Ariquel^® (Capsules) Instructions for Use

Marketing Authorization Holder

Nobel Ilac Sanayii Ve Ticaret, A.S. (Turkey)

Manufactured By

Nobel Ilac Sanayii Ve Ticaret, A.S. (Turkey)

Or

Nobel Almaty Pharmaceutical Factory, JSC (Kazakhstan)

Primary Packaging

NOBEL ALMATY PHARMACEUTICAL FACTORY, JSC (Kazakhstan)

ATC Code

A16AX04 (Nitisinone)

Active Substance

Nitisinone (Rec.INN registered by WHO)

Dosage Forms

	Ariquel®	Capsules 5 mg: 60 pcs.
		Capsules 10 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 3, opaque, with a purple body and cap; capsule contents – powder white with a yellowish tint.

Excipients: pregelatinized starch – 195 mg.

Composition of the capsule body: brilliant blue dye (E133) – 0.023%, erythrosine dye (E127) – 0.1788%, titanium dioxide (E171) – 0.7983%, sunset yellow dye (E110) – 0.016%, gelatin – q.s. to 100%.
Composition of the capsule cap brilliant blue dye (E133) – 0.023%, erythrosine dye (E127) – 0.1788%, titanium dioxide (E171) – 0.7983%, sunset yellow dye (E110) – 0.016%, gelatin – q.s. to 100%.

60 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Capsules hard gelatin, size No. 3, opaque, with a white body and a dark blue cap; capsule contents – powder white with a yellowish tint.

Excipients: pregelatinized starch – 190 mg.

Composition of the capsule body: titanium dioxide (E171) – 3%, water – 14%, gelatin – q.s. to 100%;
Composition of the capsule cap indigo carmine (E132) – 0.579%, titanium dioxide (E171) – 1.0922%, water – 14.5%, gelatin – q.s. to 100%.

60 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Tyrosinemia hereditary treatment agent

Pharmacological Action

Nitisinone is a treatment for hereditary tyrosinemia type 1, a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the enzyme precursor of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolism pathway.

By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1, Nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.

In patients with hereditary tyrosinemia type 1, these catabolic intermediates are converted into the toxic metabolites succinylacetone and succinylacetoacetate, which cause hepatotoxicity and nephrotoxicity.

Succinylacetone is also capable of inhibiting the porphyrin synthesis pathway, leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of hereditary tyrosinemia type 1.

Nitisinone inhibits the catabolism of the amino acid tyrosine, leading to an increase in plasma tyrosine levels.

Thus, treatment with nitisinone requires restriction of the intake of foods containing tyrosine and phenylalanine to prevent toxicity caused by increased plasma tyrosine levels.

Pharmacokinetics

Experimental studies have shown that Nitisinone is distributed in various organs, especially in the liver and kidneys.

It undergoes biotransformation and is excreted in the urine.

It is not known whether Nitisinone undergoes metabolism in the human body.

The mean T_1/2 in healthy men is 54 hours.

Indications

Treatment of hereditary tyrosinemia type 1, provided a diet restricting foods containing tyrosine and phenylalanine is followed.

ICD codes

Dosage Regimen

For oral administration.

The initial dose is 1 mg/kg/day in 2 divided doses (morning and evening).

The maximum dose is 2 mg/kg/day.

During treatment, the patient must follow a diet restricting foods containing tyrosine and phenylalanine.

If, after 1 month of starting nitisinone therapy, normalization of erythrocyte porphobilinogen synthase (PBG-synthase) activity and urinary levels of 5-aminolevulinic acid and succinylacetone has not occurred, the dose may be increased to 1.5 mg/kg/day.

If patients receiving 1.5 mg/kg/day do not achieve normalization of erythrocyte PBG-synthase activity and urinary levels of 5-aminolevulinic acid and succinylacetone, then 3 months after starting nitisinone therapy, the dose can be increased to the maximum – 2 mg/kg.

If it is impossible to determine the plasma concentration of nitisinone, plasma succinylacetone levels, urinary 5-aminolevulinic acid levels, and erythrocyte PBG-synthase activity, then clinical laboratory methods should include urinary succinylacetone levels, liver function tests, alpha-fetoprotein levels, and serum tyrosine and phenylalanine levels.

At the beginning of therapy and during acute manifestations of the disease, a more thorough investigation with the determination of all available biochemical parameters may be required.

Adverse Reactions

Common: liver tumor, hepatic failure, conjunctivitis, corneal opacity, keratitis, photophobia, blepharitis, eye pain, cataract, thrombocytopenia, leukopenia, granulocytopenia, porphyria, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash, alopecia.

Rare: fatal outcome, convulsions, brain tumor, encephalopathy, headache, hyperkinesis, cyanosis, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal bleeding, melena, tooth discoloration, impaired liver function, increased liver enzyme activity, hepatomegaly, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, bronchitis, respiratory failure, pathological fractures, amenorrhea, nervousness, drowsiness.

Contraindications

Hypersensitivity to nitisinone.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies in pregnant women have not been conducted.

Experimental animal studies have shown the teratogenicity of nitisinone at doses exceeding those recommended for humans by 1.6, 4, and 8 times.

It is believed that use during pregnancy is possible in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether Nitisinone is excreted in human breast milk.

If use during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

If adverse reactions from the liver occur, regular monitoring with liver imaging methods (ultrasound, computed tomography, magnetic resonance imaging) and laboratory monitoring, including serum alpha-fetoprotein concentration, should be performed.

In patients with elevated alpha-fetoprotein levels or the appearance of liver nodules during nitisinone treatment, liver malignancy should be ruled out.

Special Precautions

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

If adverse reactions from the liver occur, regular monitoring with liver imaging methods (ultrasound, computed tomography, magnetic resonance imaging) and laboratory monitoring, including serum alpha-fetoprotein concentration, should be performed.

In patients with elevated alpha-fetoprotein levels or the appearance of liver nodules during nitisinone treatment, liver malignancy should be ruled out.

During treatment, Nitisinone may cause an increase in blood tyrosine levels in patients with hereditary tyrosinemia type 1, therefore, during treatment, patients must follow a diet restricting tyrosine and phenylalanine intake.

Plasma tyrosine levels should be maintained below 500 µmol/L.

Exceeding blood tyrosine levels above 500 µmol/L can lead to adverse reactions from the organ of vision – corneal ulcers, corneal opacity, keratitis, conjunctivitis, eye pain, photophobia.

Therefore, before starting treatment and during treatment, regular monitoring by an ophthalmologist is required.

Patients who develop photophobia, eye pain, or inflammatory symptoms such as redness, swelling, or burning during treatment require regular repeated ophthalmological monitoring and determination of plasma tyrosine levels.

Slowed thought processes and developmental delays are possible.

In such cases, monitoring of neurological status and determination of plasma tyrosine levels is required.

Painful hyperkeratotic scaly layers on the palms and soles may form.

During treatment, leukocyte and platelet counts should be monitored regularly.

Drug Interactions

When nitisinone is used concomitantly with inhibitors or inducers of the CYP3A4 isoenzyme, dose adjustment may be required.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.