Orfadin - instructions for use, dose, side effects, contraindications

Active substanceNitysinoneNitysinone

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Orfadine

capsules inwards

Svedish Orphan International AB Sweden

Dosage form: & nbspcapsules

Composition:

Each capsule contains: active substance: Nitizinon 2 mg, 5 mg, 10 mg.

Excipients: pregelatinized starch, gelatin, titanium dioxide, ferric oxide black oxide (E 172).

Description:

White opaque capsules containing white or almost white powder. On the capsule is an inscription of black color "NTBC 2 nig", "NTBC 5 mg", "NTBC 10 mg".

Pharmacotherapeutic group:Tyrosinemia is a hereditary treatment

ATX: & nbsp

A.16.A.X Other drugs for the treatment of digestive and metabolic diseases

A.16.A.X.04 Nitysinone

Pharmacodynamics:Metabolic disorders in hereditary tyrosineemia type 1 (NT-1) is manifested in a shortage of fumarylacetoacetate hydrolase, which is the final enzyme of tyrosine catabolism. Nitysinone a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme that precedes fumarylacetoacetate hydrolase in tyrosine catabolism. Inhibiting the normal catabolism of tyrosine in patients with HT-1, nitinosin prevents accumulation of toxic metabolites - succinyl acetate and fumarylacetoacetate. In patients with HT-1, these metabolites are converted to toxic derivatives - succinylacetone and succinylacetoacetate. Succinyl acetate inhibits the synthesis of porphyrin, leading to to 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 the 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 in	Probability of survival
the beginning	Treatment		Dietary
treatment or	nitinosinom		cue
continued			control
the	5 years	10	5	10
diseases		years	years	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 nitizinon in the form of capsules (1 mg / kg body weight), the elimination half-life (T_1/2) of nitinosin in plasma was 54 hours. Population pharmacokinetic analysis was performed on a group of 207 patients with HT-1.

The clearance and T_1/2, which amounted to 0.0956 l / kg / day and 52.1 h respectively.

Indications:

Treatment of patients with a confirmed diagnosis of hereditary type 1 tyrosisemia (HT-1) in combination with restriction of tyrosine and phenylalanine intake with food.

Contraindications:

Hypersensitivity to any of the components of the drug.

Pregnancy and lactation:

Pregnancy

Studies of the use of nitizinon in pregnant women have not been conducted. Studies in animals have revealed reproductive toxicity. The potential risk to people is unknown. Nitysinone It can not be used during pregnancy, except when the therapeutic effect for the mother justifies the possible risk to the fetus.

Lactation

It is not known whether the nitinosin in human milk.Studies in animals have shown adverse postnatal effects when nitisinone penetrates into breast milk. Therefore, mothers who receive nitinosin, should refrain from breastfeeding, as the potential risk to the child can not be ruled out.

Dosing and Administration:

For oral administration.

The dose of nitizinon should be selected individually. Treatment nitizinonom dbzhen conduct a doctor who has experience with HT-1 patients.

The recommended initial dose is 1 mg / kg of 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 succinylacetol in the urine, the state of liver function and the concentration of alpha-floprotein. If after 1 month after the initiation of nitizinon in the urine, succinylacetone is found, 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 administered 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 course of treatment it is necessary to monitor all possible biochemical parameters (sukinilatsetone in plasma, 5-aminolevulinate in urine and activity of porphobilinogen synthase of erythrocytes).

Side effects:

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. Frequency is defined as "often" (≥1/100, <1/10) or "infrequently" (≥1 / 1,000, <1/100). Within each frequency group, adverse effects are listed in order of decreasing severity.

From the hemopoietic system and lymphatic system

Often: thrombocytopenia, leukopenia, granulocytopenia.

Infrequently: leukocytosis.

From the side of the organs of sight

Often: conjunctivitis, turbidity cornea, keratitis, photophobia, pain in the eyes.

Infrequently: blepharitis.

From the skin and subcutaneous fabrics

Often: exfoliative dermatitis, erythematous rash, itching.

Treatment with nitinosinom is followed by increase in tyrosine concentration, which is accompanied by opacity of the cornea and increased hyperkeratosis damagetions.

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

Overdose:

On cases of overdose ns reported. The occasional intake of nitizinon by persons not observing a special diet with a restriction of the consumption of tyrosine and phenylalanine leads to an increase in the tyrosine concentration 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.

Interaction:

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

Nitizinon is metabolized in vitro from participation of isoenzyme CYP ZA4, and therefore the combined use of nitizinone with inhibitors or inducers of this isofermate may require dose adjustment.

Based on the research data in vitro, it is assumed that nitinosin does not inhibit isoenzymes CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism. Studies of the interaction of nitizinon with food were not conducted. However, in the process of studying the effectiveness and safety of the drug nitinosin 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.

Special instructions:

Treatment of tyrosinemia of any type should start as soon as possible to improve overall survival and avoid such complications like hepatic insufficiency, liver cancer and kidney disease. To improve efficiency treatment with nitinosin adhere to a special diet that excludes the intake of phenylalanine and tyrosine, as well as control concentration of amino acids in blood plasma.

Control of visual impairment It is recommended that an ophthalmologist be heldbefore starting treatment with nitizinone. Patients who have there were visual disturbances in the process treatment with nitizinone, should be immediately examined by an ophthalmologist.

It should be established whether patient special diet and measure the concentration of tyrosine in plasma. If The concentration of tyrosine in plasma is more than 500 μmol / l, it is necessary more strictly limit consumption tyrosine and phenylalanine with food. Not it is recommended to reduce concentration tyrosine in plasma by reducing the dose or discontinuation of the use of nitizinon, as a metabolic disorder can lead to a worsening of clinical patient's condition.

Monitoring the liver

It is necessary to regularly investigate the function liver. It is also recommended control the concentration of alpha-fetoprotein in the blood plasma. Increase concentration of alpha-fetoprotein in plasma blood can be a sign of unadjusted treatment. When increase in the concentration of alpha-fetoprotein or the appearance of nodular changes in the liver should be checked for the presence of malignant neoplasms in the liver.

Control of platelets and leukocytes

It is recommended that the number of platelets and leukocytes, both as in the course of the clinical trial it was several cases were recorded reversible thrombocytopenia and leukopenia.

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

Effect on the ability to drive transp. cf. and fur:

Form release / dosage:

Capsules 2 mg, 5 mg, 10 mg.

Packaging:

For 60 capsules per vial of high-density polyethylene with cover with low density polyethylene with indication of the first autopsy. The bottle is glued on label. 1 bottle is placed in a cardboard box together with instructions for use.

Storage conditions:

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.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007750/09

Date of registration:02.10.2009

The owner of the registration certificate:Svedish Orphan International ABSvedish Orphan International AB Sweden

Manufacturer: & nbsp

APOTEKET AB Produktion & Laboratorier Sweden

Representation: & nbspSvedish Orphan InternationalSvedish Orphan International

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Orfadine (Orfadin)