Tizinon

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TISINON (TISINON)

Composition:

Active substance: nitisinone;

1 ml of suspension contains: nitisinone 4 mg;

Excipients: hydroxypropylmethylcellulose, glycerin, polysorbate 80, sodium benzoate (E 211), tartaric acid, "Strawberry" flavouring, purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: slightly viscous, opaque white suspension with a characteristic strawberry odour.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Other drugs for the treatment of gastrointestinal disorders and metabolic disturbances. ATC code A16AX04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The metabolic disorder in hereditary tyrosinemia type 1 is characterized by a deficiency of fumarylacetoacetate hydrolase, the terminal enzyme in the catabolism of tyrosine. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the enzyme preceding fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1, nitisinone prevents the accumulation of toxic metabolic intermediates—maleylacetoacetate and fumarylacetoacetate. In patients with hereditary tyrosinemia type 1, these intermediate metabolites are converted into toxic metabolites—succinylacetone and succinylacetoacetate. Succinylacetone inhibits porphyrin synthesis, leading to the accumulation of 5-aminolevulinic acid.

The biochemical defect in alkaptonuria is a deficiency of homogentisate 1,2-dioxygenase, the third enzyme in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the harmful metabolite homogentisic acid (HGA), which otherwise leads to ochronosis of joints and cartilage, and consequently to the development of clinical features of the disease.

Pharmacodynamic effects

In patients with hereditary tyrosinemia type 1, treatment with nitisinone normalizes porphyrin metabolism and erythrocyte porphobilinogen synthase activity, reduces urinary excretion of 5-aminolevulinic acid, decreases urinary excretion of succinylacetone, increases plasma tyrosine concentration, and increases urinary excretion of phenolic acids. Clinical study data demonstrated that in more than 90% of patients, urinary succinylacetone levels normalized within the first week of treatment. If the dose of nitisinone is appropriately adjusted, succinylacetone is not detectable in urine or plasma.

In patients with alkaptonuria, treatment with nitisinone reduces the accumulation of HGA. Available clinical study data show a 99.7% reduction in urinary HGA levels and a 98.8% reduction in serum HGA levels after 12 months of treatment with nitisinone, compared to untreated control patients.

Clinical efficacy and safety in hereditary tyrosinemia type 1

The clinical study was open-label and uncontrolled. The dosing regimen during the study was twice daily. Data on survival probability after 2, 4, and 6 years of treatment with nitisinone are presented in Table 1.

Table 1

Study NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone)] (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 %
Total	94 %	94 %	94 %

Based on the results of a retrospective study, survival probability data are presented in Table 2.

Table 2

Age at onset of symptoms	1 year	2 years
< 2 months	38 %	29 %
> 2–6 months	74 %	74 %
> 6 months	96 %	96 %

It has been observed that treatment with nitisinone reduces the risk of developing hepatocellular carcinoma (HCC) compared to treatment with diet alone. Furthermore, it has been found that treatment at early stages of the disease further reduces the risk of developing hepatocellular carcinoma.

Table 3 presents data on the probability of being free from HCC at 2, 4, and 6 years of nitisinone treatment in patients aged 24 months or younger, as well as in patients older than 24 months at the start of treatment.

Table 3

NTBC study (n = 250)

Patients' age	Number of patients				Probability of absence of GVHD (95% confidence interval)
	at baseline	after 2 years	after 4 years	after 6 years	after 2 years	after 4 years	after 6 years
All patients	250	155	86	15	98 % (95; 100)	94 % (90; 98)	91 % (81; 100)
Age at start of treatment ≤ 24 months	193	114	61	8	99 % (98; 100)	99 % (97; 100)	99 % (94; 100)
Age at start of treatment > 24 months	57	41	25	8	92 % (84; 100)	82 % (70; 95)	75 % (56; 95)

During an international study involving patients with hereditary tyrosinemia type 1 who were treated exclusively by dietary restrictions, hepatocellular carcinoma (HCC) was diagnosed in 18% of patients aged 2 years and older.

A pharmacokinetic, efficacy, and safety study comparing a once-daily dosing regimen with a twice-daily regimen was conducted in a cohort of 19 patients with hereditary tyrosinemia type 1. No clinically significant differences in adverse reactions or other safety parameters at the end of treatment were observed between the once-daily and twice-daily dosing groups. At the end of the once-daily treatment period, succinylacetone was not detected in any patient. The study results indicate that once-daily administration of the drug is safe and effective for patients of all age groups. However, data in patients with body weight < 20 kg are limited.

Clinical efficacy and safety in alkaptonuria

The efficacy and safety of 10 mg nitisinone once daily in the treatment of adult patients with alkaptonuria were demonstrated in a randomized, double-blind, placebo-controlled, parallel-group, 48-month study involving 138 patients (69 of whom received nitisinone). The primary endpoint was the effect on urinary HGA levels; after 12 months, a 99.7% reduction was observed in the nitisinone-treated group compared to untreated controls. Nitisinone treatment demonstrated a statistically significant beneficial effect on the clinical assessment of the alkaptonuria severity index (cAKUSSI), eye pigmentation, ear pigmentation, femoral osteopenia, and the number of painful spinal segments compared to untreated controls. cAKUSSI is a composite score that includes assessments of eye and ear pigmentation, kidney and prostate stones, aortic stenosis, osteopenia, bone fractures, tendon/ligament/muscle ruptures, kyphosis, scoliosis, joint replacements, and other manifestations of alkaptonuria. Thus, the reduction in HGA levels in patients receiving nitisinone led to a decrease in ochronotic processes and a reduction in clinical manifestations, supporting a slowing of disease progression.

Ocular adverse reactions such as keratopathy and eye pain, as well as infections, headache, and weight gain, were reported more frequently in patients receiving nitisinone compared to untreated patients. Keratopathy led to temporary or permanent discontinuation of treatment in 14% of patients receiving nitisinone, but was reversible upon discontinuation of nitisinone.

Data in patients over 70 years of age are lacking.

Pharmacokinetics

Studies on the absorption, distribution, metabolism, and excretion of nitisinone have not been conducted. In 10 healthy male volunteers, following a single oral dose of nitisinone capsules (1 mg/kg body weight), the terminal half-life of nitisinone in plasma was 54 hours (range: 39 to 86 hours). A population pharmacokinetic analysis was performed in a group of 207 patients with hereditary tyrosinemia type 1. Clearance and half-life were measured at 0.0956 L/kg body weight/day and 52.1 hours, respectively.

In vitro studies using human liver microsomes and cDNA-expressed cytochrome P450 enzymes demonstrated limited CYP3A4-mediated metabolism.

Clinical studies assessing the effect of steady-state 80 mg nitisinone showed that nitisinone increased the AUC∞ of the CYP2C9 substrate tolbutamide by 2.3-fold, indicating moderate inhibition of CYP2C9. Nitisinone caused approximately a 30% decrease in the AUC∞ of chlorzoxazone, suggesting weak induction of CYP2E1. Nitisinone does not inhibit CYP2D6, as nitisinone administration did not affect the AUC∞ of metoprolol. The AUC∞ of furosemide increased by 1.7-fold, indicating weak inhibition of OAT1/OAT3 (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Based on in vitro study results, nitisinone is not expected to inhibit metabolism mediated by CYP1A2, 2C19, or 3A4, or to induce CYP1A2, 2B6, or 3A4/5. Nitisinone is not expected to inhibit transport mediated by P-gp, BCRP, or OCT2. The plasma concentration of nitisinone achieved under clinical conditions is not expected to inhibit OATP1B1- or OATP1B3-mediated transport.

Results of non-clinical safety studies

Nitisinone showed embryofetal toxicity in mice and rabbits when administered at clinically relevant doses. In rabbits, nitisinone induced dose-dependent increases in developmental malformations (umbilical hernia and gastroschisis) starting at doses 2.5 times the maximum recommended human dose (2 mg/kg/day).

A pre- and postnatal development study in mice showed a statistically significant reduction in offspring survival and development during the weaning period when administered at doses 125 and 25 times the maximum recommended human dose, respectively, with a trend toward negative effects on offspring survival starting at a dose of 5 mg/kg/day. In rats, nitisinone exposure via breast milk resulted in reduced mean body weight of offspring and corneal lesions.

Non-mutagenic but weak clastogenic activity was observed in in vitro studies. There was no evidence of genotoxicity in vivo (mouse micronucleus test and DNA repair synthesis analysis in liver cells). In a 26-week carcinogenicity study in transgenic mice (TgrasH2), nitisinone showed no carcinogenic effects.

Clinical characteristics.

Indications.

Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1, provided that a diet restricting intake of products containing tyrosine and phenylalanine is maintained.

Treatment of adult patients with alkaptonuria.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Women undergoing treatment with nitisinone must refrain from breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Nitisinone is metabolized in vitro by the CYP3A4 isoenzyme; therefore, dose adjustment may be required when nitisinone is used concomitantly with inhibitors or inducers of this isoenzyme.

Based on clinical study data of the effect of 80 mg nitisinone in a steady state, nitisinone is a moderate inhibitor of CYP2C9 (2.3-fold increase in tolbutamide AUC); thus, treatment with nitisinone may lead to increased plasma concentrations of medicinal products metabolized primarily by CYP2C9 (see section "Special precautions for use").

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 furosemide AUC), whereas nitisinone does not inhibit CYP2D6 (see section "Pharmacokinetics").

Specific studies on the interaction of the drug with food have not been conducted. However, during efficacy and safety studies of nitisinone, the drug was taken with food. Therefore, if nitisinone was initially administered with food at the beginning of treatment, it is recommended to maintain this regimen throughout the entire course of treatment.

Special precautions for use.

The patient should visit the physician every 6 months; shorter intervals between visits are recommended if adverse reactions develop.

Monitoring of plasma tyrosine levels

Ophthalmological examination is recommended prior to initiating nitisinone treatment and thereafter at least once a year. Patients who develop visual disturbances during nitisinone treatment must be examined immediately by an ophthalmologist.

Hereditary tyrosinemia type 1. It is necessary to verify whether the patient is adhering to a special diet and to measure tyrosine concentration in blood plasma. If plasma tyrosine concentration exceeds 500 µmol/L, dietary intake of tyrosine and phenylalanine should be restricted. It is not recommended to reduce plasma tyrosine concentration by decreasing the dose or discontinuing nitisinone, as metabolic disturbance may lead to worsening of the patient's clinical condition.

Alkaptonuria. In patients who develop keratopathies, plasma tyrosine levels should be monitored. Patients should follow a diet restricted in tyrosine and phenylalanine to maintain plasma tyrosine levels below 500 µmol/L. In addition, nitisinone therapy should be temporarily discontinued and may be reintroduced once symptoms have resolved.

Monitoring of liver function

Hereditary tyrosinemia type 1. Liver function should be monitored regularly by liver function tests and imaging techniques. Monitoring of alpha-fetoprotein concentration in blood plasma is also recommended. Elevated plasma alpha-fetoprotein concentration may indicate inadequate treatment. If alpha-fetoprotein levels increase or liver nodules appear, the liver should be evaluated for malignant neoplasms.

Monitoring of platelets and leukocytes

Patients with hereditary tyrosinemia type 1 and alkaptonuria should have regular monitoring of platelet and leukocyte counts, as several cases of reversible thrombocytopenia and leukopenia have been observed during clinical studies of hereditary tyrosinemia type 1.

The patient should visit the physician every 6 months; shorter intervals between visits are recommended if adverse reactions occur.

Concomitant use with other medicinal products

Nitisinone is a moderate inhibitor of CYP2C9. Therefore, nitisinone treatment may increase plasma concentrations of concomitantly administered medicinal products that are primarily metabolized by CYP2C9. Close monitoring is required for patients receiving nitisinone together with medicinal products that have a narrow therapeutic index and are metabolized by CYP2C9, such as warfarin and phenytoin. Dose adjustment of these concomitant medicinal products may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

This medicinal product contains glycerol, which may cause headache, gastrointestinal irritation, and diarrhea.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of nitisinone in pregnant women. Toxic effects of nitisinone on reproductive function have been observed in animal studies (see section "Pharmacological properties"). The potential risk to humans is unknown. Nitisinone should not be used during pregnancy unless the woman's medical condition requires treatment with nitisinone.

Nitisinone crosses the human placenta.

Breastfeeding period. It is unknown whether nitisinone is excreted in human breast milk. Animal studies have shown adverse effects of nitisinone on offspring development due to excretion of nitisinone in female animal milk. Therefore, mothers receiving nitisinone should not breastfeed, as the risk to the infant cannot be excluded (see sections "Pharmacological properties" and "Contraindications").

Fertility. There are no data on harmful effects of nitisinone on fertility.

Ability to affect reaction speed when driving or operating machinery.

Nitisinone has a minor influence on the ability to drive or operate machinery. Ocular adverse reactions (see section "Adverse reactions") may affect vision. If visual impairment occurs, the patient should refrain from driving and operating machinery until this adverse effect resolves.

Administration and Dosage

Hereditary Tyrosinemia Type 1

Treatment with nitisinone must be initiated and supervised by a physician experienced in managing patients with hereditary tyrosinemia type 1.

Treatment should be started as early as possible for all genotypes of the disease to improve overall survival and prevent complications such as liver failure, hepatocellular carcinoma, and renal dysfunction. Nitisinone therapy must be accompanied by a diet restricted in tyrosine and phenylalanine, with regular monitoring of plasma amino acid concentrations (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Initial Dose in Hereditary Tyrosinemia Type 1

The recommended initial daily dose for both children and adults is 1 mg/kg body weight administered orally. The dose of nitisinone should be individualized.

The dose should be taken once daily. Due to limited data on the use of the drug in patients with body weight <20 kg, it is recommended that for this patient group the total daily dose be divided into two doses administered daily.

Dose Adjustment in Hereditary Tyrosinemia Type 1

Throughout the treatment course, monitoring of succinylacetone in urine, liver function, and alpha-fetoprotein levels is required (see section "Special Warnings and Precautions for Use"). If succinylacetone is still detected in urine one month after initiating nitisinone therapy, the dose should be increased to 1.5 mg/kg body weight per day. A dose of 2 mg/kg body weight per day may be considered after evaluation of all biochemical parameters. This dose should be regarded as the maximum for all patients. If biochemical parameters are stable and within acceptable ranges, the dose should be adjusted according to body weight.

Throughout the treatment, all relevant biochemical parameters should also be monitored, including plasma succinylacetone concentration, urinary 5-aminolevulinic acid (ALA) levels, and erythrocyte porphobilinogen synthase (PBG-synthase) activity.

Alkaptonuria

Treatment with nitisinone should be managed by a physician experienced in treating patients with alkaptonuria.

The recommended dose for adult patients with alkaptonuria is 10 mg once daily.

Special Populations

No specific dosage recommendations are available for elderly patients or for patients with renal or hepatic impairment.

Administration Method

The oral suspension should be administered directly into the patient's mouth using the dosing syringe without dilution. The medicinal product is supplied with three dosing syringes (1 mL, 3 mL, and 5 mL) to measure the prescribed dose in milliliters. The syringes are graduated in increments of 0.01 mL, 0.1 mL, and 0.2 mL, respectively. The table below provides dose conversion (mg/mL) for the three syringe sizes.

Dosage Conversion Tables for the Three Dosing Syringe Sizes

1 ml syringe-doser (with 0.01 ml graduations)	Dosing
	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 syringe-doser (with 0.1 ml graduations)	Dosing
	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 syringe-doser (with 0.2 ml graduations)	Dosing
	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 on Use

The suspension must be re-dispersed by vigorous shaking before each use. Prior to re-dispersion, the medicinal product may appear as a solid sediment with a slightly opalescent supernatant liquid. The dose should be administered immediately after re-dispersion and withdrawal using the dosing syringe.

It is essential to carefully follow the instructions below for preparing and administering the dose to ensure accurate dosing.

How to Prepare a New Vial for First Use

Before administering the first dose, the vial must be shaken vigorously, as particles may form a solid sediment at the bottom during prolonged storage.

1. Remove the vial from the refrigerator and record the date of removal on the label.
2. Shake the vial vigorously for at least 20 seconds until the solid sediment at the bottom is completely dispersed.
3. Remove the cap by pressing down firmly and turning it counterclockwise.
4. Place the open vial upright on a flat surface and firmly press the plastic adapter as deeply as possible into the vial neck. The vial should be closed with the child-resistant cap.

For subsequent dosing, refer to the instructions below.

How to Prepare a Dose of the Medicinal Product

1. Shake the vial vigorously for at least 5 seconds.
2. Immediately after shaking, open the vial by removing the cap.
3. Fully depress the plunger inside the dosing syringe.
4. Holding the vial upright, firmly insert the dosing syringe into the opening of the adapter at the top of the vial.
5. Carefully invert the vial with the syringe attached so that it is upside down.
6. To withdraw the prescribed dose (in millilitres), slowly pull the plunger down until the upper edge of the black ring aligns exactly with the dose marking line. If air bubbles are present in the filled syringe, push the plunger up until all air bubbles are expelled. Then, slowly pull the plunger down again until the upper edge of the black ring aligns exactly with the required dose marking line.
7. Return the vial to an upright position and carefully unscrew the dosing syringe from the vial.
8. The dose should be administered orally (without dilution) immediately to prevent clogging in the dosing syringe. Empty the syringe slowly to allow time for swallowing the entire suspension; rapid administration may cause choking.
9. Immediately after use, replace the cap on the vial. Do not remove the adapter from the vial.
10. The vial containing the medicinal product can be stored at a temperature not exceeding 25°C or in the refrigerator.

It is recommended that a healthcare professional instruct the patient on the correct use of dosing syringes to ensure accurate dosing in millilitres.

The medicinal product is also available in 5 mg, 10 mg, and 20 mg capsules if these are considered more suitable for the patient.

It is recommended to take the suspension during a meal (see section "Special Warnings and Precautions for Use").

Cleaning the Dosing Syringe

After use, the dosing syringe should be rinsed immediately with water. To do this, separate the barrel from the plunger and wash both parts with water. Shake off excess water and leave the disassembled syringe to dry before reassembling for the next use.

Disposal

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

Warning

Needles, intravenous tubing, or any other parenteral administration devices must not be attached to the oral dosing syringe.

TISSINON is intended for oral use only.

Children

Hereditary Tyrosinemia Type 1

The recommended dose in milligrams per kilogram of body weight is the same for children and adults.

Due to limited data on use in patients with body weight < 20 kg, it is recommended to divide the total daily dose into two daily administrations when treating patients in this category.

Alkaptonuria

The safety and efficacy of the medicinal product in children (aged 0 to 18 years) with alkaptonuria have not been established. Data are lacking.

Overdose

Accidental ingestion of nitisinone by individuals not following a special diet restricted in tyrosine and phenylalanine leads to increased tyrosine concentrations in the body. Elevated tyrosine levels are associated with toxic effects on the eyes, skin, and nervous system. Dietary restriction of tyrosine and phenylalanine intake should reduce the toxic effects associated with this form of tyrosinemia. Information on specific treatment for overdose is lacking.

Adverse Reactions

Summary of Safety Profile

Due to its mechanism of action, nitisinone increases tyrosine levels in all patients receiving the drug. As a result, tyrosine-related ocular adverse reactions such as conjunctivitis, corneal opacity, keratitis, photophobia, and eye pain are common in patients with hereditary tyrosinemia type 1 and alkaptonuria. In patients with hereditary tyrosinemia type 1, adverse reactions include thrombocytopenia, leukopenia, and granulocytopenia. Exfoliative dermatitis may occur uncommonly.

List of Adverse Reactions

The data on adverse reactions listed below by organ systems according to the MedDRA classification and frequency categories were obtained from clinical trials involving patients with hereditary tyrosinemia type 1 and alkaptonuria, as well as from post-marketing experience in hereditary tyrosinemia type 1. Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (available data do not permit estimation of frequency). Within each frequency category, reactions are listed in order of decreasing severity.

Table 4

Organ systems by MedDRA classification	Frequency during treatment of hereditary tyrosinemia type 1	Frequency during treatment of alkaptonuria1	Adverse reaction
Infections and infestations		Common	Bronchitis, pneumonia
Blood and lymphatic system disorders	Common		Thrombocytopenia, leukopenia, granulocytopenia
	Uncommon		Leukocytosis
Eye disorders	Common		Conjunctivitis, corneal opacity, keratitis, photophobia
		Very common2	Keratopathy
	Common	Very common2	Eye pain
	Uncommon		Blepharitis
Skin and subcutaneous tissue disorders	Uncommon		Exfoliative dermatitis, erythematous rash
	Uncommon	Common	Pruritus, rash
Investigations	Very common	Very common	Elevated tyrosine levels

1Frequency determined in clinical studies in alkaptonuria.

2Elevated tyrosine levels are associated with ocular adverse reactions.

Patients with alkaptonuria should follow a diet restricted in tyrosine and phenylalanine.

Description of selected adverse reactions

Treatment with nitisinone leads to increased tyrosine levels.

Elevated tyrosine levels are associated with ocular adverse reactions such as corneal opacities and hyperkeratotic lesions in patients with hereditary tyrosinemia type 1 and alkaptonuria. Restriction of dietary intake of foods containing tyrosine and phenylalanine may reduce the toxic effects of such tyrosinemia by lowering tyrosine levels (see section "Special precautions for use").

In clinical studies of hereditary tyrosinemia type 1, severe granulocytopenia (neutrophil count <0.5×10⁹/L) was infrequent and was not associated with the development of infections. Hematological and lymphatic system adverse reactions resolved during long-term treatment with nitisinone.

Children

The safety profile in hereditary tyrosinemia type 1 is primarily based on data from pediatric use, as treatment with nitisinone should be initiated as early as possible after diagnosis of hereditary tyrosinemia type 1. Data from clinical trials and post-marketing experience indicate no evidence of differences in the safety profile among pediatric subpopulations or compared to the safety profile in adult patients.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at 2–8 °C in the original packaging. Do not freeze.

After opening the vial, store at a temperature not exceeding 25 °C for up to 2 months.

Keep out of reach and sight of children.

Packaging.

90 mL of suspension in a glass vial.

One glass vial in a cardboard package containing three dosing syringes (1 mL, 3 mL, 5 mL) and an adapter.

Prescription status. Prescription only.

Manufacturer. Nobel Ilaç Sanayi ve Ticaret A.Ş.

Manufacturer's address and location of business.

Sankaklar Quarter, Eskiaakcakoca Avenue, No. 299, 81100 Duzce, Turkey.