of treatment
or diagnosis
Survival probability
Nitisinone treatment
Dietary control *
5 years
10 years
5 years
10 years
< 2 months
82
--
28
--
> 2-6 months
95
95
51
34
> 6 months
92
86
93
59
* From Figure 1,Van Spronsen et al., 1994.
Treatment with nitisinone was also found to result in reduced risk for the development of
hepatocellular carcinoma (2.3 to 3.7-fold) 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 (13.5-fold when initiated prior to the age of 12 months).
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.
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 CYP 3A4-mediated metabolism.
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 of 2.5-fold higher than the maximum recommended human dose
(2 mg/kg/day).
5
A pre and postnatal development study in the mouse showed statistically significant reduced pup
survival and pup growth during the weaning period at dose levels of 125- and 25-fold, respectively,
the maximum recommended human dose, with a trend 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). Carcinogenicity studies have not been performed.
6.
6.1 List of excipients
Capsule content
pregelatinised starch (maize)
Capsule shell
gelatin
titanium dioxide (E 171)
Imprint
black iron oxide (E 172),
shellac,
propylene glycol.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
During the shelf life the patient may store the finished product for a single period of 3 months at a
temperature not above 25°C, after which the product must be discarded.
6.5 Nature and contents of container
High density polyethylene bottle with a tamper proof low density polyethylene cap, containing 60
capsules.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Swedish Orphan Biovitrum International AB
SE-112 76 Stockholm
Sweden
6
8.
EU/1/04/303/001
9.
Date of first authorisation: 21/02/2005
Date of latest renewal: 21/02/2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
7
1.
Orfadin 5 mg hard capsules
2.
Each capsule contains 5 mg nitisinone.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
White, opaque capsules imprinted “NTBC 5mg” in black on the body of the capsule.
The capsules contain a white to off white powder.
4.
Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in
combination with dietary restriction of tyrosine and phenylalanine.
Posology
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of
HT-1 patients. Treatment of all genotypes of the disease should be initiated as early as possible to
increase overall survival and avoid complications such as liver failure, liver cancer and renal disease.
Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and
should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).
The dose of nitisinone should be adjusted individually.
The recommended initial dose in the paediatric and adult population is 1 mg/kg body weight/day
divided in 2 doses administered orally..
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 divided in 2 doses. 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 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
8
There are no specific dose recommendations for elderly or patients that have renal or hepatic
impairment.
Paediatric population
The safety and effect of nitisinone have been studied in the paediatric population. The dose
recommendation in mg/kg body weight is the same in children and adults.
Method of administration
The capsule may be opened and the content suspended in a small amount of water or formula diet
immediately before intake.
Hypersensitivity to the active substance or to any of the excipients.
Mothers receiving nitisinone
must not breast-feed (see sections 4.6 and 5.3).
Monitoring of plasma tyrosine levels
It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone
treatment. 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 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 also to monitor serum alpha-fetoprotein concentration. 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 white cell counts are monitored regularly, as a few cases of
reversible trombocytopenia 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.
No formal interaction studies with other medicinal products have been conducted.
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
in vitro
studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-
mediated metabolism.
No formal food interactions studies have been performed. However, nitisinone has been co-
administered with food during the generation of efficacy and safety data. Therefore, it is recommended
that if nitisinone treatment is initiated with food, this should be maintained on a routine basis.
9
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. Nitisinone
should not be used during pregnancy unless clearly necessary.
Lactation
It is not known 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).
No studies on the effects on the ability to drive and use machines have been performed.
If the patient experiences adverse reactions affecting the vision, the ability to drive and use machines
should be considered.
The adverse reactions considered at least possibly related to treatment are listed below, by body
system organ class, and absolute frequency. 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.
Blood and lymphatic system disorders
Common: thrombocytopenia, leucopenia, granulocytopenia
Uncommon: leucocytosis
Eye disorders
Common: conjunctivitis, corneal opacity, keratitis, photophobia, eye pain
Uncommon: blepharitis
Skin and subcutaneous tissue disorders
Uncommon: exfoliative dermatitis, erythematous rash, pruritus
Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been
associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine
in the diet should limit the toxicity associated with this type of tyrosinemia (see section 4.4).
No case of overdose has been reported. 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.
5.1 Pharmacodynamic properties
10
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract
and metabolism products, ATC code: A16A X04.
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.
Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG-
synthase activity and urine 5-ALA, 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.
Effects on overall survival
When compared to data for historical controls, it can be seen that treatment with nitisinone together
with dietary restriction results in a better survival probability in all HT-1 phenotypes. This is seen in
the following table:
Age at start of treatment
or diagnosis
Survival probability
Nitisinone treatment
Dietary control *
5 years
10 years
5 years
10 years
< 2 months
82
--
28
--
> 2-6 months
95
95
51
34
> 6 months
92
86
93
59
*
From Figure 1,Van Spronsen et al., 1994.
Treatment with nitisinone was also found to result in reduced risk for the development of
hepatocellular carcinoma (2.3 to 3.7-fold) 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 (13.5-fold when initiated prior to the age of 12 months).
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.
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 CYP 3A4-mediated metabolism.
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
11
gastroschisis) from a dose level of 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 pup
survival and pup growth during the weaning period at dose levels of 125- and 25-fold, respectively,
the maximum recommended human dose, with a trend 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). Carcinogenicity studies have not been performed.
6.
6.1 List of excipients
Capsule content
pregelatinised starch (maize)
Capsule shell
gelatin
titanium dioxide (E 171)
Imprint
black iron oxide (E 172),
shellac,
propylene glycol.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
During the shelf life the patient may store the finished product for a single period of 3 months at a
temperature not above 25°C, after which the product must be discarded.
6.5 Nature and contents of container
High density polyethylene bottle with a tamper proof low density polyethylene cap, containing 60
capsules.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Swedish Orphan Biovitrum International AB
12
SE-112 76 Stockholm
Sweden
8.
EU/1/04/303/002
9.
Date of first authorisation: 21/02/2005
Date of latest renewal: 21/02/2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
13
1.
Orfadin 10 mg hard capsules
2.
Each capsule contains 10 mg nitisinone.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
White, opaque capsules imprinted “NTBC 10mg” in black on the body of the capsule.
The capsules contain a white to off white powder.
4.
Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in
combination with dietary restriction of tyrosine and phenylalanine.
Posology
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of
HT-1 patients. Treatment of all genotypes of the disease should be initiated as early as possible to
increase overall survival and avoid complications such as liver failure, liver cancer and renal disease.
Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and
should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).
The dose of nitisinone should be adjusted individually.
The recommended initial dose in the paediatric and adult population is 1 mg/kg body weight/day
divided in 2 doses administered orally.
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 divided in 2 doses. 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 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
14
There are no specific dose recommendations for elderly or patients that have renal or hepatic
impairment.
Paediatric population
The safety and effect of nitisinone have been studied in the paediatric population. The dose
recommendation in mg/kg body weight is the same in children and adults.
Method of administration
The capsule may be opened and the content suspended in a small amount of water or formula diet
immediately before intake.
Hypersensitivity to the active substance or to any of the excipients.
Mothers receiving nitisinone must not breast-feed (see section 4.6 and 5.3).
Monitoring of plasma tyrosine levels
It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone
treatment. 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 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 also to monitor serum alpha-fetoprotein concentration. 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 white cell counts are monitored regularly, as a few cases of
reversible trombocytopenia 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.
No formal interaction studies with other medicinal products have been conducted.
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
in vitro
studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-
mediated metabolism.
No formal food interactions studies have been performed. However, nitisinone has been co-
administered with food during the generation of efficacy and safety data. Therefore, it is recommended
that if nitisinone treatment is initiated with food, this should be maintained on a routine basis.
15
Pregnancy
There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have
shown reproductive toxicity (see sections 5.3). The potential risk for humans is unknown. Nitisinone
should not be used during pregnancy unless clearly necessary.
Lactation
It is not known 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).
No studies on the effects on the ability to drive and use machines have been performed.
If the patient experiences adverse reactions affecting the vision, the ability to drive and use machines
should be considered.
The adverse reactions considered at least possibly related to treatment are listed below, by body
system organ class, and absolute frequency. 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.
Blood and lymphatic system disorders
Common: thrombocytopenia, leucopenia, granulocytopenia
Uncommon: leucocytosis
Eye disorders
Common: conjunctivitis, corneal opacity, keratitis, photophobia, eye pain
Uncommon: blepharitis
Skin and subcutaneous tissue disorders
Uncommon: pruritus, exfoliative dermatitis, erythematous rash
Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been
associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine
in the diet should limit the toxicity associated with this type of tyrosinemia (see section 4.4).
No case of overdose has been reported. 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.
5.1 Pharmacodynamic properties
16
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract
and metabolism products, ATC code: A16A X04.
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.
Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG-
synthase activity and urine 5-ALA, 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.
Effects on overall survival
When compared to data for historical controls, it can be seen that treatment with nitisinone together
with dietary restriction results in a better survival probability in all HT-1 phenotypes. This is seen in
the following table:
Age at start of treatment
or diagnosis
Survival probability
Nitisinone treatment
Dietary control *
5 years
10 years
5 years
10 years
< 2 months
82
--
28
--
> 2-6 months
95
95
51
34
> 6 months
92
86
93
59
*
From Figure 1,Van Spronsen et al., 1994.
Treatment with nitisinone was also found to result in reduced risk for the development of
hepatocellular carcinoma (2.3 to 3.7-fold) 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 (13.5-fold when initiated prior to the age of 12 months).
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.
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 CYP 3A4-mediated metabolism.
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
17
gastroschisis) from a dose level of 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 pup
survival and pup growth during the weaning period at dose levels of 125- and 25-fold, respectively,
the maximum recommended human dose, with a trend 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). Carcinogenicity studies have not been performed.
6.
6.1 List of excipients
Capsule content
pregelatinised starch (maize)
Capsule shell
gelatin
titanium dioxide (E 171)
Imprint
black iron oxide (E 172),
shellac,
propylene glycol.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
During the shelf life the patient may store the finished product for a single period of 3 months at a
temperature not above 25°C, after which the product must be discarded.
6.5 Nature and contents of container
High density polyethylene bottle with a tamper proof low density polyethylene cap, containing 60
capsules.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Swedish Orphan Biovitrum International AB
18
SE-112 76 Stockholm
Sweden
8.
EU/1/04/303/003
9.
Date of first authorisation: 21/02/2005
Date of latest renewal: 21/02/2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
19
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Apotek Produktion & Laboratorier AB
Prismavägen 2
SE-141 75 Kungens Kurva
Sweden
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
PSUR will be submitted yearly until otherwise specified by the CHMP.
21
ANNEX III
LABELLING AND PACKAGE LEAFLET
22
A. LABELLING
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/CARTON
1.
Orfadin 2 mg hard capsules
Nitisinone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 2 mg nitisinone
3.
LIST OF EXCIPIENTS
4.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
24
Swedish Orphan Biovitrum International AB
SE-112 76 Stockholm
Sweden
EU/1/04/303/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Orfadin 2 mg
25
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
IMMEDIATE PACKAGING/BOTTLE LABEL
1.
Orfadin 2 mg hard capsules
Nitisinone
Oral use
2.
METHOD OF ADMINISTRATION
3.
Swedish Orphan Biovitrum International AB
4.
EXPIRY DATE
EXP
5.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Orfadin capsules can be stored for a single period of 3 months at a temperature
not above 25°C, after which the product must be discarded.
Date removed from refrigerator:
6.
BATCH NUMBER
Lot
7.
CONTENTS BY UNIT
60 capsules
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/CARTON
1.
Orfadin 5 mg hard capsules
Nitisinone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 5 mg nitisinone
3.
LIST OF EXCIPIENTS
4.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
27
Swedish Orphan Biovitrum International AB
SE-112 76 Stockholm
Sweden
EU/1/04/303/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Orfadin 5 mg
28
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
IMMEDIATE PACKAGING/BOTTLE LABEL
1.
Orfadin 5 mg hard capsules
Nitisinone
Oral use
2.
METHOD OF ADMINISTRATION
3.
Swedish Orphan Biovitrum International AB
4.
EXPIRY DATE
EXP
5.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Orfadin capsules can be stored for a single period of 3 months at a temperature
not above 25°C, after which the product must be discarded.
Date removed from refrigerator:
6.
BATCH NUMBER
Lot
7.
CONTENTS BY UNIT
60 capsules
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/CARTON
1.
Orfadin 10 mg hard capsules
Nitisinone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 10 mg nitisinone
3.
LIST OF EXCIPIENTS
4.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
30
Swedish Orphan Biovitrum International AB
SE-112 76 Stockholm
Sweden
EU/1/04/303/003
13. MANUFACTURER’S BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Orfadin 10 mg
31
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
IMMEDIATE PACKAGING/BOTTLE LABEL
1.
Orfadin 10 mg hard capsules
Nitisinone
Oral use
2.
METHOD OF ADMINISTRATION
3.
Swedish Orphan Biovitrum International AB
4.
EXPIRY DATE
EXP
5.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Orfadin capsules can be stored for a single period of 3 months at a temperature
not above 25°C, after which the product must be discarded.
Date removed from refrigerator:
6.
BATCH NUMBER
Lot
7.
CONTENTS BY UNIT
60 capsules
32
B. PACKAGE LEAFLET
33
PACKAGE LEAFLET: INFORMATION FOR THE USER
Orfadin 2 mg hard capsules
Orfadin 5 mg hard capsules
Orfadin 10 mg hard capsules
Nitisinone
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Orfadin
is and what it is used for
2.
Before you take Orfadin
3.
How to take Orfadin
4.
Possible side effects
5
How to store Orfadin
6.
Further information
1.
WHAT ORFADIN
IS AND WHAT IT IS USED FOR
The active ingredient of Orfadin is nitisinone. Orfadin is used for treatment of a rare disease called
hereditary tyrosinemia type 1.
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 Orfadin, because tyrosine will remain in your
body. This special diet is based on low tyrosine and phenylalanine content.
2.
BEFORE YOU TAKE ORFADIN
Do not take Orfadin
-
if you are allergic (hypersensitive) to nitisinone or any of the other ingredients of Orfadin
(see section 6).
Take special care with Orfadin
- 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.
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.
Follow-up by your doctor should be performed every 6 months. If you experience any side effects,
shorter intervals are recommended.
34
-
Keep this leaflet. You may need to read it again.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Taking Orfadin with food and drink
If you start Orfadin 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 Orfadin 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..
Driving and using machines
No studies on the effect on the ability to drive and use machines have been performed.
If you experience side effects affecting the vision you should consider your ability to drive or use
machines.
3.
HOW TO TAKE ORFADIN
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of
hereditary tyrosinemia type 1 patients.
Always take Orfadin exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual total daily dose is 1 mg/kg body weight/day divided in 2 doses. Your doctor will adjust the
dose individually.
If you have problems with swallowing the capsules, they may be opened and the powder mixed 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 Orfadin 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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Orfadin can cause side effects, although not everybody gets them.
If you notice any side effects relating to the eyes, talk to your doctor immediately for an eye
examination.
35
The frequency of possible side effects listed below is defined using the following convention:
Very common: Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from the available data
Common side effects
-
Various eye symptoms; conjunctivitis (inflammation in the eye), opacity and inflammation in the
cornea, sensitivity to light, eye pain,
-
reduced number of platelets and white blood cells, shortage of certain white blood cells
(granulocytopenia).
Uncommon side effects
-
Inflammation of the eyelid,
-
increased number of white blood cells,
-
itching, skin inflammation (exfoliative dermatitis), rash.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ORFADIN
Keep out of the reach and sight of children.
Do not use Orfadin 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).
Orfadin
capsules can be removed from the refrigerator for one single period of maximum 3 months
and stored at a temperature not above 25°C, after which the product must be discarded.
Do not forget to mark the date on the bottle, when removed from the refrigerator.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Orfadin contains
The active substance is:
-
nitisinone.
Each capsule contains 2 mg, 5 mg or 10 mg nitisinone.
The other ingredients are
Capsule content:
pregelatinised starch (from maize).
Capsule shell:
gelatine
titanium dioxide (E 171).
Printing ink:
iron oxide (E 172)
36
shellac
propylene glycol
What Orfadin looks like and contents of the pack
Orfadin
capsules are white, opaque, hard gelatin capsules, imprinted with “NTBC” and the strength
“2 mg”, “5 mg” or “10 mg”, in black. The capsule contains a white to off-white powder.
The capsules are packaged in plastic bottles with child resistant 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 approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
37
Source: European Medicines Agency
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