Milurit^® (Tablets) Instructions for Use

ATC Code

M04AA01 (Allopurinol)

Active Substance

Allopurinol

Clinical-Pharmacological Group

Drug affecting uric acid metabolism. Antigout drug

Pharmacotherapeutic Group

Antigout agent – xanthine oxidase inhibitor

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Allopurinol is a structural analog of hypoxanthine. Allopurinol, as well as its main active metabolite, oxypurinol, inhibit xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine, and xanthine to uric acid. Allopurinol reduces the concentration of uric acid, both in blood serum and in urine. Thereby, it prevents the deposition of uric acid crystals in tissues and/or promotes their dissolution. In addition to suppressing purine catabolism in some (but not all) patients with hyperuricemia, a large amount of xanthine and hypoxanthine becomes available for the re-formation of purine bases, which leads to the inhibition of purine biosynthesis de novo via a feedback mechanism mediated by inhibition of the enzyme hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol are Allopurinol-riboside and oxypurinol-7-riboside.

Pharmacokinetics

Absorption

Allopurinol is active when administered orally. It is rapidly absorbed from the upper gastrointestinal tract. According to pharmacokinetic studies, Allopurinol is detected in the blood as early as 30-60 minutes after administration. The bioavailability of allopurinol varies from 67% to 90%. The C_max of the drug in blood plasma is usually recorded approximately 1.5 hours after oral administration. Then the concentration of allopurinol rapidly decreases. Six hours after administration, only a trace concentration of the drug is detected in the blood plasma. The C_max of the active metabolite, oxypurinol, is usually recorded 3-5 hours after oral administration of allopurinol. The concentration of oxypurinol in blood plasma decreases significantly more slowly.

Distribution

Allopurinol is almost not bound to plasma proteins, so changes in the degree of protein binding should not have a significant effect on the drug’s clearance. The apparent V_d of allopurinol is approximately 1.6 L/kg, which indicates a sufficiently pronounced uptake of the drug by tissues. The concentration of allopurinol in various human tissues has not been studied, but it is very likely that Allopurinol and oxypurinol at C_max accumulate in the liver and intestinal mucosa, where high xanthine oxidase activity is recorded.

Metabolism

Under the action of xanthine oxidase and aldehyde oxidase, Allopurinol is metabolized to form oxypurinol. Oxypurinol inhibits xanthine oxidase activity. However, oxypurinol is not as potent a xanthine oxidase inhibitor as allopurinol, but its T_1/2 is significantly longer. Due to these properties, after taking a single daily dose of allopurinol, effective suppression of xanthine oxidase activity is maintained for 24 hours. In patients with normal renal function, the plasma concentration of oxypurinol slowly increases until a steady-state concentration is reached. After taking allopurinol at a dose of 300 mg/day, the plasma concentration of allopurinol is usually 5-10 mg/L. Other metabolites of allopurinol include Allopurinol-riboside and oxypurinol-7-riboside.

Excretion

Approximately 20% of the allopurinol taken per os is excreted through the intestine unchanged. About 10% of the daily dose is excreted by the glomerular apparatus of the kidney in the form of unchanged allopurinol. Another 70% of the daily dose of allopurinol is excreted by the kidneys in the form of oxypurinol. Oxypurinol is excreted by the kidneys unchanged, but due to tubular reabsorption, it has a long T_1/2. The T_1/2 of allopurinol is 1-2 hours, while the T_1/2 of oxypurinol varies from 13 to 30 hours. Such significant differences are probably related to differences in study design and/or CrCl in patients.

Special patient groups

Patients with renal insufficiency. In patients with impaired renal function, the excretion of allopurinol and oxypurinol can be significantly slowed, which, with long-term therapy, leads to an increase in the plasma concentration of these compounds. In patients with impaired renal function and a CrCl of 10-20 ml/min after long-term therapy with allopurinol at a dose of 300 mg/day, the plasma concentration of oxypurinol reached approximately 30 mg/L. Such a concentration of oxypurinol can be observed in patients with normal renal function during therapy with allopurinol at a dose of 600 mg/day. Therefore, when treating patients with impaired renal function, the dose of allopurinol must be reduced.

Elderly patients. In elderly patients, significant changes in the pharmacokinetic properties of allopurinol are unlikely. The exception is patients with concomitant renal pathology.

Indications

Adults

• All forms of hyperuricemia that cannot be controlled by diet, including secondary hyperuricemia of various origins, and clinical complications of hyperuricemia, in particular, severe gout, urate nephropathy, as well as dissolution and prevention of the formation of uric acid crystals (kidney stones);
• The presence of recurrent, mixed calcium oxalate crystals accompanied by hyperuricemia, if fluid intake, diet, and similar measures are ineffective.

Children and adolescents

• Secondary hyperuricemia of various origins;
• Uric acid-induced nephropathy during the treatment of leukemia;
• Congenital enzyme deficiency, Lesch-Nyhan syndrome (complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase) and adenine phosphoribosyltransferase deficiency.

ICD codes

Dosage Regimen

Tablets

Orally.

The drug should be taken once a day after meals with plenty of water. The drug is well tolerated, especially after meals. If the daily dose exceeds 300 mg or if there are undesirable reactions from the gastrointestinal tract, the dose must be divided into several doses.

Using the score line, the tablet can be divided into two equal doses.

Adults

To reduce the risk of side effects, it is recommended to use Allopurinol at an initial dose of 100 mg once a day. If this dose is not sufficient to adequately reduce the serum uric acid concentration, the daily dose of the drug can be gradually increased.

Special caution should be exercised in case of impaired renal function.

The recommended dose of the drug is:

100-200 mg/day for mild disease;

300-600 mg/day for moderate disease;

700-900 mg/day for severe disease.

If the dose is calculated based on the patient’s body weight, the dose of allopurinol should be from 2 to 10 mg/kg/day.

Children and adolescents

The recommended dose for children and adolescents under 15 years of age is 10-20 mg/kg/day. For low doses, 100 mg tablets are used, which can be divided into two equal doses of 50 mg using the score line. The daily dose of the drug should not exceed 400 mg in three divided doses per day.

Allopurinol is rarely used in pediatric practice. Exceptions are malignant oncological diseases (especially leukemias) and some enzymatic disorders (for example, Lesch-Nyhan syndrome).

Special patient groups

Elderly patients. Since there are no specific data on the use of allopurinol in the elderly patient population, the minimum dose that provides sufficient reduction in serum uric acid concentration should be used to treat such patients. Special attention should be paid to the recommendations for dose selection for patients with impaired renal function (see the “Special Instructions” section).

Patients with impaired renal function. Since Allopurinol and its metabolites are excreted from the body by the kidneys, impaired renal function can lead to the retention of the drug and its metabolites in the body with a subsequent prolongation of the T_1/2 of these compounds from the blood plasma.

The following scheme can serve as a guide for dose adjustment in renal failure

In severe renal failure, it is recommended to use Allopurinol at a dose below 100 mg/day, or to use single doses of 100 mg at intervals of more than one day.

If it is possible to monitor the plasma concentration of oxypurinol, the dose of allopurinol should be adjusted so that the plasma concentration of oxypurinol is below 100 µmol/L (15.2 mg/L).

Allopurinol and its derivatives are removed from the body by hemodialysis. If hemodialysis sessions are performed 2-3 times a week, it is advisable to determine the need to switch to an alternative treatment regimen – taking 300-400 mg of allopurinol immediately after the end of the hemodialysis session (the drug is not taken between hemodialysis sessions).

In patients with impaired renal function, the combination of allopurinol with thiazide diuretics should be carried out with extreme caution. Allopurinol should be prescribed at the lowest effective doses with careful monitoring of renal function (see the “Drug Interactions” section).

Patients with impaired liver function. In case of impaired liver function, the dose of the drug must be reduced. Monitoring of liver function laboratory parameters is recommended at the early stage of therapy.

Conditions accompanied by increased metabolism of uric acid salts (for example, tumor diseases, Lesch-Nyhan syndrome)

Before starting therapy with cytotoxic drugs, it is recommended to correct existing hyperuricemia and/or hyperuricosuria with allopurinol. Adequate hydration, which helps maintain optimal diuresis, as well as alkalinization of urine, which increases the solubility of uric acid and its salts, are of great importance. The dose of allopurinol should be close to the lower limit of the recommended dose range.

If renal impairment is due to the development of acute uric acid nephropathy or other renal pathology, treatment should be continued in accordance with the recommendations presented in the “Pharmacokinetics” section.

The described measures may reduce the risk of accumulation of xanthine and uric acid, which complicates the course of the disease (see the “Drug Interactions” section).

Monitoring recommendations

To adjust the drug dose, it is necessary to assess the concentration of uric acid salts in the blood serum, as well as the level of uric acid and urates in the urine at optimal intervals.

Recommendations for dose adjustment in case of skin reactions

In case of skin reactions, the use of allopurinol must be immediately discontinued. Upon return to normal after mild reactions, the use of allopurinol may be resumed at a low dose (such as 50 mg/day) after careful consideration of the risks. After that, the dose can be gradually increased while monitoring for the appearance of skin reactions and other possible adverse events. If the rash reappears, the use of allopurinol should be permanently discontinued, taking into account the possibility of more severe hypersensitivity reactions.

Adverse Reactions

For allopurinol, there is no modern clinical documentation on the basis of which it is possible to determine the frequency of adverse reactions. The frequency of adverse reactions may vary depending on the dose and whether the drug was used as monotherapy or in combination with other drugs.

The classification of the frequency of side effects is based on an approximate estimate; for most side effects, there is no data to determine their frequency.

The following agreed approach is used to classify adverse reactions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to < 1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Side effects of allopurinol identified in the post-registration period are rare or very rare. In the general patient population, adverse reactions associated with allopurinol are mostly mild. The frequency is higher in cases of impaired renal and/or liver function.

Infections and infestations: very rare – furunculosis.

Blood and lymphatic system disorders: very rare – agranulocytosis, aplastic anemia, thrombocytopenia, granulocytosis, leukopenia, leukocytosis, eosinophilia and aplasia affecting only red blood cells. Very rare reports of thrombocytopenia, agranulocytosis and aplastic anemia have been received, especially in persons with impaired renal and/or liver function, which emphasizes the need for special caution in these patient groups.

Immune system disorders uncommon – hypersensitivity reactions. severe hypersensitivity reactions, including skin reactions with epidermal detachment, fever, lymphadenopathy, arthralgia and/or eosinophilia (including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) (see “Skin and subcutaneous tissue disorders”). Accompanying vasculitis or tissue reactions can have various manifestations, including hepatitis, kidney damage, acute cholangitis, xanthine stones and, in very rare cases, convulsions. In addition, the development of anaphylactic shock has been very rarely observed. If severe adverse reactions develop, therapy with allopurinol must be immediately discontinued and not resumed . In delayed multi-organ hypersensitivity (known as drug hypersensitivity syndrome, the following symptoms may develop in various combinations: fever, skin rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in liver function test results, vanishing bile duct syndrome (destruction or disappearance of intrahepatic bile ducts). Other organs may be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, and large intestine). If such reactions develop at any time during treatment, Milurit^® should be immediately discontinued and never resumed . Patients with hypersensitivity syndrome and SJS/TEN should not restart the drug. Corticosteroids may be useful in the treatment of skin hypersensitivity reactions. Generalized hypersensitivity reactions have developed in patients with impaired renal and/or liver function. Such cases have sometimes been fatal;

Very rare – angioimmunoblastic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma has been very rarely diagnosed after lymph node biopsy for generalized lymphadenopathy. Angioimmunoblastic lymphadenopathy is reversible and regresses after discontinuation of allopurinol therapy.

Metabolism and nutrition disorders: very rare – diabetes mellitus, hyperlipidemia.

Psychiatric disorders: very rare – depression.

Nervous system disorders: very rare – coma, paralysis, ataxia, peripheral neuropathy, paresthesia, drowsiness, headache, dysgeusia; frequency unknown – aseptic meningitis.

Eye disorders: very rare – cataract, visual impairment, maculopathy.

Ear and labyrinth disorders: very rare – dizziness (vertigo).

Cardiac disorders: very rare – angina pectoris, bradycardia.

Vascular disorders: very rare – increased blood pressure.

Gastrointestinal disorders: uncommon – vomiting, nausea, diarrhea (in previous clinical studies, nausea and vomiting were observed, but later observations confirmed that these reactions are not a clinically significant problem and can be avoided by prescribing Allopurinol after meals); very rare – bloody vomiting, steatorrhea, stomatitis, changes in defecation frequency and stool character; frequency unknown – abdominal pain.

Hepatobiliary disorders: uncommon – asymptomatic increase in liver enzyme activity (increased activity of ALP and transaminases in blood serum); rare – hepatitis (including necrotic and granulomatous forms). Liver function disorders may develop without obvious signs of generalized hypersensitivity.

Skin and subcutaneous tissue disorders: common – rash; rare – severe skin reactions: SJS and TEN. Skin reactions are the most common type of reactions; they can develop at any time during treatment. They may present as itchy, maculopapular, sometimes scaly or purpuric rash, and in rare cases, exfoliative lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). The greatest risk of developing SJS and TEN or other serious hypersensitivity reactions is noted during the first weeks of allopurinol use. The best treatment outcomes for such reactions are achieved with early diagnosis and immediate discontinuation of all suspected drugs. If such a reaction develops, the drug Milurit^® should be immediately discontinued. Upon return to normal after mild reactions, the use of allopurinol may be resumed at a low dose (such as 50 mg/day), which can be gradually increased. The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol-dependent hypersensitivity syndrome and SJS/TEN. If a skin reaction recurs, the use of allopurinol should be immediately and permanently discontinued, taking into account the possibility of developing more severe hypersensitivity (see subsection ” Immune system disorders “). If the presence of SJS/TEN or other serious hypersensitivity reactions cannot be ruled out, allopurinol should not be resumed, due to the possibility of a severe or even fatal reaction. The basis for the decision is the presence of a clinical diagnosis of SJS/TEN. If such reactions develop at any time during treatment, the use of allopurinol must be immediately and permanently discontinued; very rare – angioedema, localized drug rash, alopecia, hair discoloration.

According to existing data, during therapy with allopurinol, angioedema developed both in isolation and in combination with symptoms of a generalized hypersensitivity reaction.

Musculoskeletal and connective tissue disorders: very rarely – myalgia.

Renal and urinary disorders: rarely – urolithiasis; very rarely – hematuria, azotemia.

Reproductive system and breast disorders: very rarely – male infertility, erectile dysfunction, gynecomastia.

General disorders and administration site conditions: very rarely – edema, general malaise, asthenia, pyrexia. According to existing data, during therapy with allopurinol, pyrexia developed both in isolation and in combination with symptoms of a generalized hypersensitivity reaction (see "Immune system disorders").

Investigations: frequently – increased level of thyroid-stimulating hormone (TSH). The increase in TSH levels observed in relevant studies did not affect T4 levels and did not indicate the onset of subclinical hypothyroidism.

Contraindications

• Hypersensitivity to allopurinol or to any of the excipients included in the drug formulation;
• Hepatic insufficiency;
• Chronic renal failure (azotemic stage);
• Acute attack of gout;
• Children under 3 years of age (for the solid dosage form);
• Pregnancy;
• Breastfeeding period;
• Patients with rare hereditary conditions such as lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Use with caution

Impaired liver function, hypothyroidism, diabetes mellitus, arterial hypertension, primary hemochromatosis, concomitant use of ACE inhibitors or diuretics, pediatric age (under 15 years of age is prescribed only during cytostatic therapy for leukemias and other malignant diseases, as well as symptomatic treatment of enzyme disorders), elderly age, impaired renal function (impaired renal function may lead to retention of the drug and its metabolites in the body with subsequent prolongation of the T_1/2 of these compounds from plasma).

Use in Pregnancy and Lactation

Pregnancy

Currently, there is insufficient data on the safety of allopurinol therapy during pregnancy, although this drug has been widely used for many years without apparent adverse consequences. Pregnant women should not take Milurit^®, except in cases where there is no less dangerous alternative treatment and the disease poses a greater risk to the mother and fetus than taking the drug.

Breastfeeding period

Allopurinol and its metabolite oxypurinol are excreted in human breast milk. Milurit^® is not recommended during breastfeeding. In women taking Allopurinol at a dose of 300 mg/day, the concentration of allopurinol and oxypurinol in breast milk reached 1.4 mg/L and 53.7 mg/L, respectively. However, there is no information on the effect of allopurinol and its metabolites on breastfed infants.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency.

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Contraindicated in chronic renal failure (azotemic stage).

Use with caution in patients with impaired renal function.

Pediatric Use

Contraindicated in children under 3 years of age in this dosage form.

Children under 15 years of age are prescribed only during cytostatic therapy for leukemias and other malignant diseases, as well as symptomatic treatment of enzyme disorders).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Drug Hypersensitivity Syndrome, SJS and TEN (Stevens-Johnson syndrome and toxic epidermal necrolysis)

The manifestation of hypersensitivity reactions to allopurinol can be very diverse, including maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms [DRESS] and SJS/TEN. These reactions are clinical diagnoses and their clinical manifestations serve as the basis for making appropriate decisions. Therapy with Milurit^® should be discontinued immediately upon the appearance of skin rash or other manifestations of a hypersensitivity reaction. Therapy should not be restarted in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be used to treat skin reactions in hypersensitivity (see section "Adverse Reactions").

HLA-B*5801 allele

The presence of the HLA-B*5801 allele has been associated with the development of allopurinol hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies among different ethnic groups and can reach up to 20% in the Han Chinese population, 8-15% in Thais, about 12% in Koreans, and 1-2% in Japanese and Europeans.

The advisability of screening for the HLA-B*5801 allele before starting allopurinol treatment should be considered in subgroups of patients with a known high prevalence of the HLA-B*5801 allele. Chronic kidney disease may further increase this risk in such patients. If genotyping is not possible in patients of Han Chinese, Thai, or Korean ethnicity, then Allopurinol should be prescribed only if the benefit of treatment outweighs the potential increased risk. The use of genotyping for making decisions about allopurinol therapy in other patient groups has not been studied.

If a patient is known to be a carrier of the HLA-B*5801 allele (especially in Han Chinese, Thai, Korean), allopurinol therapy should not be initiated, except in cases where there are no other possible adequate treatment options.

Close monitoring for the development of hypersensitivity syndrome and SJS/TEN is necessary, and patients should be informed of the need for immediate discontinuation of treatment at the first appearance of such symptoms.

SJS/TEN can also develop in patients who do not carry the HLA-B*5801 allele, regardless of their ethnic origin.

Chronic renal failure

Patients with chronic renal failure concomitantly using diuretics, especially thiazide diuretics, may be at increased risk of developing hypersensitivity reactions, including SJS/TEN, associated with allopurinol. Particular vigilance is required regarding signs of hypersensitivity syndrome or SJS/TEN, and patients should be informed of the need for immediate and permanent discontinuation of allopurinol treatment at the first appearance of symptoms (see section "Adverse Reactions").

Impaired liver or kidney function

Reduced doses of allopurinol should be used in patients with impaired liver or kidney function. Patients receiving treatment for arterial hypertension or heart failure, for example, with diuretics or ACE inhibitors, may have some degree of renal impairment. Allopurinol should be used with caution in such patients.

Asymptomatic hyperuricemia

Allopurinol is not indicated in all cases of hyperuricemia without clinical manifestations. In such cases, improvement in the patient’s condition can be achieved through dietary changes and fluid intake, along with addressing the underlying cause of hyperuricemia.

Acute attack of gout

Allopurinol should not be initiated until an acute attack of gout has completely subsided, as this may provoke an additional exacerbation of the disease.

Similarly to therapy with uricosuric agents, starting treatment with Milurit^® can also provoke an acute attack of gout. To avoid this complication, prophylactic therapy with NSAIDs or colchicine is recommended for at least one month before prescribing allopurinol. Detailed information on recommended doses, warnings, and precautions can be found in the relevant literature.

If an acute attack of gout develops during therapy with allopurinol, the drug should be continued at the same dose, and a suitable NSAID should be prescribed to treat the attack.

Azathioprine or 6-mercaptopurine

Allopurinol should not be prescribed to patients receiving treatment with azathioprine or 6-mercaptopurine unless the dose of these drugs is reduced to 25% of the originally prescribed dose.

Xanthine deposition

In cases where uric acid production is significantly increased (e.g., malignant tumor pathology and corresponding antitumor therapy, Lesch-Nyhan syndrome), the absolute concentration of xanthine in the urine may, in rare cases, increase significantly, promoting the deposition of xanthine in the tissues of the urinary tract. The likelihood of xanthine deposition in tissues can be minimized by adequate hydration, which ensures optimal urine dilution.

Effect on uric acid stones

Adequate therapy with allopurinol can lead to the dissolution of large uric acid stones located in the renal pelvis, with a remote possibility of their passage into the ureter.

When treating gouty kidney disease and urate stones, the daily urine output should be at least 2 liters, and the urine pH should be in the range of 6.4-6.8.

Hemochromatosis

The main effect of allopurinol in the treatment of gout is the suppression of the enzyme xanthine oxidase. Xanthine oxidase may be involved in reducing the content and excretion of iron deposited in the liver. There are no studies demonstrating the safety of allopurinol therapy in the population of patients with hemochromatosis. Allopurinol should be prescribed with caution to patients with hemochromatosis, as well as their blood relatives.

Thyroid disorders

Elevated TSH (thyroid-stimulating hormone) values (>5.5 µIU/mL) were observed in patients receiving Allopurinol for a long time (5.8%) during a long-term open-label extension clinical study. Caution should be exercised when using allopurinol in patients with thyroid disorders.

Lactose

Each Milurit^® 100 mg tablet contains 50 mg of lactose. Therefore, Milurit^® in the 100 mg dosage should not be taken by patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Sodium content

The drug contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is essentially sodium-free.

Effect on ability to drive and use machines

Adverse reactions such as somnolence, dizziness (vertigo), and ataxia have been observed during therapy with allopurinol. These adverse events may affect the ability to drive vehicles and operate machinery. Patients taking Milurit^® tablets should not drive vehicles or operate machinery until they are sure that Allopurinol does not adversely affect their relevant abilities.

Overdose

A case of oral intake of allopurinol in a dose of up to 22.5 g without adverse events has been described.

Symptoms nausea, vomiting, diarrhea, and dizziness were observed in a patient who took 20 g of allopurinol. Severe allopurinol overdose may lead to significant inhibition of xanthine oxidase activity. This effect alone should not be accompanied by adverse reactions. An exception is the effect on concomitant therapy, especially treatment with 6-mercaptopurine and/or azathioprine.

Treatment a specific antidote for allopurinol is unknown. Adequate hydration, maintaining optimal diuresis, promotes the excretion of allopurinol and its derivatives in the urine. Hemodialysis is performed if clinically indicated.

Drug Interactions

6 -mercaptopurine and azathioprine

Azathioprine is metabolized to form 6-mercaptopurine, which is inactivated by the enzyme xanthine oxidase. When therapy with 6-mercaptopurine or azathioprine is combined with allopurinol, patients should be prescribed only one quarter of the usual dose of 6-mercaptopurine or azathioprine, since inhibition of xanthine oxidase activity increases the duration of action of these compounds. If the dose of these drugs is not reduced, their serum concentrations may reach toxic levels.

Vidarabine (adenine arabinoside)

In the presence of allopurinol, the T_1/2 of vidarabine increases. Particular caution is required regarding enhanced toxic effects of therapy when these drugs are used concomitantly.

Salicylates and uricosuric agents

The main active metabolite of allopurinol is oxypurinol, which is excreted by the kidneys similarly to uric acid salts. Therefore, drugs with uricosuric activity, such as probenecid or high doses of salicylates, may enhance the excretion of oxypurinol. In turn, enhanced excretion of oxypurinol is accompanied by a decrease in the therapeutic activity of allopurinol; however, the significance of this type of interaction must be assessed individually in each case.

Chlorpropamide

Concomitant use of allopurinol and chlorpropamide in patients with impaired renal function increases the risk of prolonged hypoglycemia, as Allopurinol and chlorpropamide compete with each other at the stage of tubular excretion.

Coumarin derivative anticoagulants

Enhanced effects of warfarin and other coumarin derivative anticoagulants have been observed with concomitant use with allopurinol. Therefore, the condition of patients receiving concomitant therapy with these drugs should be carefully monitored.

Phenytoin

Allopurinol can inhibit the oxidation of phenytoin in the liver, but the clinical significance of this interaction has not been established.

Theophylline

Allopurinol is known to inhibit the metabolism of theophylline. This interaction can be explained by the involvement of xanthine oxidase in the biotransformation process of theophylline in the human body. Serum theophylline concentration should be monitored at the start of concomitant therapy with allopurinol and when increasing the dose of the latter.

Ampicillin and amoxicillin

An increased frequency of skin reactions was recorded in patients simultaneously receiving ampicillin or amoxicillin and Allopurinol, compared to patients who did not receive such concomitant therapy. The reason for this type of drug interaction has not been established. Nevertheless, patients receiving Allopurinol are recommended to be prescribed other antibacterial drugs instead of ampicillin and amoxicillin.

Cytotoxic drugs (cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamine)

When allopurinol is used concomitantly with cytostatic drugs (such as cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), blood dyscrasias develop more frequently than when these drugs are used separately.

Blood cell counts should be performed regularly.

Cyclosporine

According to some reports, the plasma concentration of cyclosporine may increase during concomitant therapy with allopurinol. The possibility of increased cyclosporine toxicity should be taken into account when these drugs are used concomitantly.

Aluminum hydroxide

When allopurinol is used concomitantly with aluminum hydroxide, the effect of allopurinol may decrease. A break of at least 3 hours should be made between taking both drugs.

Didanosine

In healthy volunteers and patients infected with the human immunodeficiency virus receiving didanosine, an approximately 2-fold increase in the C_max in plasma and AUC of didanosine was observed during concomitant therapy with allopurinol (300 mg/day). The T_1/2 of didanosine did not change. As a rule, concomitant use of these drugs is not recommended. If concomitant therapy is unavoidable, a reduction in the dose of didanosine and careful monitoring of the patient’s condition may be required.

ACE inhibitors

Concomitant use of ACE inhibitors with allopurinol is associated with an increased risk of leukopenia; therefore, these drugs should be combined with caution.

An increased risk of hypersensitivity has been reported when Allopurinol was used with ACE inhibitors, especially in renal failure.

When allopurinol is used concomitantly with captopril, the risk of skin reactions may increase, especially in patients with chronic renal failure.

Diuretics

An interaction between allopurinol and furosemide has been reported, leading to an increase in serum urate levels and plasma oxypurinol concentration.

Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the risk of developing hypersensitivity adverse effects associated with allopurinol, especially in patients with impaired renal function.

Storage Conditions

The drug should be stored out of the reach of children.

100 mg tablets should be stored at a temperature not exceeding 30°C (86°F).

300 mg tablets should be stored at a temperature not exceeding 25°C (77°F)

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

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.