Tizinon

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

Composition:

Active substance: nitisinone;

1 hard capsule contains 5 mg or 10 mg of nitisinone;

Excipients:

5 mg capsules: pregelatinized starch, hard gelatin capsule No. 3*;

*Composition of hard gelatin capsule No. 3:

Diamond Blue FCF (E 133), erythrosine (E 127), titanium dioxide (E 171), Yellow Sunset FCF (E 110), gelatin;

10 mg capsules: pregelatinized starch, hard gelatin capsule No. 3*;

*Composition of hard gelatin capsule No. 3:

indigo carmine (E 132), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

5 mg capsules: hard gelatin capsules No. 3 with opaque violet body and cap, containing white powder;

10 mg capsules: hard gelatin capsules No. 3 with opaque white body and opaque dark blue cap, containing white powder.

Pharmacotherapeutic group. Drugs 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 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 manifestations 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 succinylacetone, increases plasma tyrosine concentration, and increases urinary excretion of phenolic acids. Clinical study data have demonstrated that in more than 90% of patients, urinary succinylacetone levels normalized within the first week of treatment. If the nitisinone dose 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 at 2, 4, and 6 years of nitisinone treatment are presented in Table 1.

Table 1

NTBC Study [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 diet alone. Furthermore, it has been found that treatment at early stages of the disease leads to a further reduction in the risk of developing hepatocellular carcinoma.

Table 3 presents data on the probability of absence of HCC after 2, 4, and 6 years of nitisinone treatment 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 were observed at the end of treatment between the once-daily and twice-daily 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, untreated-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 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 that includes 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 receiving nitisinone led to a reduction in ochronotic processes and clinical manifestations, supporting a slowing of disease progression.

Ocular adverse reactions such as keratopathy and eye pain, 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 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 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/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, steady-state 80 mg 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% decrease in the AUC∞ of chlorzoxazone, indicating weak induction of CYP2E1. Nitisinone does not inhibit CYP2D6, as nitisinone administration does not affect the AUC∞ of metoprolol. The AUC∞ of furosemide increased 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 studies, nitisinone is not expected to inhibit CYP1A2-, 2C19-, or 3A4-mediated metabolism, or to induce CYP1A2, 2B6, or 3A4/5. Nitisinone is not expected to inhibit P-gp-, BCRP-, or OCT2-mediated transport. Plasma concentrations of nitisinone achieved under clinical conditions are not expected to inhibit OATP1B1- or OATP1B3-mediated transport.

Results of non-clinical studies on safety

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).

Prenatal and postnatal development studies in mice showed a statistically significant reduction in offspring survival and development at weaning when doses 125 and 25 times 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 resulted in reduced offspring body weight and corneal lesions.

Nitisinone showed non-mutagenic but weak clastogenic activity in in vitro studies. There was no evidence of genotoxicity in vivo (mouse micronucleus test and liver DNA repair synthesis analysis). 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, under a diet restricted in tyrosine- and phenylalanine-containing products.

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 avoid breastfeeding.

Interaction with other medicinal products and other forms of interaction.

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

Based on clinical study data, 80 mg nitisinone administered under steady-state conditions is a moderate inhibitor of CYP2C9 (increasing tolbutamide AUC by 2.3-fold); therefore, nitisinone treatment 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 (reducing chlorzoxazone AUC by 30%) and a weak inhibitor of OAT1 and OAT3 (increasing furosemide AUC by 1.7-fold), whereas nitisinone does not inhibit CYP2D6 (see section "Pharmacokinetics").

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

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 nitisinone treatment should be examined immediately by an ophthalmologist.

Hereditary tyrosinemia type 1. It is important to verify patient compliance with a special 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 metabolic disruption 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 through liver function tests and liver imaging. Monitoring of plasma alpha-fetoprotein 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 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 and simultaneously taking medicinal products with a narrow therapeutic window that 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 interactions").

The product contains the colouring agent 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 were 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 necessitates 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 milk of lactating animals. Therefore, breastfeeding women receiving nitisinone should refrain from breastfeeding, 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 influence 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, patients should refrain from driving and operating machinery until this adverse effect resolves.

Method of Administration and Dosage

The capsule may be opened immediately before administration, 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 consistently continued in the same manner (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Hereditary Tyrosinemia Type 1

Nitisinone treatment should be managed by a physician experienced in treating patients with hereditary tyrosinemia type 1.

Treatment of all genotypes of the disease should be initiated as early as possible to improve overall survival and to prevent complications such as liver failure, hepatocellular carcinoma, and renal cancer. During nitisinone treatment, patients must adhere to a diet restricted in tyrosine- and phenylalanine-containing products, accompanied by 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 individually adjusted.

The dose is recommended to be taken once daily. Due to limited data on use in patients with body weight <20 kg, in this patient population 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 is required (see section "Special Warnings and Precautions for Use"). If succinylacetone is still detected in urine one month after initiation of 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 considered the maximum for all patients. If biochemical parameters are satisfactory, the dose should be adjusted according to body weight.

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

Alkaptonuria

Nitisinone treatment 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 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 use in patients with body weight <20 kg, in this patient population 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 special diet restricted in tyrosine and phenylalanine intake leads to elevated 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 antidotal 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 ocular adverse reactions such as conjunctivitis, corneal opacities, 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 list of adverse reactions below is categorized by MedDRA organ system classes and frequency categories, based on data from clinical trials in patients with hereditary tyrosinemia type 1 and alkaptonuria, as well as post-marketing experience in hereditary tyrosinemia type 1. Adverse reactions are listed by frequency categories 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 not known (cannot be estimated from available data).

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

Table 4

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 "Dosage and Administration").

In clinical studies of hereditary tyrosinemia type 1, severe granulocytopenia (<0.5×10⁹/L) was infrequent and not associated with 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 soon as possible after diagnosis of hereditary tyrosinemia type 1. Data from clinical studies and post-marketing experience indicate no evidence of differences in safety profile among different pediatric subpopulations or compared to adult patients.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions occurring after marketing authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged 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 place of business.

Sankaklar Quarter, Eskikaraağaç Street No:299, 81100 Düzce, Turkey.