Universal reference book for medicines
Product name: ORFADIN (ORFADIN)

Active substance: nitisinone

Type: The drug for the treatment of hereditary enzymatic insufficiency

Manufacturer: SWEDISH ORPHAN INTERNATIONAL AB (Sweden) manufactured by APOTEKET AB Produktion & Laboratorier (Sweden)
Composition, form of production and packaging
Capsules
1 caps.

Nitizinon 2 mg

60 pcs.
- polyethylene bottles (1) - cardboard packs.
Capsules 1 caps.

Nitizinon 10 mg

60 pcs.
- polyethylene bottles (1) - cardboard packs.
Capsules 1 caps.

Nitizinon 5 mg

60 pcs.
- polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Metabolic disturbances in hereditary type 1 tyrosinemia (HT-1) is manifested in a shortage of fumarylacetoacetate hydrolase, which is the final enzyme of tyrosine catabolysis.
Nitizinon is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme that precedes fumarylacetoacetate hydrolase in tyrosine catabolism. By inhibiting normal tyrosine catabolism in patients with HT-1, nitizinon prevents the accumulation of toxic metabolites-succinyl acetate and fumaryl acetoacetate. In patients with HT-1, these metabolites are converted to toxic derivatives - succinylacetone and succinylacetoacetate. Succinyl acetate inhibits the synthesis of porphyrin, leading to the accumulation of 5-aminolevulinate.
Treatment with nitinzinom leads to a normalization of the metabolism of porphyrin and the activity of porphybilinogen synthase of erythrocytes, as well as to a decrease in the excretion of succinylacetone in the urine, an increase in the concentration of tyrosine in plasma, and an increase in the excretion of phenolic acids in the urine.
Clinical trial data show that more than 90% of patients had succinylacetone in the urine normalized during the first week of treatment. If the dose of nitizinon is selected correctly, succinylacetone in urine or plasma is not detected.
Impact on overall survival

Age at the beginning of treatment or duration of the disease Probability of survival

Treatment with Nitinosinom Diet 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

It was noted that treatment with nitizinone reduces the risk of developing hepatocellular carcinoma in comparison with the accumulated statistical data on treatment only with the help of a special diet.
In addition, it was found that treatment in the early stages of the disease subsequently led to a reduction in the risk of developing hepatocellular carcinoma.
PHARMACOKINETICS

Absorption, distribution, metabolism and excretion studies for nitinosinone have not been performed.
In ten healthy male volunteers, after taking a single dose of nitizinone in the form of capsules (1 mg / kg body weight), the half-life (T 1/2 ) of nitinosin in plasma was 54 hours. Population pharmacokinetic analysis was performed in a group of 207 patients with HT- 1.
The clearance and T 1/2 were measured, which were 0.0956 l / kg / day and 52.1, respectively.

INDICATIONS

- treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in combination with the restriction of tyrosine and phenylalanine intake with food.

DOSING MODE

For oral administration.

The dose of nitizinon should be selected individually.
Treatment with nitizinone should be performed by a doctor who has experience in treating HT-1 patients.
The recommended initial dose is 1 mg / kg body weight per day, divided into 2 doses.

The capsule can be opened and the content dissolved in a small amount of water or other product corresponding to a special diet, just before the intake.

Dose selection

During the course of treatment it is necessary to monitor the content of succinylacetone in the urine, the state of liver function and the concentrations of alpha-fetoprotein.
If after 1 month after the initiation of nitizinon in the urine, succinylacetone is detected, the dose of nitizinon should be increased to 1.5 mg / kg of body weight per day, divided into 2 divided doses. A dose of 2 mg / kg of body weight per day can be prescribed after a study of all biochemical parameters. This dose should be considered as the maximum for all patients.
If the results of biochemical analysis are satisfactory, the dose should be adjusted in accordance with body weight.

During the entire course of treatment, it is necessary to monitor all possible biochemical parameters (succinyl acetone plasma 5-aminolevulinate in the urine and the activity of porphobilinogen synthase of red blood cells).

SIDE EFFECT

The following are adverse reactions that can be caused by treatment, distributed among the organs and systems of the body and the absolute frequency of manifestation.
The frequency is defined as "often" (? 1/100, <1/10) or "infrequently" (? 1/1000, <1/100). Within each frequency group, adverse effects are listed in order of decreasing severity.
On the part of the hematopoiesis and lymphatic system

Often: thrombocytopenia, leukopenia, granulocytopenia.

Infrequently: leukocytosis.

From the side of the organ of vision

Often: conjunctivitis, corneal opacity, keratitis, photophobia, pain in the eyes.

Infrequently: blepharitis.

From the skin and subcutaneous tissues

Often: exfoliative dermatitis, erythematous rash, itching.

Treatment with nitinzinom is accompanied by an increase in the concentration of tyrosine, which is accompanied by opacity of the cornea and increased hyperkeratosis damage.

Restriction of tyrosine and phenylalanine intake with food should limit the toxicity associated with this type of tyrosinemia.

CONTRAINDICATIONS

- Hypersensitivity to any of the components of the drug.

PREGNANCY AND LACTATION

The use of the drug during pregnancy is possible only if the intended benefit for the mother exceeds the potential risk to the fetus.

Mothers taking nitizinon should refrain from breastfeeding, since the potential risk to the baby can not be ruled out.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

The liver function should be investigated regularly.
With an increase in the concentration of alpha-fetoprotein or the appearance of nodular changes in the liver, they should be checked for malignant neoplasms in the liver.
SPECIAL INSTRUCTIONS

Treatment of tyrosinemia of any type should be started as early as possible in order to improve overall survival and avoid complications such as hepatic insufficiency, liver cancer and kidney disease.
To increase the effectiveness of treatment with nitizinone, one should adhere to a special diet that excludes the intake of phenylalanine and tyrosine, and also monitor the concentration of amino acids in the blood plasma.
Control of visual impairment

It is recommended to conduct an ophthalmologic examination before starting treatment with nitizinone.
Patients who developed vision disorders during treatment with nitizinone should be immediately examined by an ophthalmologist. It should be determined whether the patient adheres to a special diet and measures the concentration of tyrosine in the plasma. If the concentration of tyrosine in the plasma is more than 500 μmol / L, then it is necessary to more strictly limit the consumption of tyrosine and phenylalanine with food. It is not recommended to reduce the concentration of tyrosine in the plasma by reducing the dose or stopping the use of nitizinone, since a metabolic disorder can lead to a deterioration in the clinical state of the patient.
Monitoring the liver

The liver function should be investigated regularly.
It is also recommended to monitor the concentration of alpha-fetoprotein in the blood plasma. An increase in the concentration of alpha-fetoprotein in the blood plasma may be a sign of uncorrected treatment. With an increase in the concentration of alpha-fetoprotein or the appearance of nodular changes in the liver, they should be checked for malignant neoplasms in the liver.
Control of platelets and leukocytes

It is recommended to regularly determine the number of platelets and white blood cells, since several cases of reversible thrombocytopenia and leukopenia have been documented during the clinical trial.

The patient must visit the doctor every 6 months;
shorter intervals between visits are recommended in case of development of undesirable phenomena.
OVERDOSE

No cases of overdose have been reported.
Accidental administration of nitizinon to persons who do not observe a special diet with a restriction of the consumption of tyrosine and phenylalanine leads to an increase in the concentration of tyrosine in the body, which is accompanied by a toxic effect on the organ of vision, skin and the nervous system. Limiting the intake of tyrosine and phenylalanine with food should reduce the toxic effect associated with this type of tyrosinemia. Information on the specific treatment of overdose is absent.
DRUG INTERACTION

Studies of the interaction of nitizinon with other drugs have not been conducted.

Nitizinone is metabolized in vitro with the participation of the CYP3A4 isoenzyme, and therefore, when the nitizinone is used together with the inhibitors or inducers of this isoenzyme, dose adjustment may be required.

Based on in vitro studies, it is suggested that nitizinone does not inhibit the isoenzymes CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism.

Studies of the interaction of nitizinon with food were not conducted.
However, in the process of investigating the efficacy and safety of the drug, nitizinon was taken with food. Therefore, if the treatment with nitizinone was started along with food intake, it is recommended to stick to it throughout the course of treatment.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored at a temperature of 2 - 8? C.
Keep out of the reach of children.
Shelf life 1.5 years.

Do not use after the time specified on the package.

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