Milurite, tablets 300 mg 30 pcs

Pharmacotherapeutic group: antipodagric agent – xanthine oxidase inhibitor

ATX CODE: M04AA01

Indications

Adults:

– All types of hyperuricaemia that cannot be controlled by diet, including secondary hyperuricaemia of different origin, and clinical complications of hyperuricaemia, in particular, severe gout, urate nephropathy, as well as dissolution and prevention of uric acid crystals (kidney stones) formation.

– Treatment of recurrent, mixed calcium oxalate crystals accompanied by hyperuricemia, if the consumption of various liquids, diet and similar measures have no effect.

Children and adolescents:

– Secondary hyperuricemia of various origins.

– Uric acid-induced nephropathy in the treatment of leukemia.

– Congenital enzyme deficiency, Lesch-Nichan syndrome (complete or partial hypoxanthine guanine phosphoribosyltransferase deficiency) and adenine phosphoribosyltransferase deficiency.

Active ingredient

Allopurinol

Composition

Per 1 tablet:

active ingredient: allopurinol 300 mg;

excipients:

Microcrystalline cellulose (type PH 101) 52 mg,

sodium carboxymethyl starch (type A) 20 mg,

gelatin 12 mg,

magnesium stearate 3 mg,

colloidal anhydrous silica 3 mg.

How to take, the dosage

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

The tablets can be divided into two equal doses using the risk.

Adult patients

In order to reduce the risk of side effects, an initial dose of allopurinol of 100 mg once daily is recommended. If this dose is not sufficient to adequately lower serum uric acid concentrations, the daily dose of the drug can be gradually increased.

Particular caution should be exercised if renal function is impaired. The recommended dose of the drug is:

100-200 mg per day in a mild course of the disease;

300-600 mg per day in a moderate course;

700-900 mg per day in a severe course.

Allopurinol doses should be 2 to 10 mg/kg/day, based on body weight.

Children and adolescents under 15 years of age

The recommended dose 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 with a risk. The daily dose of the drug should not exceed 400 mg in three doses per day.

Allopurinol is rarely used in pediatric practice. The exceptions are malignant cancers (especially leukemia) and some enzymatic disorders (e.g., Lesch-Nyhan syndrome).

Elderly patients

Since there are no specific data on the use of allopurinol in the elderly population, for the treatment of these patients the drug should be used in the lowest dose that provides sufficient reduction of serum uric acid concentration. Particular attention should be paid to the recommendations on the selection of the drug dose for patients with impaired renal function (see section Cautions).

In impaired renal function

Because allopurinol and its metabolites are excreted by the kidneys, impaired renal function may lead to retention of the drug and its metabolites in the body with subsequent prolongation of the plasma elimination half-life of these compounds.

The following chart may serve as a guide for dose adjustment in renal function impairment:

For severe renal impairment, allopurinol doses below 100 mg per day are recommended, or use single doses of 100 mg at intervals of more than one day.

If conditions allow for monitoring plasma oxypurinol concentrations, the dose of allopurinol should be adjusted so that plasma oxypurinol levels are 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 reasonable to determine the need to switch to an alternative therapy regimen – taking 300-400 mg of allopurinol immediately after hemodialysis session (the drug is not taken between hemodialysis sessions).

In patients with impaired renal function, allopurinol should be combined with thiazide diuretics with extreme caution. Allopurinol should be prescribed at the lowest effective dose with close monitoring of renal function.

Hepatic disorders

If liver function is impaired, the drug dose should be reduced. In the early phase of therapy, monitoring of laboratory indicators of liver function is recommended.

States associated with increased uric acid salt metabolism (e.g., tumor disease, Lesch-Nyhan syndrome)

Before cytotoxic drug therapy is initiated, correction of existing hyperuricemia and/or hyperuricosuria with allopurinol is recommended. Adequate hydration to maintain optimal diuresis is important, as is alkalinization of the urine, which increases the solubility of uric acid and its salts. The allopurinol dose should be close to the lower limit of the recommended dose range.

If the impairment in renal function is due to the development of acute urolithiasis or other renal pathology, then treatment should continue as described in the renal impairment section.

The measures described may reduce the risk of xanthine and uric acid accumulation complicating the course of the disease.

Monitoring recommendations

The serum uric acid salt concentrations and urinary uric acid and urate levels should be assessed at optimal intervals to adjust the drug dose.

Dose recommendations for skin reactions

The use of allopurinol should be stopped immediately if skin reactions occur. Allopurinol can be resumed at a low dose (such as 50 mg/day) when reactions return to normal after mild reactions, after careful consideration of the risks. Thereafter, the dose can be gradually increased while monitoring for skin reactions and other possible adverse events. If the rash reappears, allopurinol should be discontinued permanently, given the possibility of more severe hypersensitivity reactions.

Interaction

6-mercaptopurine and azathioprine

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

Vidarabine (adenine arabinoside)

In the presence of allopurinol the half-life of vidarabine is extended. If these drugs are used concomitantly, special caution should be exercised with regard to the increased toxic effects of therapy.

Salicylates and uricosuric agents

The main active metabolite of allopurinol is oxypurinol, which is excreted by the kidneys as uric acid salts. Consequently, drugs with uricosuric activity, such as probenecid or high doses of salicylates, can enhance excretion of oxypurinol. In turn, enhanced excretion of oxypurinol is accompanied by a decrease in the therapeutic activity of allopurinol, but the significance of this type of interaction must be assessed on a case-by-case basis.

Chlorpropamide

In concomitant use of allopurinol and chlorpropamide, in patients with impaired renal function the risk of prolonged hypoglycemia increases because allopurinol and chlorpropamide compete with each other during the tubular excretion phase.

Coumarin derived anticoagulants

An increase in the effects of warfarin and other coumarin derived anticoagulants has been observed with allopurinol. In this regard, the condition of patients receiving concomitant therapy with these drugs should be carefully monitored.

Phenytoin

Allopurinol can inhibit hepatic oxidation of phenytoin, 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 of theophylline in humans. Serum theophylline concentration should be monitored at the beginning of concomitant therapy with allopurinol, as well as when increasing the dose of the latter.

Ampicillin and amoxicillin

Patients who received ampicillin or amoxicillin and allopurinol simultaneously had an increased incidence of skin reactions compared to patients who did not receive this concomitant therapy. The reason for this type of drug interaction has not been established. Nevertheless, patients receiving allopurinol are advised to prescribe other antibacterial drugs instead of ampicillin and amoxicillin.

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

. 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 alone.

The number of blood cells should be counted regularly.

Cyclosporine

Some reports indicate that plasma concentrations of cyclosporine may increase with concomitant therapy with allopurinol. When concomitant use of these drugs it is necessary to consider the possibility of increased toxicity of cyclosporine.

Aluminum hydroxide

The effect of allopurinol with aluminum hydroxide may decrease when using allopurinol concomitantly. A break of at least 3 hours should be taken between the intake of both drugs.

Didanosine

In healthy volunteers and patients infected with human immunodeficiency virus receiving didanosine on concomitant therapy with allopurinol (300 mg daily) there was an increase in C_max (maximum plasma concentration of the drug) and AUC (area under the concentration-time curve) of didanosine approximately doubled. The half-life of didanosine did not change. As a rule, concomitant use of these drugs is not recommended. If concomitant therapy is unavoidable, reduction in the dose of didanosine and close monitoring of the patient’s condition may be required.

ACE inhibitors

The concomitant use of ACEs with allopurinol is associated with an increased risk of leukopenia, so these drugs should be combined with caution.

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

The co-administration of allopurinol with captopril may increase the risk of skin reactions, especially in patients with chronic renal impairment.

Diuretics

A interaction between allopurinol and furosemide has been reported, with increased serum urate levels and plasma oxypurinol concentrations.

The concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the risk of hypersensitivity side effects associated with allopurinol, especially in patients with impaired renal function.

Special Instructions

Drug hypersensitivity syndrome, CDS and TEN (Stevens-Johnson syndrome and toxic epidermal necrolysis)

The manifestation of hypersensitivity reactions to allopurinol can vary widely, including maculopapular exanthema, drug hypersensitivity syndrome [DRESS] and CDS/TEN. These reactions are the clinical diagnosis and their clinical manifestations are the basis for appropriate decisions. Therapy with Milurit should be discontinued immediately if a skin rash or other manifestations of hypersensitivity reactions occur. Therapy should not be resumed in patients with hypersensitivity syndrome and SDS/TEH. Glucocorticosteroids may be used to treat skin reactions in hypersensitivity.

The HLA-B*5801 allele

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

The feasibility 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 these patients. If genotyping is not available in Han Chinese, Thai, or Korean patients, allopurinol should be prescribed only if the benefit of treatment outweighs the possible increased risk. The use of genotyping for allopurinol therapy decisions in other patient groups has not been studied.

If a patient is known to be a carrier of the HLA-B*5801 allele (particularly in Han Chinese, Thais, and Koreans), allopurinol therapy should not be started unless there are no other possible adequate treatment options.

The development of hypersensitivity syndrome and SSD/TEH should be monitored very closely and patients should be informed of the need for immediate withdrawal of treatment at the first appearance of such symptoms.

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

Chronic renal failure

Patients with chronic renal failure with concomitant use of diuretics, particularly thiazide diuretics, may be at increased risk for hypersensitivity reactions, including allopurinol-related SSD/TEN. Particular vigilance is required for signs of hypersensitivity syndrome or SSD/TEN, and patients should be informed of the need for immediate and permanent discontinuation of allopurinol treatment at the first onset of symptoms.

Disorders of liver or renal function

In patients with impaired liver or renal function, reduced doses of allopurinol should be used. In patients treated for arterial hypertension or heart failure, such as with diuretics or ACE inhibitors, some reduction in renal function may be noted. Allopurinol should be used with caution in such patients.

Asymptomatic hyperuricemia

Allopurinol is not indicated in all cases of hyperuricemia without clinical manifestations. In these cases, patients may improve with changes in diet and fluid intake along with addressing the underlying cause of the hyperuricemia.

An acute attack of gout

The use of allopurinol should not be started until the acute attack of gout has completely resolved, because this could provoke an additional exacerbation of the disease.

In a similar fashion to uricosuric therapy, initiation of treatment with Milurit® may also provoke an acute attack of gout. To avoid this complication, prophylactic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine for at least one month before allopurinol administration is recommended. Details on recommended doses, cautions, and precautions can be found in the relevant literature.

If an acute attack of gout develops with allopurinol therapy, 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 given to patients treated with azathioprine or 6-mercaptopurine unless the dose of these drugs is reduced to 25% of the original dose.

Deposition of xanthine

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

Impact on uric acid concrements

Adequate allopurinol therapy may lead to dissolution of large uric acid concrements in the renal pelvis, with a remote likelihood of their reaching the ureters.

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

Hemochromatosis

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

Thyroid dysfunction

Elevated TTH (thyrotropic hormone) values (>5.5 µIU/ml) were observed in patients who received allopurinol for a long time (5.8%) in a long-term open-label follow-up clinical trial. Caution should be exercised when using allopurinol in patients with thyroid dysfunction.

Lactose

Each 100 mg tablet of Milurit® contains 50 mg of lactose. Therefore, patients with lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome should not take this medicine.

Impact on the ability to drive vehicles and mechanisms

With allopurinol therapy development of such adverse reactions as somnolence, dizziness (vertigo) and ataxia has been observed. These adverse events may affect the ability to drive vehicles and operate mechanisms. Patients taking Milurit® Tablets should not drive vehicles and operate machinery until they are sure that allopurinol has no adverse effect on the respective abilities.

Synopsis

Tablets of 300 mg: Round, flat tablets, white or grayish-white, beveled, with a rib on one side and E 352 engraved on the other, odorless or almost odorless.

Contraindications

Hypersensitivity to allopurinol or any of the excipients in the drug.

Hepatic failure, chronic renal failure (stage of azotemia), acute onset of gout, children under 3 years of age (with solid dosage form)

Pregnancy and breast-feeding (see section “Administration during pregnancy and breast-feeding”).

Patients with rare hereditary conditions such as lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (tablets contain lactose monohydrate – for 100 mg tablets only.

With caution

Hepatic disorders, hypothyroidism, diabetes, arterial hypertension, primary hemochromatosis, simultaneous use of angiotensin-converting enzyme inhibitors (ACE) or diuretics, childhood age (under 15 years old are prescribed only during cytostatic therapy for leukemia and other malignant diseases, as well as symptomatic treatment of enzyme disorders), advanced age, renal dysfunction (renal dysfunction may lead to retention of the drug and its metabolites in the body with subsequent prolongation of T_½ of these compounds from blood plasma).

Side effects

There are no current clinical data available to determine the incidence of side effects. Their frequency may vary depending on the dose and whether the drug was administered as monotherapy or in combination with other drugs.

The classification of the frequency of side effects is based on a rough estimate; for most side effects, no data are available to determine their frequency.

The classification of adverse reactions according to frequency of occurrence is as follows:

very frequent (>1/10),

frequent (>1/100 to < 1/10),

infrequent (>1/1000 to < 1/100),

rare (>1/10,000 to < 1/1000),

very rare (<1/10,000),

frequency unknown (impossible to determine based on available data).

Allopurinol therapy-related adverse reactions observed in the post-registration period are rare or very rare. In the general patient population, the majority of cases are mild. The incidence of adverse events increases with renal and/or hepatic dysfunction.

Infections and parasitic diseases:

Very rare: furunculosis.

Disorders of the blood and lymphatic system:

Very rare: agranulocytosis, aplastic anemia, thrombocytopenia, granulocytosis, leukopenia, leukocytosis, eosinophilia, and aplasia involving red blood cells only.

There have been very rare reports of thrombocytopenia, agranulocytosis, and aplastic anemia, particularly in those with renal and/or hepatic impairment, which emphasizes the need for special caution in these patient groups.

Disorders of the immune system:

Infrequent: hypersensitivity reactions; severe hypersensitivity reactions, including skin reactions with epidermal detachment, fever, lymphadenopathy, arthralgia and/or eosinophilia (including Stevens-Johnson syndrome (SSD) and toxic epidermal necrolysis (TEN)) (see “Skin and Subcutaneous Tissue Disorders”). Associated vasculitis or tissue reactions may have various manifestations, including hepatitis, renal damage, acute cholangitis, xanthine concrements and, in very rare cases, seizures. In addition, the development of anaphylactic shock has very rarely been observed. If severe adverse reactions develop, allopurinol therapy should 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, hepato-splenomegaly, changes of liver function tests results, disappearing 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 during any period of treatment, Milurit should be stopped immediately and never resumed. Patients with hypersensitivity syndrome and SSD/TEH should not be restarted. Corticosteroids may be useful in the treatment of skin hypersensitivity reactions.

Generalized hypersensitivity reactions have developed in patients with impaired renal and/or hepatic function. These cases have sometimes been fatal.

Very rare: angioimmunoblastic T-cell lymphoma.

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

Disorders of metabolism and nutrition:

Very rare: diabetes mellitus, hyperlipidemia.

Mental disorders:

very rare: depression.

Nervous system disorders:

Very rare: coma, paralysis, ataxia, peripheral neuropathy, paresthesias, somnolence, headache, dysgeusia.

Visual disorders:

Very rare: cataracts, visual disturbances, maculopathy.

Hearing organ disorders and labyrinth disorders:

Very rare: dizziness (vertigo).

Heart disorders:

Very rare: angina pectoris, bradycardia.

vascular disorders:

very rare: increased blood pressure.

Gastrointestinal disorders:

Infrequent: Vomiting, nausea, diarrhea;

In earlier clinical trials, nausea and vomiting were observed, but more recent observations have 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 patterns;

Prevalence unknown: abdominal pain.

Liver and biliary tract disorders:

Infrequent: Asymptomatic increase in the activity of liver enzymes (increased activity of alkaline phosphatase and transaminases in serum);

Rare: hepatitis (including necrotic and granulomatous forms).

Disorders of liver function may develop without obvious signs of generalized hypersensitivity.

Skin and subcutaneous tissue disorders:

Frequent: rash;

Rare: severe skin reactions: SSD and TEN

Skin reactions are the most common type of reaction and can develop at any time during treatment. They can present as an itchy, maculopapular, sometimes scaly or purpuric rash, and rarely as exfoliative lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SED/TEN). The greatest risk of SSD and TEN or other serious hypersensitivity reactions is noted during the first weeks of allopurinol use. The best results of treatment of such reactions are achieved with early diagnosis and immediate discontinuation of all suspected drugs. If such a reaction develops, Miluritol^® should be discontinued immediately. Allopurinol use may be resumed at a low dose (such as 50 mg/day), which may be gradually increased when the reactions return to normal after mild severity. The HLA-B*5801 allele has been shown to be associated with the risk of allopurinol-dependent hypersensitivity syndrome and SSD/TEN. If skin reactions occur repeatedly, allopurinol should be discontinued immediately and permanently, given the possibility of more severe hypersensitivity (see subsection “Immune system disorders”). If the presence of SDS/TEN or other serious hypersensitivity reactions cannot be ruled out, allopurinol should NOT be restarted due to the possibility of a severe or even fatal reaction. The basis for the decision is the presence of a clinical diagnosis of SDS/TEN. If such reactions develop at any time during treatment, allopurinol should be immediately and permanently discontinued;

Very rare: angioedema, localized medicated rash, alopecia, hair discoloration.

In allopurinol therapy, angioedema has been reported to develop in isolation as well as in combination with symptoms of a generalized hypersensitivity reaction.

Musculoskeletal and connective tissue disorders:

Very rare: myalgia.

Renal and urinary tract disorders:

Rare: urolithiasis

Very rare: Hematuria, azotemia;

Reproductive system and breast disorders:

Very rare: male infertility, erectile dysfunction, gynecomastia.

General disorders and disorders at the site of administration:

Very rare: edema, general malaise, asthenia, fever.

In allopurinol therapy, fever has been reported to develop both in isolation and in conjunction with symptoms of a generalized hypersensitivity reaction (see “Immune system disorders”).

Impact on laboratory and instrumental findings

Prevalent: increased thyrotropic hormone (TSH) levels

The increased TSH levels observed in relevant studies had no effect on T4 levels and were not indicative of the appearance of subclinical hypothyroidism.

Possible adverse reactions reported

The reporting of suspected adverse reactions to the drug is very important to allow for ongoing monitoring of the risk/benefit ratio of the drug. Healthcare providers should provide information about any suspected adverse reactions through the contacts listed at the end of the instructions, as well as through the national information collection system.

Overdose

A case of oral allopurinol ingestion of up to 22.5 g has been described without adverse events.

Symptoms of overdose: nausea, vomiting, diarrhea and dizziness were observed in a patient who took 20 g of allopurinol.

Severe overdose of allopurinol can lead to significant inhibition of xanthine oxidase activity. This effect alone should not be accompanied by adverse reactions. The exception is the effect on concomitant therapy, especially treatment with 6-mercaptopurine and/or azathioprine.

Treatment:

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

Pregnancy use

Pregnancy

There are currently insufficient data on the safety of allopurinol therapy during pregnancy, although the drug has been widely used for many years without obvious adverse effects. Pregnant women should not take Miluritus^® tablets unless there is no less dangerous alternative treatment and the disease poses a greater risk to the mother and fetus than taking the drug.

Breastfeeding

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

Similarities

Allopurinol