Tizynon

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

Composition:

active substance: nitisinone;

1 hard capsule contains nitisinone 20 mg;

excipients:

pregelatinized starch, hard gelatin capsule No. 3*;

*composition of hard gelatin capsule No. 3:

titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules No. 3 with opaque white body and cap containing a white powder.

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 immediately 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 intermediate metabolites—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 have shown that in more than 90% of patients, urinary succinylacetone levels normalized within the first week of treatment. With an appropriately adjusted dose of nitisinone, succinylacetone is not detectable in urine or plasma.

In patients with alkaptonuria, treatment with nitisinone reduces the accumulation of HGA. Available clinical study data indicate 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 probability of survival after 2, 4, and 6 years of treatment with nitisinone are presented in Table 1.

Table 1

Study of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone)] (n=250)

The data on survival probability obtained from the retrospective control study are presented in Table 2.

Table 2

It has been observed that treatment with nitisinone reduces the risk of developing hepatocellular carcinoma (HCC) compared to retrospective data on treatment with a special diet alone. Furthermore, it has been found that treatment initiated at earlier stages of the disease leads to a further reduction in the risk of developing HCC.

Table 3 presents data on the probability of absence of HCC after 2, 4, and 6 years of treatment with nitisinone in patients aged 24 months or younger at the start of treatment, as well as in patients older than 24 months at the start of treatment:

Table 3

NTBC Study (n=250)

During an international study involving patients with hereditary tyrosinemia type 1 who were treated exclusively by dietary restrictions, 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 dosing 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, blinded, 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 with nitisinone treatment compared to untreated controls. Nitisinone treatment demonstrated a statistically significant positive effect on the clinical assessment of the alkaptonuria severity score (cAKUSSI), eye pigmentation, ear pigmentation, femoral osteopenia, and the number of painful spinal segments compared to untreated controls. cAKUSSI is a composite score including assessment 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 treated with nitisinone led to a reduction in ochronotic processes and a decrease in clinical manifestations, supporting a slowing of disease progression.

Adverse reactions involving the visual organs, such as keratopathy and eye pain, infections, headache, and weight gain, were reported more frequently in patients treated with nitisinone than in untreated patients. Keratopathy led to temporary or permanent discontinuation of treatment in 14% of patients treated with nitisinone, but was reversible upon discontinuation of nitisinone.

Data in patients aged 70 years and older are lacking.

Results of preclinical safety studies

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

Prenatal and postnatal development studies in mice demonstrated a statistically significant reduction in offspring survival and development during the weaning period when doses 125 and 25 times higher than the maximum recommended human dose were administered, with a trend toward negative effects on offspring survival starting at a dose of 5 mg/kg/day. In rats, exposure via breast milk led to reduced offspring body weight 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.

Pharmacokinetics.

Studies on the absorption, distribution, metabolism, and excretion of nitisinone have not been conducted. In 10 healthy male volunteers after a single oral dose of nitisinone capsules (1 mg/kg body weight), the terminal elimination 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 elimination half-life were measured at 0.0956 L/kg/day and 52.1 hours, respectively.

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

Based on clinical drug interaction studies at steady-state with 80 mg nitisinone, nitisinone caused a 2.3-fold increase in the AUC∞ of the CYP2C9 substrate tolbutamide, indicating moderate inhibition of CYP2C9. Nitisinone caused approximately a 30% reduction in the AUC∞ of chlorzoxazone, indicating 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 instructions").

Based on in vitro studies, 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. It is expected that the plasma concentration of nitisinone achieved under clinical conditions will not inhibit OATP1B1- or OATP1B3-mediated transport.

Clinical characteristics.

Indications.

Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1, under conditions of a diet restricted in products containing tyrosine and phenylalanine.

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 showing the effect of 80 mg nitisinone at steady state, nitisinone is a moderate inhibitor of CYP2C9 (a 2.3-fold increase in tolbutamide AUC); therefore, treatment with nitisinone may lead to increased plasma concentrations of medicinal products primarily metabolized 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").

Special studies on interaction with food have not been conducted. However, during studies assessing efficacy and safety, nitisinone was administered with food. Therefore, if nitisinone was initially taken with food at the start 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

An ophthalmological examination is recommended prior to initiating nitisinone treatment and at least once annually thereafter. Patients who develop visual disturbances during treatment with nitisinone should be examined immediately by an ophthalmologist.

Hereditary tyrosinemia type 1. It is important to verify whether the patient is adhering to the prescribed diet and to measure plasma tyrosine concentration. 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 disruption of metabolism may lead to worsening of the patient's clinical condition.

Alkaptonuria. In patients who develop keratopathy, 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 through liver function tests and imaging techniques. Monitoring of alpha-fetoprotein plasma concentration is also recommended. Elevated plasma alpha-fetoprotein levels may indicate inadequate treatment. If alpha-fetoprotein levels increase or liver nodules appear, the liver should be evaluated for the presence of malignant neoplasms.

Monitoring of platelets and leukocytes

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

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

Concomitant use with other medicinal products

Nitisinone is a moderate inhibitor of CYP2C9. Therefore, treatment with nitisinone 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 adjustments of these concomitant medicinal products may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

The product contains the dye sunset yellow FCF (E 110), which may cause allergic reactions.

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. Unfavourable effects of nitisinone on offspring development due to excretion of nitisinone in female animal milk have been observed in animal studies. Therefore, mothers receiving nitisinone should refrain from breastfeeding, as 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 negligible 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.

Method of Administration and Dosage

Immediately before administration, the capsule can be opened and its contents mixed with a small amount of water or another liquid compatible with the patient's prescribed diet to form a suspension.

Treatment with nitisinone should be initiated together with food intake, and thereafter the drug should be consistently administered in the same manner (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Hereditary Tyrosinemia Type 1

Treatment with nitisinone should be managed by a physician experienced in the management of patients with hereditary tyrosinemia type 1.

Treatment of all disease genotypes should be initiated as early as possible to improve overall survival and to prevent complications such as liver failure, hepatocellular carcinoma, and renal cancer. Treatment with nitisinone must be accompanied by a diet restricted in tyrosine- and phenylalanine-containing products, with concurrent monitoring of plasma amino acid levels (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

Initial Dose in Hereditary Tyrosinemia Type 1

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

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

Dose Adjustment in Hereditary Tyrosinemia Type 1

Throughout the treatment course, monitoring of succinylacetone in urine, liver function, and alpha-fetoprotein concentration should be performed (see section "Special Warnings and Precautions for Use"). If succinylacetone is still detectable in urine one month after initiating nitisinone therapy, the dose of nitisinone 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 considered the maximum for all patients. If biochemical test results are satisfactory, the dose should be adjusted according to body weight.

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

Alkaptonuria

Treatment with nitisinone should be managed by a physician experienced in the management of patients with alkaptonuria.

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

Special Populations

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

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 the use of the drug in patients with body weight <20 kg, in patients of this category the total daily dose should be divided into two daily doses.

Alkaptonuria

The safety and efficacy of nitisinone 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 diet restricted in tyrosine and phenylalanine intake leads to increased tyrosine concentrations in the body. Elevated tyrosine levels are associated with toxic effects on the eyes, skin, and nervous system. Restriction of dietary tyrosine and phenylalanine intake should reduce the toxic effects associated with this form of tyrosinemia. Information on specific treatment for overdose is not available.

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 adverse reactions affecting the eyes, such as conjunctivitis, corneal opacities, keratitis, photophobia, and eye pain, are common. In patients with hereditary tyrosinemia type 1, adverse reactions include thrombocytopenia, leukopenia, and granulocytopenia. Exfoliative dermatitis may occur uncommonly.

List of adverse reactions

The list of adverse reactions below is categorized by MedDRA organ system classes and according to frequency categories, based on data obtained from clinical trials involving patients with hereditary tyrosinemia type 1 and alkaptonuria, as well as post-marketing experience in hereditary tyrosinemia type 1. Adverse reactions are classified 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 (the available data do not allow estimation of frequency).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 4

1Frequency determined in clinical study in alkaptonuria.

2Elevation of tyrosine levels is associated with adverse reactions affecting the eyes.

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

Description of individual adverse reactions

Treatment with nitisinone leads to an increase in 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 products containing tyrosine and phenylalanine may reduce the toxic effects of such tyrosinemia by lowering tyrosine levels (see section "Dosage and Administration").

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

Children

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions occurring during the post-marketing period. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store at 2–8 °C in the original packaging.

After opening the container, store at a temperature not exceeding 25 °C in the original packaging for up to 3 months.

Keep out of reach of children.

Packaging.

60 capsules in a plastic container. 1 container in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Nobel Ilaç Sanayi ve Ticaret A.Ş.

Manufacturer's address and location of operations.

Sankaklar Quarter, Eskı Akcakoca Avenue, No: 299, 81100 Duzce, Turkey.