Allopurinol, tablets 300 mg 30 pcs

Pharmacotherapeutic group:

antipodagric agent – xanthine oxidase inhibitor

ATC code: [M04AA01]

Pharmacological properties

Firmacodynamics

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

Pharmacokinetics

Allopurinol is quickly and well absorbed from the gastrointestinal tract (up to 90%). When using a single dose of the drug, its concentration in plasma reaches a maximum level within 1.5 hours. About 20% of allopurinol and its metabolites are excreted through the intestine, 10% – by the kidneys. In the liver under the influence of xanthine oxidase allopurinol is converted into oxypurinol, which also inhibits the formation of uric acid. Half-life for allopurinol is 1-2 hours, as it is quickly metabolized to oxypurinol and is extensively excreted by the kidneys through glomerular filtration. The elimination half-life for oxypurinol is about 15 h. Allopurinol is actively reabsorbed in the renal tubules. Allopurinol and its metabolites do not bind to proteins, being distributed in the tissue fluid. The drug penetrates into the breast milk.

Pharmacokinetics in special clinical cases

In renal failure allopurinol and oxipurinol clearance may be significantly decreased, due to which their plasma concentrations increase. Therefore, an appropriate dose reduction is required in patients with renal impairment. In elderly patients there is no significant age-related change in allopurinol pharmacokinetics in the absence of reduced renal function.

Indications

Diseases accompanied by hyperuricemia (treatment and prevention): gout (primary and secondary), urolithiasis (with urate formation).

Hyperuricemia (primary and secondary), arising from diseases accompanied by increased decomposition of nucleoproteins and increased uric acid in the blood, including. at various hematoblastosis (acute leukemia, chronic myeloleukemia, lymphosarcoma, etc.), at cytostatic and radiation therapy of tumors (including in children), psoriasis, extensive traumatic injuries, due to enzyme disorders (Lesh-Nayhan syndrome), and also at massive therapy with glucocorticoids, when due to intensive decay of tissues the amount of purines in blood increases significantly. Renal nephropathy with impaired renal function (renal failure).

Recurrent mixed oxalate-calcium kidney stones (in the presence of uricosuria).

Active ingredient

Allopurinol

Composition

1 tablet of the drug contains:

active ingredient:

allopurinol – 300 mg;

excipients:

lactose monohydrate (milk sugar) – 49 mg;

microcrystalline cellulose – 20 mg;

sodium carboxymethyl starch (primogel) – 20 mg;

food gelatin – 5 mg;

magnesium stearate – 4 mg;

colloidal silica (aerosil) – 2 mg.

How to take, the dosage

Oral. The drug should be taken once a day after meals with plenty of water. If the daily dose exceeds 300 mg or gastrointestinal intolerance symptoms are observed, the dose should be divided into several doses.

Allopurinol should be used in different dosages (100 mg) once a day for initial therapy. If this dose is not sufficient to properly reduce the uric acid concentration in the blood serum, the daily dose of the drug can be gradually increased until the desired effect is achieved. Caution should be exercised with impaired renal function.

If the dose of allopurinol is increased every 1-3 weeks the uric acid concentration in serum should be determined.

The recommended dose of the drug is 300-600 mg per day in a moderate course; 600-900 mg per day in a severe course. The maximum daily dose is 900 mg.

The recommended dose for children aged 3 to 10 years is 5-10 mg/kg/day.

The recommended dose for children aged 10 to 15 years is 10-20 mg/kg/day. The daily dose of the drug should not exceed 400 mg.

Allopurinol is rarely used for pediatric therapy. Exceptions are malignant cancers (especially leukemia) and some enzymatic disorders (e.g., Lesha-Nyhan syndrome).

Since 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 blood plasma elimination half-life of these compounds. Allopurinol and its derivatives are removed from the body by hemodialysis. If hemodialysis sessions are conducted 2-3 times a week, it is reasonable to determine the necessity of switching to an alternative therapy regime – taking 300-400 mg of allopurinol immediately after hemodialysis session (the drug is not taken between hemodialysis sessions).

The concentration of uric acid salts in blood serum, as well as uric acid and urate concentrations in urine should be assessed at optimal intervals to adjust the drug dose.

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.

Vidarabine (adenine arabinoside)

In the presence of allopurinol the half-life of vidarabine is prolonged. When concomitant use of these drugs it is necessary to be particularly vigilant about increased toxic effects of therapy.

Salicylates and uricosuric agents

The main active metabolite of allopurinol is oxypurinol, which is excreted by kidneys similarly to 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 therapeutic activity of allopurinol, but the significance of this type of interaction should be assessed individually in each case.

Chlorpropamide

In concomitant use of allopurinol and chlorpropamide, in patients with impaired renal function the risk of long-term hypoglycemia increases because allopurinol and chlorpropamide compete with each other at the tubular excretion stage.

Coumarin derivative anticoagulants

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

Phenytoin

Allopurinol is able to inhibit phenytoin oxidation in liver, but clinical significance of this interaction is not established.

Theophylline

Allopurinol is known to inhibit theophylline metabolism. This interaction can be explained by the participation of xanthine oxidase in the process of theophylline biotransformation in human body. The concentration of theophylline in blood serum 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 simultaneously received ampicillin or amoxicillin and allopurinol registered an increased incidence of skin reactions, compared with patients who did not receive such concomitant therapy. The reason for this type of drug interaction has not been established. Nevertheless, it is recommended to prescribe other antibacterial drugs instead of ampicillin and amoxicillin for patients receiving allopurinol.

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

In patients suffering from tumor diseases (except leukemia) and receiving allopurinol, increased suppression of bone marrow activity by cyclophosphamide and other cytotoxic drugs was observed. However, according to the results of controlled studies involving patients receiving cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechlorethamine (chlormethine hydrochloride), concomitant therapy with allopurinol did not increase the toxic effects of these cytotoxic drugs.

Cyclosporine

According to some reports, 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 increasing toxicity of cyclosporine.

Didanosine

In healthy volunteers and HIV-infected patients receiving didanosine during concomitant therapy with allopurinol (300 mg per day) Cmax (maximum drug concentration in plasma) and AUC (area under the concentration-time curve) of didanosine approximately doubled. Half-life of didanosine did not change. As a rule, concomitant use of these drugs is not recommended. If concomitant therapy is unavoidable, reduction of didanosine dose and close monitoring of the patient’s condition may be required.

ACE inhibitors

Concomitant use of iACE with allopurinol is accompanied by an increased risk of leukopenia, thus, these drugs should be combined with caution.
Thiazide diuretics
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. SDS and TEN

Life-threatening skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SDS/TEN) have been reported with allopurinol. Patients should be informed about the symptoms of these reactions (progressive skin rash, often with vesicles and mucosal lesions) and their development should be closely monitored. SSRIs/TEH develop most frequently during the first weeks of taking the drug. If signs and symptoms of SUD/TEN are present, Allopurinol should be stopped immediately and no longer prescribed!

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

Corticosteroids may be used to treat skin reactions in hypersensitivity.

Chronic renal impairment

Patients with chronic renal impairment have a greater risk of developing hypersensitivity reactions associated with allopurinol, including SSD/TEN.

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 be as high as 20% in the Han Chinese population, about 12% in Koreans, and 1-2% in Japanese and Europeans. The use of genotyping for allopurinol therapy decisions has not been investigated. If a patient is known to be a carrier of the HLA-B*5801 allele, allopurinol should be prescribed only if the benefit of treatment outweighs the risk. The development of hypersensitivity syndrome and SSD/TEH should be monitored very closely. The patient should be informed of the need for immediate withdrawal of treatment at the first occurrence of such symptoms.

Hepatic and renal dysfunction

The dose of allopurinol should be reduced when treating patients with impaired renal or hepatic function. Patients treated for arterial hypertension or heart failure (e.g., patients taking diuretics or ACE inhibitors) may have concomitant impaired renal function, so allopurinol should be used with caution in this group of patients.

Asymptomatic hyperuricemia alone is not an indication for allopurinol use. 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.

Allopurinol should not be used until the acute attack of gout has completely resolved, as this could provoke an additional exacerbation of the disease.
Similar to therapy with uricosuric agents, starting allopurinol treatment may provoke an acute attack of gout. To avoid this complication, prophylactic therapy with nonsteroidal anti-inflammatory drugs or colchicine for at least one month before allopurinol administration is recommended. Details on recommended doses, precautions, 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 nonsteroidal anti-inflammatory drug should be prescribed to treat the attack.

Xanthine deposits

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

Uuric acid concretions implantation

Adequate allopurinol therapy may result in dissolution of large uric acid concretions in the renal pelvis; however, the probability of implantation of these concretions into the ureters is low.

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.

Lactose

Each 300 mg tablet of Allopurinol contains 49 mg of lactose. Therefore, this medication should not be taken by patients with rare hereditary galactose intolerance, lactase deficiency, and glucose and galactose malabsorption syndrome.

Impact on the ability to drive vehicles

Allopurinol is used with caution in patients whose activities require high concentration and quick psychomotor reactions. The degree of restriction or prohibition of driving and operating machinery must be determined by the physician for each patient individually.

Contraindications

Hypersensitivity to allopurinol or any other drug component; hepatic insufficiency; severe renal failure (stage of azotemia); primary (idiopathic) hemochromatosis; asymptomatic hyperuricemia, acute attack of gout; lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome; pregnancy, breast-feeding, children under 3 years of age.

With caution

Hepatic impairment, chronic heart failure, diabetes, arterial hypertension, liver function disorders, hypothyroidism, advanced age. Patients taking angiotensin-converting enzyme inhibitors (ACE) or diuretics. Children under 15 years of age (prescribed only during cytostatic therapy of leukemia and other malignant diseases, as well as symptomatic treatment of enzyme disorders).

Side effects

There are no current clinical data 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. Classification of the frequency of side effects is based on a rough estimate, for most side effects there are no data to determine the frequency of their development. Classification of adverse reactions by frequency of occurrence is as follows: very common (≥1/10); frequent (from ≥1/100 to infrequent (from ≥1/1000 to rare (from ≥1 /10000 to very rare (frequency is unknown (impossible to determine based on available data).

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

Infections and parasitic diseases: very rare: furunculosis.

Blood and lymphatic system disorders:very rare: agranulocytosis, aplastic anemia, thrombocytopenia, granulocytosis, leukopenia, leukocytosis, eosinophilia and aplasia involving red blood cells only.

Very rare reports of thrombocytopenia, agranulocytosis, and aplastic anemia have been reported, particularly in individuals with renal and/or hepatic dysfunction, which emphasizes the need for special caution in these patient groups.

Immune system disorders: infrequent: hypersensitivity reactions; rare: severe hypersensitivity reactions, including skin reactions with epidermal detachment, fever, lymphadenopathy, arthralgia and/or eosinophilia (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

The accompanying 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 multiorgan hypersensitivity (known as drug hypersensitivity syndrome /DRESS/), the following symptoms may develop in various combinations: Fever, skin rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function test results, disappearing bile duct syndrome (destruction or disappearance of intrahepatic bile ducts). If such reactions develop during any period of treatment, Allopurinol should be stopped immediately and never resumed.

Generalized hypersensitivity reactions have developed in patients with impaired renal and/or hepatic function. These cases have sometimes had a fatal outcome;
very rare: angioimmunoblastic lymphadenopathy. Angioimmunoblastic lymphadenopathy was very rarely diagnosed after lymph node biopsy for generalized lymphadenopathy. Angioimmunoblastic lymphadenopathy is reversible and regresses after discontinuation of allopurinol therapy.

Metabolic and nutritional disorders: very rare: diabetes mellitus, hyperlipidemia.

Mental disorders: very rare: depression.

Nervous system disorders: very rare: coma, paralysis, ataxia, neuropathy, paresthesias, somnolence, headache, perversion of sense of taste.

Visual disorders: very rare: cataracts, visual disturbances, macular changes.

Hearing organ and labyrinth disorders: very rare: vertigo.

Chronic disorders: very rare: angina pectoris, bradycardia.

Vascular disorders: very rare: increased blood pressure.

Gastrointestinal disorders: infrequent: vomiting, nausea, diarrhea (nausea and vomiting were observed in earlier clinical trials, 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 recurrent bloody vomiting, steatorrhea, stomatitis, changes in defecation frequency; frequency unknown: abdominal pain.

Hepatic and biliary tract disorders: infrequent: asymptomatic increase in liver enzymes (elevated serum levels of alkaline phosphatase and transaminases); rare: hepatitis (including necrotic and granulomatous forms).

Liver function abnormalities may develop without obvious signs of generalized hypersensitivity.

Skin and subcutaneous tissue disorders: frequent: rash; rare: severe skin reactions: Stevens-Johnson syndrome (SSD) and toxic epidermal necrolysis (TEN); very rare: angioedema, local medicated rash, alopecia, hair discoloration.

In patients taking allopurinol, the most common are adverse reactions of the skin. Against the background of therapy with the drug, these reactions may develop at any time. Skin reactions may be manifested by itching, maculopapular and scaly rashes. In other cases, purpura may develop. In rare cases, exfoliative skin lesions (SSD/TEN) are observed. If such reactions develop, therapy with allopurinol should be stopped immediately. If skin reactions are mild, allopurinol may be resumed at a lower dose (e.g., 50 mg daily) after these changes have disappeared.

Thereafter, the dose can be gradually increased. If there is a recurrence of skin reactions, allopurinol therapy should be stopped and should not be restarted, as further use of the drug may lead to more severe hypersensitivity reactions.

An allopurinol therapy has reportedly produced angioedema in isolation as well as in association with symptoms of generalized hypersensitivity reactions.

Muscular and connective tissue disorders: very rare: myalgia.

Renal and urinary tract disorders: very rare: hematuria, renal failure, uremia; frequency unknown: urolithiasis.

Reproductive system and mammary gland disorders: very rare: male infertility, erectile dysfunction, gynecomastia.

General disorders and disorders at the site of administration: very rare: edema, general malaise, general weakness, fever.

In allopurinol therapy, fever has been reported to develop both in isolation and in combination with symptoms of a generalized hypersensitivity reaction.

Reports of possible adverse reactions

In case of adverse reactions, including those not specified in these instructions, the use of the drug should be discontinued.

Any information about possible adverse reactions is important during the post-registration period, because these reports help keep track of the safety of the medication.

Health care providers have a responsibility to report any suspected adverse reactions to local pharmacovigilance agencies.

Overdose

Symptoms: nausea, vomiting, diarrhea, dizziness, oliguria. Most symptoms of allopurinol overdose may be attenuated by increasing its renal excretion with abundant fluid intake and a corresponding increase in diuresis.

Treatment: forced diuresis; allopurinol and its metabolites are eliminated by hemodialysis and peritoneal dialysis.

Pregnancy use

There have been no reliable studies on the use of allopurinol during pregnancy and breastfeeding in humans. Allopurinol during pregnancy should be taken only by prescription and only in the absence of a therapeutic alternative, when the disease poses a greater risk to the fetus and the mother than taking allopurinol.

If allopurinol should be used during breastfeeding, the question of stopping breastfeeding or refraining from prescribing the drug should be decided.

Similarities

Milourite