Nitizynone difarma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITISINONE DIPHARMA (NITISINONE DIPHARMA)

Composition:

Active substance: nitisinone;

One hard capsule contains 2 mg, 5 mg, or 10 mg of nitisinone;

Excipients: capsule contents – pregelatinized starch, stearic acid; capsule shell – gelatin, titanium dioxide (E 171);

printing ink on capsule – shellac, propylene glycol, indigo carmine aluminum lake (E 132).

Pharmaceutical form. Hard capsules.

Main physical and chemical properties:

2 mg capsules: white, opaque capsules (size 3 shell, length 15.9 mm) with dark blue printing of the "company logo" on the cap and "2" on the body of the capsule, containing white or almost white powder inside;

5 mg capsules: white, opaque capsules (size 3 shell, length 15.9 mm) with dark blue printing of the "company logo" on the cap and "5" on the body of the capsule, containing white or almost white powder inside;

10 mg capsules: white, opaque capsules (size 2 shell, length 18.0 mm) with dark blue printing of the "company logo" on the cap and "10" on the body of the capsule, containing white or almost white powder inside.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Other drugs for the treatment of gastrointestinal tract disorders and metabolic disturbances. Nitisinone.

ATC code A16AX04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the tyrosine metabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 and alkaptonuria, nitisinone prevents the accumulation of toxic metabolites downstream of 4-hydroxyphenylpyruvate dioxygenase.

The biochemical defect in hereditary tyrosinemia type 1 is a deficiency of fumarylacetoacetate hydrolase, the terminal enzyme in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of toxic intermediary metabolites—maleylacetoacetate and fumarylacetoacetate. These intermediates 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 succinylacetone levels in urine normalized within the first week of treatment in over 90% of patients. 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 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 probability of survival at 2, 4, and 6 years of nitisinone treatment are summarized in Table 1.

Study NTBC (n=250)

Table 1

Based on the results of the study as a retrospective control, survival probability data 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 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 remaining free from HCC at 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

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 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 dosing groups. At the end of the once-daily treatment period, succinylacetone was not detected in any patient. 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 administering 10 mg of 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 the untreated control group. Treatment with nitisinone 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 the untreated control group. 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 decrease in the ochronotic process and a reduction in 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 body weight per day and 52.1 hours, respectively.

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

Based on clinical drug interaction studies at a steady state of 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% decrease 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 "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

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. The plasma concentration of nitisinone achieved under clinical conditions is not expected to inhibit transport mediated by OATP1B1 or OATP1B3.

Preclinical safety data

Nitisinone showed embryofetal toxicity in mice and rabbits when administered 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).

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 higher than the maximum recommended human dose, 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. Evidence of in vivo genotoxicity (mouse micronucleus test and DNA repair synthesis analysis in liver cells) was negative. In a 26-week carcinogenicity study in transgenic mice (TgrasH2), nitisinone did not show carcinogenic effects.

Clinical characteristics.

Indications.

Hereditary tyrosinemia type 1 (HT-1)

The medicinal product Nitizino Difarma is indicated for the treatment of adult patients and children with a confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1), provided that a diet restricted in tyrosine- and phenylalanine-containing products is maintained.

Alkaptonuria (AKU)

The medicinal product Nitizino Difarma is indicated for the treatment of adult patients with alkaptonuria (AKU).

Contraindications.

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

Women receiving nitizino treatment should avoid breastfeeding. (See sections “Use in pregnancy or breastfeeding” and “Preclinical safety data”).

Interaction with other medicinal products and other forms of interaction.

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

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

Nitizino is a weak inducer of CYP2E1 (a 30% decrease in chlorzoxazone AUC) and a weak inhibitor of OAT1 and OAT3 (a 1.7-fold increase in furosemide AUC), whereas nitizino does not inhibit CYP2D6 (see section “Pharmacokinetics”).

Specific studies on the interaction of Nitizino Difarma with food have not been conducted. However, during efficacy and safety studies, nitizino was administered with food. Therefore, if Nitizino Difarma was initially taken with food at the start of treatment, it is recommended to maintain this regimen throughout the entire course of treatment (see section “Method of administration and dosage”).

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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 must 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 treatment, as metabolic decompensation may lead to worsening of the patient's clinical condition.

Alkaptonuria: Patients who develop keratopathies should have plasma tyrosine levels monitored. A diet restricted in tyrosine and phenylalanine should be maintained to keep plasma tyrosine levels below 500 µmol/L. In addition, nitisinone therapy should be temporarily discontinued and restarted after resolution of symptoms.

Liver function monitoring

Hereditary tyrosinemia type 1: Liver function should be monitored regularly through liver function tests and liver imaging. Monitoring 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 platelet and leukocyte counts monitored regularly, as reversible thrombocytopenia and leukopenia have been observed during clinical studies in hereditary tyrosinemia type 1.

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. Patients receiving nitisinone together with medicinal products having a narrow therapeutic index that are metabolized by CYP2C9 (e.g., warfarin and phenytoin) should be closely monitored. Dose adjustments of these concomitant medicinal products may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of nitisinone in pregnant women. Animal studies have shown toxic effects of nitisinone on reproductive function (see section "Preclinical safety data"). The potential risk in humans is unknown. Nitisinone Difarma should not be used during pregnancy unless the woman's medical condition necessitates treatment with nitisinone. Nitisinone crosses the human placenta.

Breastfeeding

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 females. Therefore, mothers receiving nitisinone therapy should not breastfeed, as the risk to the infant cannot be excluded (see sections "Contraindications" and "Preclinical safety data").

Fertility

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

Ability to affect reaction speed when driving or operating machinery

The medicinal product Nitisinone Difarma 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 such adverse effects resolve.

Method of Administration and Dosage

Dosage

Hereditary Tyrosinemia Type 1:

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

Treatment for all genotypes of the disease should be started as early as possible to improve overall survival and prevent complications such as liver failure, hepatocellular carcinoma, and renal disease. Nitisinone therapy must be accompanied by a diet restricted in tyrosine and phenylalanine, with regular monitoring of plasma amino acid levels (see sections "Special Warnings and Precautions for Use" and "Side 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 should be taken once daily. Due to limited data on use in patients with body weight < 20 kg, in this patient population it is recommended to divide the total daily dose into two doses per day.

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 considered the maximum dose 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 (succinylacetone levels in plasma, urinary 5-aminolevulinic acid (ALA), erythrocyte porphobilinogen synthase (PBG-synthase) activity).

Alkaptonuria

Treatment with nitisinone should be initiated and supervised by a physician experienced in managing 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 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.

However, due to limited data on use in patients with body weight < 20 kg, in this patient population it is recommended to divide the total daily dose into two doses per day.

Alkaptonuria:

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

Method of Administration

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

Administration of nitisinone is recommended to be started with food, and thereafter the drug should be consistently taken in the same manner (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

Administer to children with hereditary tyrosinemia type 1 according to the dosage specified in the section "Method of Administration and Dosage."

The safety and efficacy of nitisinone in children 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 may lead 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 intake of tyrosine and phenylalanine should reduce the toxic effects associated with this form of tyrosinemia. Information on specific treatment for overdose is lacking.

Side effects

Summary of safety profile

Due to its mechanism of action, nitisinone increases tyrosine levels in all patients receiving the medication. As a result, ocular adverse reactions associated with elevated tyrosine levels—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 in tabular form

The list of adverse reactions provided in Table 4 below, classified by system organ classes according to the MedDRA classification and by frequency categories, is based on data obtained from clinical trials involving patients with hereditary tyrosinemia type 1 and alkaptonuria, as well as post-marketing experience in patients with hereditary tyrosinemia type 1.

Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1000), very rare (≤1/10,000), frequency not known (available data do not allow estimation of frequency).

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

Table 4

1 Frequency identified in clinical trial for alkaptonuria.

2 Elevated tyrosine levels are associated with adverse reactions affecting the organs of vision. Patients with alkaptonuria should follow a diet restricted in tyrosine and phenylalanine.

Description of selected adverse reactions

Treatment with nitisinone leads to increased levels of tyrosine.

Elevated tyrosine levels are associated with adverse reactions affecting the organs of vision, 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 trials of hereditary tyrosinemia type 1, severe granulocytopenia was infrequent (< 0.5×10⁹/L) and was not associated with the development of infections. Hematologic and lymphatic system adverse reactions during long-term nitisinone treatment were reversible.

Children

The safety profile of hereditary tyrosinemia type 1 is primarily based on data from pediatric use, as nitisinone treatment 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 different pediatric subpopulations or compared to the safety profile in adult patients.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging. 60 capsules in a high-density polyethylene (HDPE) bottle closed with a child-resistant screw cap. One bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Doppel Farmaceutici S.r.l. / Doppel Farmaceutici S.r.l.

Manufacturer's address.

Via Volturno 48, Rozzano, 20089, Italy / Via Volturno 48, Rozzano, 20089, Italy.

Marketing Authorization Holder.

Almeda Pharmaceuticals AG / Almeda Pharmaceuticals AG.

Address of Marketing Authorization Holder.

Dammstrasse 19, CH-6300, ZUG, Switzerland / Dammstrasse 19, CH-6300, ZUG, Switzerland.