Allopurinol - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 49 mg; cellulose microcrystalline - 20 mg; carboxymethyl starch sodium (primogel) - 20 mg; gelatin food - 5 mg; magnesium stearate - 4 mg; silicon dioxide colloid (aerosil) - 2 mg.

Description:

Round, flat-cylindrical tablets of white or almost white color with a facet and a risk.

Pharmacotherapeutic group:Antifungal agent - xanthine oxidase inhibitor

ATX: & nbsp

M.04.A.A Inhibitors of uric acid synthesis

Pharmacodynamics:

Allopurinol is a structural analogue of hypoxanthine. Allopurinol, as well as its main active metabolite, oxypurinol, inhibit xanthine oxidase, an enzyme that converts 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) facilitates their dissolution. In addition to suppressing the catabolism of purines 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 inhibition of purine biosynthesis de novo by the feedback mechanism, which is mediated by inhibition of the hypoxanthine-guanine phosphoribosyl transferase enzyme. Other metabolites of allopurinol are allopurinol-riboside and oxypurinol-7 riboside.

Pharmacokinetics:

Allopurinol is rapidly and well absorbed from the gastrointestinal tract (up to 90%). When using a single dose of the drug, its concentration in the 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 turns into oxypurinol, which also inhibits the formation of uric acid. The half-life for allopurinol is 1-2 hours, because it is rapidly metabolized into oxypurinol and is intensively excreted by the kidneys due to glomerular filtration. The half-life for oxypurinol is about 15 hours. In the renal tubules allopurinol is actively reabsorbed. Allopurinol and its metabolites do not bind to proteins, being distributed in the tissue fluid. The drug penetrates into breast milk.

Pharmacokinetics in special clinical cases

With renal insufficiency the clearance of allopurinol and oxypurinol can be greatly reduced, and therefore their concentrations in the blood plasma increase. Therefore, in patients with renal insufficiency, an appropriate dose reduction is required.

In elderly patients There is no significant age-related change in the pharmacokinetics of allopurinol in the absence of a decrease in renal function.

Indications:

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

Hyperuricemia (primary and secondary) that occurs in diseases accompanied by increased decay of nucleoproteins and an increase in the content of uric acid in the blood, incl. with various hematoblastoses (acute leukemia, chronic myeloleukemia, lymphosarcoma, etc.), with cytostatic and radiation therapy of tumors (incl.in children), psoriasis, extensive traumatic injuries, due to enzymatic disorders (Lesch-Naikhan syndrome), as well as with massive therapy with glucocorticosteroids, when the amount of purines in blood is significantly increased as a result of intensive tissue decay.

Urinary acid nephropathy with impaired renal function (renal failure).

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

Contraindications:

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

Carefully:

Renal failure, chronic heart failure, diabetes mellitus, arterial hypertension, liver dysfunction, hypothyroidism, elderly age.

Patients taking angiotensin converting enzyme (ACE) inhibitors or diuretics.

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

Pregnancy and lactation:

There were no reliable studies on the use of allopurinol during pregnancy and lactation in humans. Allopurinol during pregnancy should be taken only according to the doctor's prescription and only in the absence of a therapeutic alternative, when the disease presents a greater risk to the fetus and the mother than the intake of allopurinol.

If you need to use allopurinol during breastfeeding, you should decide whether to stop breastfeeding or refrain from prescribing.

Dosing and Administration:

Inside. The drug should be taken once a day after meals, washed down with plenty of water. If the daily dose exceeds 300 mg or there are signs of intolerance from the gastrointestinal tract, then the dose should be divided into several doses.

For the initial therapy should be used allopurinol in other dosages (100 mg) once a day.If this dose is not enough to properly reduce the concentration of uric acid in the blood serum, then the daily dose of the drug can be gradually increased to achieve the desired effect. Care should be taken if the renal function is impaired.

With an increase in the dose of allopurinol every 1-3 weeks, it is necessary to determine the concentration of uric acid in the serum.

The recommended dose of the drug is 300-600 mg per day for moderate to moderate flow; 600-900 mg per day in severe conditions. The maximum daily dose is 900 mg. The recommended dose for children from 3 to 10 years is 5-10 mg / kg / day.

The recommended dose for children from 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. The exception is malignant oncological diseases (especially leukemia) and some enzymatic disorders (for example, Lesha-Naikhan syndrome).

Because the allopurinol and its metabolites are excreted from the body by the kidneys, impaired renal function can lead to a delay in the drug and its metabolites in the body, followed by an elongation of the half-life of these compounds from the blood plasma.

Allopurinol and its derivatives are removed from the body by hemodialysis. If hemodialysis sessions are held 2-3 times a week, it is advisable to determine the need for switching to an alternative treatment regimen - receiving 300-400 mg allopurinol immediately after hemodialysis (between hemodialysis drug is not accepted).

To correct drug dose with optimum intervals necessary to estimate the concentration of uric acid salts in the blood serum, as well as the concentration of uric acid and urate in urine.

Side effects:

There are no modern clinical data for determining the incidence of side effects. Their frequency may vary depending on the dose and on whether the drug was administered as monotherapy or in combination with other drugs. Classification of frequency of side effects is based on a rough estimate, for the majority of side effects no data to determine the frequency of their development.

Classification undesirable reactions depending on the frequency of occurrence is as follows: very frequent (≥1 / 10), frequent (from ≥ 1 / 100th to <1/10), infrequent (from ≥1 / 1000 to <1/100), rare (from ≥1 / 10,000 to <1/1000), very rare (<1/10000) frequency not known (can not be determined on the basis of available data).

The undesirable reactions associated with allopurinol therapy observed in the postgrade period are rare or very rare. In the general population of patients in most cases are of an easy nature. The incidence of adverse events increases with impaired renal and / or liver function.

Infections and parasitic diseases:

very rare: furunculosis.

Disorders from the blood and lymphatic system:

very rare: agranulocytosis, aplastic anemia, thrombocytopenia, granulocytosis, leukopenia, leukocytosis, eosinophilia and aplasia, relating only to erythrocytes.

There have been very few reports of thrombocytopenia, agranulocytosis, and aplastic anemia, especially in individuals with impaired renal and / or liver function, which underscores the need for extreme 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) (see "Skin and subcutaneous tissue disorders" section).

Concomitant vasculitis or reactions from the tissue may have various manifestations, including hepatitis, kidney damage, acute cholangitis, xanthine stones and, in very rare cases, convulsions.

In addition, the development of anaphylactic shock was very rare.

In the development of severe adverse reactions, allopurinol therapy must be immediately stopped and not renewed.

With delayed multi-organ hypersensitivity (known as drug hypersensitivity /DRESS/) the following symptoms can develop in different combinations: fever, skin rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in liver function tests, disappearing bile duct syndrome (intrahepatic bile duct destruction or disappearance). With the development of such reactions in any period of treatment, Allopurinol should be immediately canceled and never renewed.

Generalized hypersensitivity reactions developed in patients with impaired renal and / or liver function. Such cases were sometimes fatal;

highly rare: angioimmunoblastic lymphadenopathy.

Angioimmunoblastic lymphadenopathy was very rarely diagnosed after lymph node biopsy for generalized lymphadenopathy. Angioimmunoblastic lymphadenopathy is reversible and regresses after cessation of therapy with allopurinol.

Disorders from the metabolism and nutrition:

very rare: diabetes mellitus, hyperlipidemia.

Disorders of the psyche:

very rare: depression.

Disturbances from the nervous system:

very rare: coma, paralysis, ataxia, neuropathy, paresthesia, drowsiness, headache, perversion of taste sensations.

Disturbances on the part of the organ of sight:

very rare: cataract, visual impairment, macular changes.

Hearing disorders and labyrinthine disorders:

very rare: dizziness (vertigo).

Heart Disease:

very rare: angina, bradycardia.

Vascular disorders:

very rare: increase in blood pressure.

Disorders from the gastrointestinal tract:

infrequent: vomiting, nausea, diarrhea;

In previous clinical studies, nausea and vomiting were observed,However, later observations confirmed that these reactions are not a clinically significant problem and can be avoided by assigning allopurinol after meal.

very rare: recurrent bloody vomiting, steatorrhea, stomatitis, changes in the frequency of defecation;

frequency is unknown: abdominal pain.

Disturbances from the liver and bile ducts:

infrequent: asymptomatic increase in the concentration of hepatic enzymes (elevated levels of alkaline phosphatase and transaminases in blood serum);

rare: Hepatitis (including necrotic and granulomatous forms).

Dysfunction of the liver can develop without obvious signs of generalized hypersensitivity.

Disturbances from the skin and subcutaneous tissues:

Frequent: rash;

rare: severe skin reactions: Stevens-Johnson syndrome (SDS) and toxic epidermal necrolysis (TEN);

very rare: angioedema, local medical ailment, alopecia, hair discoloration.

In patients receiving allopurinol, the most common adverse reactions from the skin. Against the background of drug therapy, these reactions can develop at any time.Skin reactions can be manifested by itching, maculopapular and scaly rashes. In other cases purple may develop. In rare cases, exfoliative skin lesions are observed (SSD / TEN). With the development of such reactions, therapy with allopurinol should be stopped immediately. If the reaction from the skin is light, then after the disappearance of these changes, you can resume taking allopurinol in a smaller dose (for example, 50 mg per day). Subsequently, the dose can be gradually increased. In case of recurrence of skin reactions, allopurinol therapy should be stopped and no longer restarted, as further administration of the drug may lead to the development of more severe hypersensitivity reactions (see "Immune system disorders").

According to existing information, against the background of therapy with allopurinol, angioedema has developed in isolation, as well as in combination with the symptoms of a generalized hypersensitivity reaction.

Disturbances from the musculoskeletal and connective tissue:

very rare: myalgia.

Disorders from the kidneys and urinary tract:

very rare: hematuria, renal insufficiency, uremia;

frequency is unknown: urolithiasis disease.

Disorders from the reproductive system and breast:

very rare: male infertility, erectile dysfunction, gynecomastia.

General disorders and disorders at the injection site:

very rare: edema, general malaise, general weakness, fever.

According to existing information, against the background of therapy with allopurinol, fever developed both in isolation and in combination with the symptoms of a generalized hypersensitivity reaction (see "Immune system disorders").

Reports of possible adverse reactions

In case of adverse reactions, including those not indicated in this manual, the use of the drug should be discontinued.

In the post-marketing period, any information on possible adverse reactions, because these messages help to constantly monitor the safety of the drug. Health professionals are required to report any suspicion of adverse reactions to the local pharmacovigilance authorities.

Overdose:

Symptoms: nausea, vomiting, diarrhea, dizziness, oliguria.Most of the symptoms of an overdose of allopurinol can 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 excreted in hemodialysis and peritoneal dialysis.

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 be given 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.

Vidarabine (adenine arabinoside)

In the presence of allopurinol, the half-life of vidarabine increases. When these drugs are used concomitantly, special caution must be exercised in respect of the increased toxic effects of therapy.

Salicylates and uricosuric agents

The main active metabolite of allopurinol is oxypurinol, which is excreted by the kidneys similarly to salts of uric acid.Therefore, drugs with uricosuric activity, such as probenecid or high doses of salicylates, can enhance the excretion of oxypurinol. In turn, increased 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 individually in each case.

Chloropropamide

With the simultaneous use of allopurinol and chlorpropamide, patients with impaired renal function increase the risk of developing prolonged hypoglycemia, since the tubular excretion allopurinol and chlorpropamide compete with each other.

Anticoagulant coumarin derivatives

With simultaneous use with allopurinol, there was an increase in the effects of warfarin and other anticoagulants of coumarin derivatives. In this regard, it is necessary to carefully monitor the condition of patients receiving concomitant therapy with these drugs.

Phenytoin

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

Theophylline

It is known that allopurinol depresses the metabolism of theophylline.Such an interaction can be explained by the involvement of xanthine oxidase in the process of biotransformation of theophylline in the human body. The concentration of theophylline in serum should be monitored at the beginning of concomitant therapy with allopurinol, and also with an increase in the dose of the latter.

Ampicillin and amoxicillin

In patients who simultaneously received ampicillin or amoxicillin and allopurinol, an increased incidence of skin reactions was recorded, compared with patients who did not receive similar concomitant therapy. The cause of this type of drug interaction is not established. However, patients receiving allopurinol, instead of ampicillin and amoxicillin it is recommended to prescribe other antibacterial drugs.

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

In patients suffering from tumor diseases (except leukemia) and receiving allopurinol, enhanced suppression of bone marrow activity by cyclophosphamide and other cytotoxic drugs was observed.Nevertheless, according to the results of controlled trials, in which patients who received cyclophosphamide, doxorubicin, bleomycin, procarbazine and (or) mechlorethamine (chloromethine hydrochloride), concomitant allopurinol therapy did not enhance the toxic effect of these cytotoxic drugs.

Cyclosporin

According to some reports, the concentration of cyclosporine in the blood plasma may increase against the background of concomitant therapy with allopurinol. With the simultaneous use of these drugs must take into account the possibility of increasing the toxicity of cyclosporine.

Didanosine

In healthy volunteers and HIV-infected patients receiving didanosine, against the background of concomitant therapy with allopurinol (300 mg per day) there was an increase in C_mOh (the maximum concentration of the drug in the blood plasma) and AUC (the area under the concentration-time curve) didanosine is approximately twice. The half-life of Didanosine did not change. As a rule, the simultaneous use of these drugs is not recommended. If concomitant therapy is unavoidable, a reduction in didanosine dose and careful monitoring of the patient's condition may be required.

ACE Inhibitors

Simultaneous use of ACE inhibitors with allopurinol is accompanied by an increased risk of developing leukopenia, so these drugs should be combined with caution.

Thiazide diuretics

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

Special instructions:

Syndrome of drug hypersensitivity. SSD and TEN

Against the background of the use of allopurinol, there have been reports of life-threatening reactions from the skin, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SSD / TEN). Patients should be informed of the symptoms of these reactions (progressive skin rash, often with vesicles and mucosal lesions) and carefully monitor their development. Most often, SSD / TEN develop during the first weeks of taking the drug. In the presence of signs and symptoms of SSD / TEC, the drug Allopurinol should be immediately canceled and no longer assigned! The manifestation of hypersensitivity reactions to allopurinol can be very different, including maculopapular exanthema, drug hypersensitivity syndrome (DRESS) and SSD / TEN.These reactions are a clinical diagnosis and their clinical manifestations are the basis for making appropriate decisions. Drug therapy Allopurinol should immediately stop when skin rash or other manifestations of hypersensitivity reaction appear. It is impossible to resume therapy in patients with hypersensitivity syndrome and SSD / TEN. Corticosteroids can be used to treat skin reactions with hypersensitivity.

Chronic renal dysfunction

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

Allele HLA-B*5801

It was found that the presence of an allele HLA-B* 5801 is associated with the development of hypersensitivity syndrome to allopurinol and SSD / TEN. Allele frequency HLA- В * 5801 is different in different ethnic groups and can reach 20% in the Chinese Han population, about 12% in Koreans and 1-2% in Japanese and Europeans. The use of genotyping to make decisions about the therapy with allopurinol has not been investigated. If it is known that the patient is the carrier of the allele HLA-B* 5801, then allopurinol It should be prescribed only if the benefit of the treatment exceeds the risk. It should be very closely monitor the development of the hypersensitivity syndrome and SSD / TEN. The patient should be informed of the need for immediate withdrawal of treatment at the first occurrence of such symptoms.

Impaired liver and kidney function

In the treatment of patients with impaired renal or hepatic function, the dose of allopurinol should be reduced. Patients receiving treatment for hypertension or heart failure (eg, patients taking diuretics or ACE inhibitors) may experience concomitant renal impairment, so allopurinol in this group of patients should be used with caution.

Asymptomatic hyperuricemia in itself is not an indication for the use of allopurinol. In such cases, the improvement of the patient's condition can be achieved through changes in diet and fluid intake along with the elimination of the underlying cause of hyperuricemia.

Acute attack of gout

Allopurinol should not be used until the acute acute attack of gout is completely stopped, as this can provoke an additional exacerbation of the disease.Similarly to uricosuric therapy, the onset of allopurinol treatment can trigger an acute attack of gout. In order to avoid this complication, it is recommended that preventive therapy with non-steroidal anti-inflammatory drugs or colchicine is carried out for at least one month prior to the appointment of allopurinol. Details on recommended doses, warnings and precautions can be found in the relevant literature.

If an acute attack of gout develops with allopurinol therapy, then the drug should be continued at the same dose, and an appropriate non-steroidal anti-inflammatory agent should be prescribed to treat the attack.

Xanthine deposits

In cases where the formation of uric acid is significantly increased (for example, malignant tumor pathology and the corresponding antitumor therapy, Lesch-Naikhan syndrome), the absolute concentration of xanthine in urine in rare cases can significantly increase, which contributes to the deposition of xanthine in the tissues of the urinary tract. The likelihood of xanthine deposition in tissues can be minimized due to adequate hydration,which provides optimal urine dilution.

Injection of stones from uric acid

Adequate therapy with allopurinol may lead to the dissolution of large concrements from uric acid in the renal pelvis, however, the probability of wedging these concrements into the ureters is low.

Hemochromatosis

The main effect of allopurinol in the treatment of gout is to suppress the activity of the enzyme xanthine oxidase. Xanthine oxidase may be involved in reducing the content and excretion of iron deposited in the liver. Studies demonstrating the safety of allopurinol therapy in the population of patients with hemochromatosis are lacking. Patients with hemochromatosis, as well as their blood relatives allopurinol should be administered with caution.

Lactose

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

Effect on the ability to drive transp. cf. and fur:

Allopurinol is used with caution in patients whose activity requires high concentration of attention and rapid psychomotor reactions.The degree of restriction or prohibition on driving and the work with mechanisms the doctor must determine for each patient individually.

Form release / dosage:Tablets, 300 mg.

Packaging:

For 10 tablets in a contour cell pack or 30 or 50 tablets in a jar of lightproof glass.

Each bank or 3 or 5 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003429

Date of registration:25.01.2016 / 02.11.2016

Expiration Date:25.01.2021

The owner of the registration certificate:ORGANICS, JSC ORGANICS, JSC Russia

Manufacturer: & nbsp

ORGANICS, JSC Russia

Information update date: & nbsp10.07.2017

Illustrated instructions

Instructions

Allopurinol (Allopurinol)