Allopurinol-zdorov'ya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALLOPURINOL-ZDOROVYE (ALLOPURINOL-ZDOROVYE)

Composition:

Active substance: allopurinol;

One tablet contains allopurinol 100 mg or 300 mg;

Excipients: lactose monohydrate; corn starch; povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round-shaped, with a flat surface, beveled edge and a score line on one side.

Pharmacotherapeutic group. Medicinal products used in gout. Uric acid synthesis inhibitors. Allopurinol.

ATC code M04AA01.

Pharmacological properties.

Pharmacodynamics.

Allopurinol is an inhibitor of xanthine oxidase. Allopurinol and its main metabolite, oxypurinol, reduce the level of uric acid in blood plasma and urine by inhibiting xanthine oxidase — the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to suppressing purine catabolism, in some but not all patients with hyperuricemia, de novo purine biosynthesis is also inhibited due to reversible inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol riboside and oxypurinol-7-riboside.

Pharmacokinetics.

Absorption. Allopurinol is active when administered orally and is rapidly absorbed in the upper gastrointestinal tract. After administration, allopurinol is detectable in the blood within 30–60 minutes. Bioavailability ranges from 67% to 90%. Peak plasma concentrations of allopurinol are usually reached approximately 1.5 hours after oral administration, but decline rapidly to barely detectable levels within 6 hours. Peak plasma concentrations of oxypurinol are typically reached 3–5 hours after oral administration and are more sustained.

Distribution. Allopurinol is minimally bound to plasma proteins, and thus changes in protein binding are not considered to significantly affect the drug's clearance. The apparent volume of distribution of allopurinol is approximately 1.6 L/kg, indicating relatively extensive tissue uptake. Tissue concentrations of allopurinol in humans have not been studied, but it is likely that the highest concentrations of allopurinol and oxypurinol will be found in the liver and intestinal mucosa, where xanthine oxidase activity is high.

Biotransformation. The main metabolite of allopurinol is oxypurinol. Other metabolites include allopurinol riboside and oxypurinol-7-riboside.

Elimination. Approximately 20% of orally administered allopurinol is excreted in feces. Elimination of allopurinol occurs via metabolic conversion to oxypurinol by xanthine oxidase and aldehyde oxidase. Less than 10% of the drug is excreted unchanged in urine. The elimination half-life is approximately 0.5 to 1.5 hours. Oxypurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but its half-life in humans is considerably longer — from 13 to 30 hours. Because of this, effective inhibition of xanthine oxidase lasts more than 24 hours after a single daily dose. Patients with normal renal function gradually accumulate oxypurinol until a steady-state plasma concentration is reached. Such patients taking 300 mg of allopurinol daily typically achieve oxypurinol plasma concentrations of 5–10 mg/L.

Oxypurinol is excreted in urine but has a prolonged half-life due to tubular reabsorption. The reported half-life ranges from 13.6 to 29 hours. Variability in these values may be explained by differences in study design and/or varying creatinine clearance among patients.

Pharmacokinetics in patients with renal impairment. In patients with impaired renal function, the clearance of allopurinol and oxypurinol is significantly reduced, leading to increased plasma concentrations during chronic treatment. In patients with renal impairment and creatinine clearance of 10–20 mL/min, plasma oxypurinol concentrations of approximately 30 mg/L have been observed after long-term treatment with 300 mg allopurinol daily. This is roughly equivalent to the concentration that would be achieved in a patient with normal renal function taking 600 mg daily. In patients with impaired renal function, the dose of the drug should be reduced.

Pharmacokinetics in elderly patients. Changes in drug kinetics are unlikely in elderly patients, except in those with impaired renal function (see section "Pharmacokinetics in patients with renal impairment").

Clinical characteristics.

Indications.

The medicinal product is indicated for reduction of uric acid and its salt formation in confirmed accumulation of these salts (e.g., gouty arthritis, gouty tophi, nephrolithiasis) or when there is a foreseeable clinical risk of their accumulation (e.g., treatment of malignant neoplasms may potentially lead to acute uric acid nephropathy).

Main clinical conditions associated with accumulation of uric acid and its salts: idiopathic gout; urolithiasis (formation of uric acid calculi); acute uric acid nephropathy; tumor and myeloproliferative disorders with high cell turnover rate, where elevated urate levels occur spontaneously or following cytotoxic therapy; certain enzymopathies leading to excessive urate formation, e.g.: hypoxanthine-guanine phosphoribosyltransferase deficiency, including Lesch-Nyhan syndrome; glucose-6-phosphatase deficiency, including glycogenoses; phosphoribosylpyrophosphate synthetase, phosphoribosylpyrophosphate aminotransferase, or adenine phosphoribosyltransferase dysfunction.

The medicinal product is indicated for the treatment of diseases caused by adenine phosphoribosyltransferase deficiency and formation of 2,8-dihydroxyadenine (2,8-DHA) kidney stones.

The medicinal product is indicated for the treatment of recurrent formation of mixed calcium-oxalate kidney stones in hyperuricosuria when dietary measures, increased fluid intake, and similar interventions have proven ineffective.

Contraindications.

Hypersensitivity to allopurinol or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.

6-Mercaptopurine and azathioprine. Azathioprine is metabolized to 6-mercaptopurine, which is inactivated by xanthine oxidase. When used concomitantly with allopurinol, a xanthine oxidase inhibitor, the inactivation of 6-mercaptopurine or azathioprine is inhibited, thereby prolonging their effects. Serum concentrations of 6-mercaptopurine or azathioprine may reach toxic levels, leading to life-threatening pancytopenia and myelosuppression when these drugs are used concomitantly with allopurinol. Therefore, concomitant use of allopurinol with 6-mercaptopurine or azathioprine should be avoided. If concomitant use with 6-mercaptopurine or azathioprine is considered clinically necessary, the dose should be reduced to one-quarter (25%) of the usual dose of 6-mercaptopurine or azathioprine, and frequent hematological monitoring should be ensured (see section "Special precautions for use").

Patients should be advised to report any signs or symptoms of bone marrow suppression (unexplained bruising or bleeding, sore throat, fever).

Vidarabine (adenine arabinoside). Data indicate that the plasma half-life of vidarabine is prolonged in the presence of allopurinol. Additional monitoring for enhanced toxic effects is required when these medicinal products are used concomitantly.

Salicylates and uricosuric agents. Oxipurinol, the main metabolite of allopurinol with independent therapeutic activity, is excreted by the kidneys similarly to uric acid salts. Therefore, uricosuric agents such as probenecid or high doses of salicylates may accelerate the excretion of oxipurinol. This may reduce the therapeutic efficacy of the medicinal product, although this possibility should be evaluated on a case-by-case basis.

Chlorpropamide. When allopurinol is used concomitantly with chlorpropamide in patients with impaired renal function, the risk of prolonged hypoglycemia increases, as both allopurinol and chlorpropamide may compete for tubular excretion.

Coumarin anticoagulants. There have been isolated reports of enhanced effect of warfarin and other coumarin anticoagulants when used concomitantly with allopurinol; therefore, careful monitoring of all patients receiving anticoagulants is necessary.

Phenytoin. Allopurinol may inhibit hepatic oxidation of phenytoin, but the clinical significance of this interaction has not been established.

Theophylline. Inhibition of theophylline metabolism has been reported. The mechanism of interaction may be explained by the involvement of xanthine oxidase in the biotransformation of theophylline in the body. Plasma levels of theophylline should be monitored at the initiation of allopurinol therapy or when its dose is increased.

Ampicillin/amoxicillin. A higher incidence of skin allergic reactions has been observed when allopurinol is used concomitantly with ampicillin or amoxicillin, compared to patients not receiving these drugs simultaneously. The cause of this interaction has not been determined. Nevertheless, patients taking allopurinol are advised to use alternative antibacterial agents.

Cytostatics. When allopurinol is used concomitantly with cytostatic agents (e.g., cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), blood dyscrasias have been observed more frequently than with use of these agents alone; therefore, blood parameters should be monitored regularly in such patients.

Cyclosporine. Concomitant use with allopurinol may increase cyclosporine plasma concentration. Increased cyclosporine toxicity should also be considered.

Didanosine. In healthy volunteers and HIV patients receiving didanosine concomitantly with allopurinol (300 mg daily), plasma Cmax and AUC values doubled, without affecting terminal half-life. Concomitant use of these two drugs is generally not recommended. If concomitant use is necessary, a dose reduction of didanosine may be required, and careful patient monitoring is essential.

Diuretics. Interaction between allopurinol and furosemide leads to increased serum urate concentration and increased plasma oxipurinol concentration.

An increased risk of hypersensitivity reactions has been reported when allopurinol is used with diuretics, particularly thiazides, especially in patients with impaired renal function.

ACE inhibitors. An increased risk of hypersensitivity reactions has been reported when allopurinol is used concomitantly with ACE inhibitors, particularly in patients with impaired renal function.

Aluminium hydroxide. The effect of allopurinol may be reduced when used concomitantly with aluminium hydroxide. An interval of at least 3 hours should be maintained between administration of these medicinal products.

Special precautions for use.

Concomitant use of allopurinol with 6-mercaptopurine or azathioprine should be avoided, as there have been reports of fatal cases (see section "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Hypersensitivity reactions may manifest in various ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis. These reactions are clinically significant and warrant decisions regarding further treatment. If such reactions occur during treatment, allopurinol should be discontinued immediately. Re-administration of the drug is contraindicated in patients who have experienced hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Corticosteroids may be appropriate for managing skin reactions.

HLA-B *5801 allele. The presence of the HLA-B *5801 allele is associated with an increased risk of developing allopurinol-induced hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The frequency of this genetic marker varies significantly among different ethnic groups (it is present in 20% of the Han Chinese population, 8–15% of Thais, 12% of Koreans, and 1–2% of Japanese and Caucasian populations). Screening for HLA-B *5801 should be performed before initiating allopurinol therapy in patient subgroups with a high likelihood of carrying this allele. Chronic renal impairment may further increase the risk. When HLA-B *5801 genotyping is not available for Han Chinese, Thai, or Korean patients, the decision to initiate therapy should carefully weigh the potentially higher risks against the expected benefits. Allopurinol treatment may be considered in patients positive for HLA-B *5801 (particularly those of Han Chinese, Thai, or Korean descent) only if no alternative treatment options exist and the anticipated benefit outweighs the risks. Close monitoring for signs of hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis is essential. Patients must be informed of the necessity to discontinue treatment at the first sign of hypersensitivity symptoms.

Stevens-Johnson syndrome and toxic epidermal necrolysis may occur even in patients who do not carry the HLA-B *5801 allele, regardless of ethnicity.

Chronic renal impairment. In patients with chronic renal impairment and concomitant use of diuretics, particularly thiazides, the risk of allopurinol-related hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may be increased. Close monitoring for signs of hypersensitivity or Stevens-Johnson syndrome is required, and patients must be informed of the need to immediately and permanently discontinue treatment at the first appearance of symptoms (see section "Contraindications").

Hepatic or renal dysfunction. Reduced doses of the drug should be used in patients with hepatic or renal impairment (see section "Posology and method of administration"). Patients receiving medications for hypertension or heart failure, such as diuretics or ACE inhibitors, may have concomitant renal impairment, and allopurinol should be used with caution in these individuals.

Asymptomatic hyperuricemia. Asymptomatic hyperuricemia per se is not considered an indication for allopurinol therapy. Increased fluid intake and dietary modifications, along with treatment of the underlying cause, may correct the condition.

Acute gout attacks. Allopurinol therapy should not be initiated during an acute gout attack until the attack has completely subsided, as initiation during an attack may provoke recurrent episodes.

At the beginning of allopurinol treatment, as with uricosuric agents, an acute gouty arthritis attack may occur. Therefore, prophylaxis with an appropriate anti-inflammatory agent or colchicine for at least one month is recommended. Details regarding appropriate dosing, precautions, and warnings for these agents should be reviewed in available literature.

If acute attacks occur in patients already on allopurinol therapy, treatment should be continued at the same dose, and the acute attack should be managed with an appropriate anti-inflammatory agent.

Xanthine deposition. In conditions where urate production is markedly increased (e.g., in the presence of malignant tumors and their treatment, or Lesch-Nyhan syndrome), the absolute concentration of xanthine in urine may rarely rise to levels sufficient for deposition in the urinary tract. This risk can be minimized by adequate hydration to achieve optimal urine dilution.

Effect on uric acid kidney stones. Adequate allopurinol therapy leads to the dissolution of large uric acid kidney stones, which may subsequently cause ureteral obstruction.

Thyroid dysfunction. During long-term allopurinol therapy, elevated thyroid-stimulating hormone (TSH) levels (> 5.5 mIU/mL) have been observed in patients (5.8%). Caution is required when administering allopurinol to patients with thyroid dysfunction.

The medicinal product contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient evidence of allopurinol safety during pregnancy, although there is long-term experience of its use without apparent adverse effects.

Allopurinol may be used during pregnancy only if no safer alternative is available and when the underlying disease itself poses risks to the mother or fetus.

Breastfeeding. Allopurinol and its metabolite oxypurinol are excreted into breast milk. Data show concentrations of 1.4 mg/L of allopurinol and 53.7 mg/L of oxypurinol in the breast milk of a woman taking 300 mg allopurinol daily. However, there are no data on the effects of allopurinol or its metabolites on the breastfed infant. Allopurinol is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions such as somnolence, vertigo, and ataxia may occur in patients receiving allopurinol, patients should exercise caution when driving or operating machinery until it is established that allopurinol does not cause such adverse reactions.

Dosage and Administration.

Dosage.

Adults. The medicinal product should be initiated at low doses, e.g., 100 mg/day, in order to minimize the risk of adverse reactions, and the dose should be increased only if serum urate concentrations remain unsatisfactory. Particular caution should be exercised in patients with renal impairment (see section "Dosage and Administration. Renal Impairment"). The following dosage regimens are recommended:

• for mild conditions: 100 mg to 200 mg daily;
• for moderate conditions: 300 mg to 600 mg daily;
• for severe conditions: 700 mg to 900 mg daily.

When calculating the dose based on body weight, administer 2–10 mg/kg body weight daily.

Children. Children under 15 years of age: 10 to 20 mg/kg body weight daily. Maximum daily dose: 400 mg. Allopurinol is rarely used in pediatric practice. Exceptions include malignant diseases (particularly leukemia) and certain enzyme disorders (e.g., Lesch-Nyhan syndrome).

Elderly patients. In the absence of specific data, the lowest effective dose that achieves satisfactory reduction of urate levels should be used. Reduced renal function should be considered (see sections "Dosage and Administration. Renal Impairment" and "Special Warnings and Precautions for Use").

Renal Impairment.

Since allopurinol and its metabolites are excreted by the kidneys, impaired renal function may lead to accumulation of the drug and/or its metabolites, with prolonged plasma half-life. In severe renal impairment, a dose lower than 100 mg daily or single 100 mg doses administered at intervals longer than 24 hours may be appropriate. If plasma oxypurinol concentration monitoring is available, the dose should be adjusted to maintain plasma oxypurinol concentrations below 100 µmol/litre (15.2 mg/l). Allopurinol and its metabolites are dialyzable. In patients undergoing hemodialysis 2–3 times weekly, an alternative dosing regimen should be considered: 300–400 mg allopurinol immediately after each dialysis session, with no dosing in the interim.

Hepatic Impairment. Lower doses should be prescribed for patients with impaired liver function. Periodic monitoring of liver function tests is recommended at the beginning of treatment.

Treatment in conditions with high urate turnover, e.g., neoplasms, Lesch-Nyhan syndrome. Prior to initiating cytotoxic therapy, it is advisable to correct pre-existing hyperuricemia and/or hyperuricosuria with allopurinol. Adequate hydration should be ensured to maintain optimal diuresis, and urine alkalinization should be performed to enhance the solubility of uric acid and its salts. Allopurinol dosage should be at the lower end of the recommended range.

If urate nephropathy or other renal dysfunction is present, follow the recommendations in the section "Dosage and Administration. Renal Impairment."

These measures may reduce the risk of xanthine and/or oxypurinol accumulation, which may complicate the clinical course (see also sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Adverse Reactions").

Monitoring Advice. Doses should be adjusted based on periodic monitoring of serum urate concentrations and urinary uric acid and its salt levels at appropriate intervals.

Administration. The medicinal product is taken orally once daily after food. It is well tolerated, especially when administered after meals. If the daily dose exceeds 300 mg and gastrointestinal intolerance symptoms occur, dose splitting may be considered.

Children. Children under 15 years of age. Allopurinol is rarely used in pediatric practice. Exceptions include malignant diseases (particularly leukemia) and certain enzyme disorders (e.g., Lesch-Nyhan syndrome).

Overdose.

Oral doses up to 22.5 g of allopurinol have been reported in one patient without adverse effects. In another patient, ingestion of 20 g of allopurinol orally resulted in nausea, vomiting, diarrhea, and dizziness. Recovery was achieved with general supportive measures. Absorption of large doses of allopurinol may lead to profound xanthine oxidase inhibition, which is not associated with adverse effects except when allopurinol is co-administered with other medicinal products, particularly 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimal diuresis promotes the elimination of allopurinol and its metabolites. Hemodialysis may be performed if necessary.

Adverse reactions.

There are no current clinical data available for the product that can be used to determine the frequency of adverse effects. The frequency of adverse effects may vary depending on the dose, as well as when co-administered with other medicinal products.

The following estimated frequency categories of adverse reactions are provided: for most reactions, appropriate data for calculating incidence are lacking. Adverse reactions identified through post-marketing surveillance are considered rare or very rare. The frequency of adverse reactions was assessed as follows:

Unknown – cannot be evaluated based on available data

Adverse reactions associated with allopurinol are rare and are generally mild in most of the population. The frequency of their occurrence is higher in the presence of renal and/or hepatic pathology.

1 Very rare cases of thrombocytopenia, agranulocytosis, and aplastic anemia have been reported, particularly in patients with impaired renal and/or hepatic function, necessitating careful monitoring of such patients.

2 Delayed-type hypersensitivity reactions (known as DRESS syndrome), accompanied by fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilic hepatosplenomegaly, abnormal liver function tests, bile duct destruction syndrome (destruction and disappearance of intrahepatic bile ducts), may occur in various combinations. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, and colon). If such reactions occur, allopurinol should be discontinued immediately and permanently.

In the event of hypersensitivity reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, allopurinol should not be re-administered. Corticosteroids may be used to manage cutaneous hypersensitivity reactions. Generalized hypersensitivity reactions are usually associated with renal and/or hepatic disorders, particularly in fatal cases.

3 Very rare cases of angioimmunoblastic T-cell lymphoma have been reported following biopsy of generalized lymphadenopathy. This condition has been found to be reversible upon discontinuation of allopurinol.

4 In early clinical studies, nausea and vomiting were reported. This problem can be avoided by taking allopurinol after meals.

5 Cases of hepatic dysfunction without the occurrence of generalized hypersensitivity reactions have been reported.

6 Skin reactions are the most common and may occur at any time during treatment. These reactions may present as pruritus, maculopapular rash, sometimes exfoliative dermatitis, purpuric rash, and rarely exfoliative eruptions (such as Stevens–Johnson syndrome and toxic epidermal necrolysis). The highest risk of developing Stevens–Johnson syndrome, toxic epidermal necrolysis, or other serious hypersensitivity reactions occurs during the first weeks of treatment. Early diagnosis and immediate discontinuation of any suspected drug are essential for optimal management of such reactions. Allopurinol should be discontinued immediately if such reactions occur. After recovery from mild reactions, allopurinol may be reinitiated at a low dose (e.g., 50 mg/day) with gradual dose escalation, if necessary. The presence of the HLA-B*5801 allele has been associated with an increased risk of hypersensitivity reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis. However, the use of genotyping as a screening tool to guide allopurinol therapy has not been proven. If rash recurs during allopurinol treatment, the drug should be discontinued immediately, as more severe hypersensitivity may develop (see section "Adverse Reactions. Immune system disorders"). Allopurinol should not be re-administered if Stevens–Johnson syndrome, toxic epidermal necrolysis, or other serious hypersensitivity reactions cannot be ruled out, as this may lead to severe or even fatal outcomes. A clinical diagnosis of Stevens–Johnson syndrome or toxic epidermal necrolysis constitutes a contraindication to further allopurinol therapy. If such reactions occur at any time during treatment, allopurinol should be discontinued immediately and permanently.

7 Angioedema has been reported, with or without signs and symptoms of generalized hypersensitivity reaction.

8 Fever has been reported, with or without signs and symptoms of generalized hypersensitivity reaction.

9 Elevated TSH levels detected in relevant studies do not necessarily indicate any effect on free T4 levels, or may indicate subclinical hypothyroidism.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets 100 mg, pack size 50 (10×5) in blister pack in a carton, or 300 mg, pack size 10 (10×1), 50 (10×5) in blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenko Street, 22.