Allopurinol: instructions for use

Indications and contraindications for taking Allopurironol

The main indications for prescribing the drug are the following conditions:

• Gout and kidney stones (pathologies accompanied by hyperuricemia).
• Psoriasis.
• Hemoblastoses (acute and chronic leukemia, lymphosarcoma).
• Urinary nephropathy and concomitant renal failure.

There are a number of absolute and relative contraindications to taking Allopurinol. The first include:

• Chronic kidney disease.
• Acute attack of gout.
• Pregnancy and breastfeeding period.
• Allergic reactions to one or more substances included in the drug.
• Hemochromatosis.

Relative contraindications are diabetes mellitus types 1 and 2, as well as arterial hypertension with high cardiovascular risk.

TREATMENT AND PREVENTION OF GOUT: DRUGS OF CHOICE (Part 1)

Preferanskaya Nina Germanovna

Associate Professor, Department of Pharmacology, Faculty of Pharmacy, First Moscow State Medical University named after. THEM. Sechenova, Ph.D.

In 1955, the English biochemist Egon Orovan even coined the term “gouty genius.” This disease has been known since ancient times - it was described by Hippocrates. , and in 1683, Thomas Sidey described the symptoms of gout in his “Treatise on Salt Deposition and Dropsy”: “The victim goes to bed and goes to sleep in perfect health ... But at about 2 o’clock in the morning he wakes up from severe pain ... Soon a feeling of cold and chills appears ... After some time, the pain reaches its limit... It seems to twist and tear the ligaments, then bite and gnaw at the bone, like a dog... The torture continues all night... Relief finally comes, but only by the next morning.”

Gout is a disease associated with the deposition of crystals of uric acid and its salts (urates) in various tissues of the body, a decrease in its excretion by the kidneys and an increase in the concentration of urates in the blood (hyperuricemia). Gout affects any joints: fingers, hands, elbows, knees, feet. Most often, gout affects the joints of the toes.

The view of it as a “royal disease” or “disease of the rich” has long been outdated; the disease is detected in various socio-economic groups. With gout, symptoms such as recurrent acute inflammation (arthritis), unbearable pain and the formation of gouty nodes (tophi) occur. ). Tophi are the same deposits of uric acid salts, surrounded by connective tissue. Most often they appear in the ear area, but this is only the beginning. Tophi can occur anywhere, and even on internal organs.

There is no direct connection between gout and genius. This phenomenon can be explained by the fact that the pathogenesis is based on a violation of the metabolism of purine bases. In humans, the main product of the catabolism of purine nucleotides (adenylic acid, adenosine, adenosine triphosphoric acid, guanosine, etc.) is uric acid. Uric acid is a weak acid and exists in two tautomeric forms: the lactim form has OH acid centers and a pyrimidine nitrogen atom as a basic center. The content of the undissociated form and salts depends on the pH of the solution. At physiological pH values, only one of the three protons in uric acid can dissociate (pK5.8). Due to the transfer of a proton, the lactim form becomes lactam.

Uric acid is a dibasic acid and forms salts - urates, respectively, with one and two equivalents of alkali. Alkali metal dihydrourates do not dissolve in water and accumulate in the body in the form of crystals. Normally, uric acid, which is the end product of cell activity, enters the blood and is excreted mainly by the kidneys in the urine. According to statistics, with a total content of 1000 mg of uric acid in the body, 650 mg of it is renewed daily. This does not happen with hyperuricemia; in the body of such patients, production increases and excretion from the body of uric acid and its salts decreases. A high content of uric acid salts is determined in the blood (in men more than 0.48 mmol/l and in women - 0.38 mmol/l). With hyperuricemia, the renal clearance of uric acid is impaired, which is recorded in more than 90% of cases.

The structure and effect of uric acid salts are identical to purine derivatives: 1,3,7-trimethylxanthine (caffeine), 3,7-dimethylxanthine (theobromine) and 1,3-dimethylxanthine (theophylline), which are stimulants of cerebral cortex activity (psychostimulants). Thus, with gout, the brain is constantly in an excited state, which contributes to the development of phenomenal abilities.

Men suffer from gout 20 times more often, because... their serum urate background is 2 times higher than that of women. This disease occurs more often in people suffering from obesity, nephropathy and alcoholism, because alcohol increases susceptibility to disease. The disease usually begins at the age of 35−50 years. In women, gout develops after menopause and therefore has a peak incidence between 50 and 70 years of age. The symptoms of this disease are very unpleasant. Characteristic symptoms include repeated attacks of acute inflammation of the joints. The attack usually begins unexpectedly, often at night, and is characterized by swelling and redness of the joints of the legs (most often the big toe), severe pain and high temperature (up to 38–40°C). When monosodium urate crystals interact with the endothelium, joint cells and leukocytes, pro-inflammatory cytokines are synthesized and trigger a cascade of inflammatory processes. Since leukocytes phagocytose urate crystals, the latter destroy the lysosomal membranes of leukocytes. Lysosomal enzymes that destroy cells are released into the cytosol, and the products of cellular catabolism cause inflammation and severe pain.

If gout is left untreated, attacks become more frequent and periods of exacerbation last longer. Arthritis takes root in more and more new joints, often affecting the kidneys and urinary tract. The disease progresses to chronic gouty arthritis. The following forms are distinguished:

• primary gout (hereditary), associated with hereditary defects of enzyme systems;
• metabolic, when the body experiences overproduction of uric acid;
• renal – impaired excretion of uric acid by the kidneys;
• mixed, in which both violations occur.

There are four stages in the development of gout:

• acute gouty arthritis;
• interictal “interval” gout and recurrent arthritis;
• chronic gouty arthritis;
• chronic tophi gout.

The number of patients with gouty arthritis in all countries is growing steadily. The incidence is increasing in women, which is partly due to increased life expectancy in postmenopause and the cessation of the uricosuric effect of estrogens. The spread of diseases pathogenetically associated with hyperuricemia is also important: arterial hypertension, type II diabetes mellitus. The effect of uric acid on blood pressure is associated with the activation of the sympathetic, renin-angiotensin-aldosterone, human hormonal systems that regulate blood pressure and blood volume in the body, leading to changes in blood vessels, incl. renal, and reduce the level of endothelial relaxing factor (NO). High levels of uric acid become a risk factor for the development of pathological processes. In a modern person who consumes excess amounts of sodium chloride (table salt), hyperuricemia can lead to arterial hypertension. Hyperuricemia can also occur with long-term use of drugs: diuretics (hypothiazide, furosemide), cytostatics, corticosteroids, NSAIDs (acetylsalicylic acid). Hyperuricemia is one of the components of metabolic syndrome along with endothelial dysfunction, insulin resistance, and lipid metabolism disorders. Metabolic syndrome is present in more than 3/4 of patients suffering from gout. This combination not only increases the risk of cardiovascular complications, but also worsens the course of the disease itself. Therefore, it is incorrect to assume that hyperuricemia is associated only with gout and urolithiasis. “Asymptomatic” hyperuricemia became widespread (18%). Therefore, regular monitoring of uric acid levels in the blood is necessary.

Unfortunately, there is no complete cure for gout, but you can control the level of uric acid in the blood. To do this, it is necessary not only to change the nature of nutrition, but also to choose the right therapy.

The main goal of systematic treatment of gout is a persistent reduction in the concentration of uric acid in the blood. The most famous hypouricemic drug Allopurinol

Available in tablets of 0.1 and 0.3 g. The daily dose of the drug depends on the severity of gout and the level of uric acid in the blood. By inhibiting xanthine oxidase, the drug reduces the synthesis of uric acid. The concentration of uric acid and its salts in the blood, as well as their accumulation in tissues, decreases. By oxidizing purine substrates, xanthine oxidase simultaneously generates free radicals and reduces oxidative stress.

In order to avoid a sharp decrease in uric acid levels, which can provoke an acute attack of gout, treatment is started with a small dose. The initial dose of the drug is 100 mg per day, then daily the daily dose is increased by 100 mg and increased to 200 or 300 mg for mild forms of the disease. For moderate and severe forms, the dose is 400–800 mg. To reduce the risk of side effects and drug interactions (very likely in patients with gout and concomitant diseases), it is necessary to determine the target level of uric acid in the blood (less than 0.36 mmol/l). During treatment with Allopurinol, serum uric acid levels begin to decrease within the first 2 days and reach a stable maximum effect no earlier than 7–10 days. Persistent and complete normalization usually occurs after 4–6 months, after which a maintenance dose of 100 mg per day is prescribed. At the same time, uricosuria is reduced, so there is no risk of urate stones forming in the urinary tract. The drug can also be used in the presence of renal pathology, but without severe renal failure.

Important!

Allopurinol cannot be used to relieve acute gouty arthritis; it is prescribed only after the attack has subsided. During the interictal period, the drug is taken continuously. The need for lifelong treatment is generally recognized in the case of arterial hypertension, diabetes mellitus and other chronic diseases. It is not advisable to carry out combined treatment of gout with Allopurinol in combination with uricoeliminators, because with combination therapy, the elimination of oxypurinol (a metabolite of Allopurinol) is accelerated and the inhibition of xanthine oxidase is reduced.

According to clinical studies, unsatisfactory tolerability of Allopurinol is observed in 20% of patients. Possible hypersensitivity reactions (rash, fever, itching, skin rashes, urticaria, Quincke's edema, vasculitis), agranulocytosis, eosinophilia, gastrointestinal complaints (dyspepsia, diarrhea), hepatitis, impaired renal function, acute renal failure. They often occur in patients with asymptomatic hyperuricemia (50% of cases), which, according to most experts, does not require drug correction. Allopurinol may cause drowsiness and dizziness, so you should avoid driving or operating machinery.

Allopurinol blocks purine breakdown, the level of xanthine in the blood and urine increases, xanthinemia and xanthinuria develop, which can have a harmful effect on the kidneys. In 20–50% of cases, urolithiasis and renal failure develop (18–25%). The so-called gouty nephropathy develops, and it is this that most often causes the death of patients. If the patient already has signs of nephropathy, prescribing him drugs that increase the effect of uric acid on kidney tissue is strictly prohibited

. To avoid the formation of xanthine stones in the kidneys, it is necessary not only to ensure plenty of fluid intake (preferably alkaline table mineral water), diuresis within 2 liters, but also to create a neutral or slightly alkaline urine reaction (within 6.2–7.8). With an increase in diuresis, the concentration of urates in the urine decreases and their tendency to crystallize decreases, and alkalinization of the urine keeps xanthine and hypoxanthine in a dissolved state.

Allopurinol

when used together with
Ampicillin
and
Amoxicillin
, it increases the risk of allergic reactions, skin manifestations and anaphylactoid reactions - when used with
Captopril
, it slows down the metabolism
of Theophylline
.
When used together with indirect anticoagulants or coumarin derivatives, it is necessary to reduce the doses of the latter, because inhibition of metabolism occurs and their effectiveness increases, more frequent monitoring of blood coagulation parameters is required. When using the drug with Azathioprine
and
Mercaptopurine,
not only the therapeutic but also the toxic effect of the latter increases. When combined with large doses of salicylates, the effectiveness of the drug itself decreases.

Contraindications to the use of Allopurinol

: hypersensitivity, acute attack of gout, severe liver dysfunction, hemochromatosis, pregnancy, breastfeeding, childhood (except for malignant diseases with hyperuricemia). Use with caution in congestive heart failure, renal failure, diabetes mellitus, arterial hypertension.

Possible adverse reactions and symptoms of overdose

Adverse effects when taking Allopurinol can occur in various organs and systems, so side effects should be classified into groups:

1. On the part of sensitive analyzers: visual impairment, amblyopia, allergic conjunctivitis, taste perversion.
2. Gastrointestinal tract: dyspeptic syndrome, cholestasis, enlarged liver, hepatitis, hepatonecrosis.
3. CVS: decreased heart rate, hypertension, vasculitis, pericarditis.
4. From the central and peripheral nervous system: drowsiness or insomnia, paresis, disturbances in the emotional state, neuritis, paresthesia.
5. Musculoskeletal system: pain in muscles and joints.
6. Hematopoietic organs: anemia, thrombocyto-, leuko- and pancytopenia.
7. From the urinary and reproductive systems: edema, increased urea concentration, nephritis, impotence, enlarged mammary glands, changes in libido, infertility.

An overdose of the drug is accompanied by weakness, dizziness and typical symptoms of poisoning (nausea, vomiting, loose stools). It is also possible to reduce the daily volume of urine excreted.

Possible side effects

Like all medicines, allopurinol can cause side effects, although not everyone gets them. These symptoms include:

Hypersensitivity

Uncommon side effects (may affect less than 1 in 100 people)

If you experience an allergic reaction, stop taking allopurinol immediately and contact your doctor or the nearest hospital.

These symptoms include:

• exfoliative dermatitis, furunculosis and stomatitis
• very rarely symptoms such as sudden wheezing, anxiety and chest tightness and collapse

Rare side effects ( may affect less than 1 in 1000 people )

• fever, chills, headache, muscle aches (flu-like symptoms) and general feeling unwell.
• Serious allergic reactions, including fever, skin rash, joint pain, abnormal blood counts and liver tests, which are signs of impaired sensitivity in multiple organs.
• Bleeding from the lips, eyes, mouth, nose and genitals.
• Any changes in the skin, such as ulcers of the mouth, larynx, nose, genitals, conjunctivitis (red and swollen eyes), the spread of blisters and desquamation of the epidermis throughout the body.

You should not take more allopurinol than prescribed by your doctor.

Other possible side effects

Common side effects ( may affect 1 in 10 people )

• skin rash

Uncommon side effects (may affect 1 in 100 people)

• nausea and vomiting
• abnormal liver tests

Rare side effects (may affect 1 in 1,000 people)

• liver problems such as liver inflammation

Very rare side effects ( may affect 1 in 10,000 people )

• disorders of the hematopoietic system, which can lead to bruising from minor impacts or a sore throat or other symptoms of infection. These symptoms often appear in patients with impaired liver or kidney function. In this case, you should immediately consult a doctor.
• lymph node damage
• heat
• presence of blood in the urine (hematuria)
• elevated blood cholesterol levels (hyperlipidemia)
• general unwellness or feeling of weakness
• weakness, numbness, unsteadiness in a standing position, a feeling of inability to make voluntary muscle movements (paralysis) or loss of consciousness
• headache, dizziness, drowsiness, or blurred vision
• chest pain (angina), high blood pressure, or weak pulse
• male infertility or erectile dysfunction
• breast enlargement in both men and women
• bowel dysfunction
• taste disturbances
• cataract
• hair loss or bleaching
• depression
• impairment of voluntary coordination of muscle movements (ataxia)
• tingling, tickling, and burning sensations (paresthesia)
• swelling of the lower extremities, especially in the ankle area.
• impaired glucose tolerance. If this occurs, your doctor will need to periodically measure your blood glucose levels.

If you have any serious side effects or side effects not listed in this leaflet, contact your doctor or pharmacist.

Reporting Adverse Events

If you notice any side effects, tell your doctor, pharmacist or pharmacist, including any side effects not listed in this leaflet. You can also report side effects by going to the website www.arpimed.com and filling out the appropriate form “Report a side effect or ineffectiveness of a drug” and to the Scientific Center for Expertise of Medicines and Medical Technologies named after. Academician E. Gabrielyan by going to the website www.pharm.am to the “Report a side effect of a drug” section and fill out the form “Card of reporting a side effect of a drug.” Scientific center hotline phone number: +37410237665; +37498773368

How to store Allopurinol

• Store out of reach of children, protected from moisture and light at a temperature of 150C-250C.
• Shelf life – 3 years. Do not take allopurinol after the expiration date indicated on the drug package. When indicating the expiration date, we mean the last day of the specified month.
• Medicines should not be disposed of in wastewater or sewer systems. Ask your pharmacist how to dispose of any medicine you no longer need. These measures are aimed at protecting the environment.

Package contents and additional information

What Allopurinol contains

One tablet contains:

active substance : allopurinol-300 mg;

excipients : microcrystalline cellulose, corn starch, sodium starch glycolate, magnesium stearate, sodium lauryl sulfate.

What Allopurinol looks like and contents of the pack:

Round, biconvex, white tablets with a score line on one side.

Cardboard packaging containing 30 tablets (3 blisters of 10 tablets each) along with an insert.

Vacation conditions

Available with prescription

Instructions for use of the drug

Tablets are always taken orally with plenty of liquid and always after meals. The dosage, frequency and duration of administration are selected by the doctor and depend on the pathology.

For gout, the daily dose can vary from 200 to 600 milligrams of Allopurinol. In this case, the severity and degree of the disease are the main criteria for selecting the amount of medication.

For urate nephropathy and oncology, the drug is taken in the amount of 600-800 mg per day.

If it is necessary to prescribe medication to children, the dosage is calculated based on body weight. It is recommended to prescribe from 5 to 10 mg per kilogram of body weight per day, depending on the type and severity of the disease. Under the age of 15 years, the daily dosage should not exceed 300 milligrams.

Allopurinol tablets 100 mg No. 10x5

Name

Allopurinol tablet 100 mg in blister pack No. 10x5 Basic physical and chemical properties of the tablet are round in shape, white or almost white in color, with a flat surface, with a chamfer and a notch.

Composition of the drug

active ingredient: allopurinol; 1 tablet contains allopurinol - 100 mg; excipients: lactose monohydrate, microcrystalline cellulose, corn starch, hypromelose, magnesium stearate.

Pharmacotherapeutic group

Antigout drugs. Agents that inhibit the formation of uric acid. ATC code M04AA01.

Indications for use

Allopurinol is indicated to reduce urate/uric acid concentrations in conditions involving accumulation of urate/uric acid deposits (eg, gouty arthritis, cutaneous tophi, nephrolithiasis) or when there is a predictable clinical risk (eg, treatment of a malignant tumor has the potential to lead to acute uric acid nephropathy). . The main clinical conditions in which urate accumulation/uric acid deposits may occur are: idiopathic gout; urate urolithiasis; acute uric acid nephropathy; neoplastic and myeloproliferative diseases with a high rate of cell population renewal, in which hyperuricemia occurs spontaneously or after cytotoxic therapy; certain enzymatic disorders leading to overproduction of urates, for example, deficiency of hypoxanthine-guanine phosphoribosyltransferase (including Lesch-Nyhan syndrome), deficiency of glucose-6-phosphatase (including glycogenosis), increased activity of phosphoribosylpyrophosphate synthetase, increased activity of phosphoribosylpyrophosphate amidotransferase, deficiency of adenine phosphoribosyltransferase. Allopurinol is indicated for the treatment of urolithiasis associated with the formation of 2,8-dihydroxyadenine (2,8-DHA) stones as a result of decreased adenine phosphoribosyltransferase activity. Allopurinol is indicated for the treatment of recurrent urolithiasis associated with the formation of mixed calcium-oxalate stones against the background of hyperuricosuria, when increased fluid intake, diet and other methods have been ineffective.

Contraindications

Hypersensitivity to allopurinol or other components of the drug.

Precautionary measures

Hypersensitivity syndrome, SJS and TEN At the first appearance of skin rash or any other signs of hypersensitivity, allopurinol should be discontinued immediately to prevent the development of more serious hypersensitivity reactions (including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)), hypersensitivity syndrome ( drug hypersensitivity syndrome with eosinophilia and systemic symptoms, DRESS). HLA-B*58:01 allele The HLA-B*58:01 allele was identified as a genetic risk factor for the development of allopurinol-associated SJS/TEN‚ (and possibly other serious hypersensitivity reactions) in a retrospective pharmacogenetic case-control study in a Chinese Han population , Taiwanese, Koreans, Japanese and Europeans. The frequency of the HLA-B*58:01 allele can reach 20-30% in the Han Chinese population, and people of African and Indian descent, while only 1-2% of Japanese, northern Europeans and European Americans are carriers of the HLA- allele. B*58:01. Screening for HLA-B*58:01 should be considered before initiating allopurinol treatment in patient subgroups where the prevalence of this allele is known to be high. If patients are carriers of the HLA-B*58:01 allele, then allopurinol should not be prescribed unless there are no other acceptable therapeutic options and the benefits outweigh the potential risks. Patients who do not carry the HLA-B*58:01 allele still have a low risk of developing SJS/TEN. Clinical diagnosis of SJS/TEN and other hypersensitivity reactions is the basis for therapeutic decision making. If such reactions occur at any time during treatment, allopurinol should be discontinued immediately and permanently. Corticosteroids may be effective in treating skin hypersensitivity reactions. Chronic renal failure Patients with chronic renal impairment and concomitant use of diuretics, particularly thiazides, may be at increased risk of developing hypersensitivity reactions, including SJS/TEN, associated with allopurinol. Particular attention is required to identify signs of hypersensitive syndrome or SJS/TEN and the patient should be informed of the need for immediate and discontinuation of treatment at the first appearance of symptoms. Hepatic or renal impairment In patients with hepatic or renal impairment, reduced doses should be used. Patients with hypertension or heart failure receiving, for example, diuretics or ACE inhibitors may have concomitant renal impairment, and allopurinol should be used with caution in this group. Asymptomatic hyperuricemia in itself is generally not considered an indication for the use of allopurinol, since an appropriate diet and adequate fluid intake are usually sufficient. Foods high in purines should not be consumed (for example, organ organs: kidney, brain, liver, heart and tongue, meat broths and alcohol, especially beer). Acute attack of gout Treatment with allopurinol should not be started until the acute attack of gout has completely resolved, as further attacks may be provoked. At the beginning of treatment with allopurinol, as with other uricosuric drugs, acute attacks of gout are possible due to the mobilization of large amounts of uric acid. Therefore, it is advisable to simultaneously use appropriate anti-inflammatory drugs (except aspirin or salicylates) or colchicine for the purpose of prevention during the first month. Detailed information about recommended doses, warnings and precautions can be found in the relevant literature. If an acute attack of gout occurs in patients already taking allopurinol, treatment should be continued at the same dose and the acute attack treated with appropriate anti-inflammatory drugs. Xanthine deposition In cases where the intensity of urate formation increases significantly (for example, malignant diseases and their therapy, Lesch-Nyhan syndrome), the absolute concentration of xanthine in the urine can, in rare cases, reach levels that promote xanthine deposition in the urinary tract. This risk can be minimized by adequate hydration to achieve optimal urine dilution by alkalinizing the urine. Blockage of the urinary tract by uric acid kidney stones With adequate therapy with allopurinol, it is possible to dissolve large urate stones in the renal pelvis and enter the urinary tract (renal colic) with possible blockage. Lactose intolerance Allopurinol tablets contain lactose; patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not take the drug.

Use during pregnancy or breastfeeding

There is limited data on the safety of allopurinol during pregnancy, although it has been widely used for many years without apparent adverse effects. The use of allopurinol during pregnancy is possible only in the absence of a safer alternative treatment and when the disease itself carries great risks for the mother or unborn child. Allopurinol and oxypurinol are excreted into breast milk. In the breast milk of women taking allopurinol at a dose of 300 mg/day, the concentration of allopurinol reached 1.4 mg/l, oxypurinol - 53.7 mg/l. However, there are no data regarding the effects of allopurinol and its metabolites on the breastfed infant. The drug is not recommended during breastfeeding.

Children

Allopurinol tablets are not used in children under 3 years of age. The ability to influence the reaction rate when driving vehicles or operating other mechanisms. Adverse reactions such as drowsiness, dizziness (vertigo), ataxia, which may affect the ability to drive vehicles OR operate other mechanisms, have been reported with the use of allopurinol. Patients taking allopurinol should not operate vehicles or machinery until they are sure that allopurinol does not adversely affect these abilities.

Interaction with other drugs

Azathioprine, 6-mercaptopurine Azathioprine is metabolized to 6-mercaptopurine, which is inactivated by xanthine oxidase. Since allopurinol inhibits xanthine oxidase, the metabolism of these purine derivatives is slowed, the effects are prolonged, and toxicity increases, so their usual dose should be reduced to 1/4 of the usual dose when used together with allopurinol. Vidarabine (adenine arabinoside) Coadministration of these drugs prolongs the half-life of vidarabine with the risk of increased toxicity. This combination should be used with caution. Salicylates (large doses), uricosurics (eg, sulfinpyrazone, probenecid, benzbromarone) Oxypurinol, the main metabolite of allopurinol, is itself therapeutically active and is excreted by the kidneys in a manner similar to urates. Thus, drugs with uricosuric activity, such as probenecid or large doses of salicylates, may accelerate the excretion of oxypurinol. This may reduce the therapeutic activity of allopurinol, but the significance of this must be assessed on a case-by-case basis. Chlorpropamide If renal function is impaired, the use of allopurinol with chlorpropamide increases the risk of prolonged hypoglycemia, since allopurinol and chlorpropamide may compete for excretion in the renal tubules. Coumarin-type anticoagulants There have been rare reports of increased effects of warfarin and other coumarins when used concomitantly with allopurinol, therefore more frequent monitoring of coagulation parameters in patients receiving these drugs is required. Phenytoin Allopurinol may inhibit the oxidation of phenytoin in the liver; the clinical significance of this interaction has not been established. Theophylline, caffeine Allopurinol in high doses suppresses metabolism and increases plasma concentrations of theophylline and caffeine. At the beginning of treatment with allopurinol or when increasing its dose, the level of theophylline in the blood plasma should be monitored. Ampicillin, amoxicillin The incidence of skin rashes is increased in patients receiving these antibiotics and allopurinol concomitantly, compared with patients who did not receive this combination. The reason for this has not been established. However, patients taking allopurinol should use other antibiotics. Cytostatics (eg, cyclophosphamide doxorubicin, bleomycin, procarbazine, mechlorethamine) Bone marrow suppression with cyclophosphamide and other cytotoxic drugs is increased in patients with neoplastic diseases (other than leukemia) receiving allopurinol. However, in a well-controlled study in patients receiving cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine, allopurinol did not increase the toxicity of these cytotoxic drugs. Cyclosporine It is possible to increase the concentration of cyclosporine in the blood plasma with concomitant therapy with allopurinol. The possibility of increased cyclosporine toxicity should be considered if these drugs are taken together. Capecitabine The manufacturer of capecitabine recommends avoiding co-administration with allopurinol. Didanosine In healthy volunteers and HIV-infected patients receiving didanosine, during concomitant therapy with allopurinol (300 mg per day), an approximately 2-fold increase in Cmax and AUC was observed without a change in the terminal half-life. As a rule, the concomitant use of these drugs is not recommended. If concomitant use is unavoidable, a dose reduction of didanosine and careful monitoring of the patient may be necessary. Diuretics An interaction between allopurinol and furosemide has been reported, leading to an increase in serum urate and plasma oxypurinol concentrations. An increased risk of hypersensitivity reactions has been reported when allopurinol is used concomitantly with diuretics, in particular thiazides, especially in patients with impaired renal function. ACE inhibitors An increased risk of hypersensitivity reactions has been reported when allopurinol is used concomitantly with ACE inhibitors, especially in cases of impaired renal function.

Directions for use and dosage

Take after meals, without chewing, with plenty of water. Adults To reduce the risk of adverse reactions, treatment is started with a low dose, for example, 100 mg / day, which is increased only if there is an insufficient response to reduce the concentration of urate in the blood serum. Particular caution should be exercised in patients with impaired renal function (see subsection "Patients with impaired renal function"). When selecting the dose of the drug, it is recommended to use the following dosage regimens: 100-200 mg per day for mild disease; 300-600 mg per day for moderate disease; 700-900 mg per day for severe disease. If, when calculating the dose, it is necessary to proceed from the patient’s body weight, then the dose should be from 2 to 10 mg/kg/day. Pediatric population Children under 15 years of age: 10-20 mg/kg body weight per day up to a maximum daily dose of 400 mg. Allopurinol is used in children in rare cases, with the exception of cancer (especially leukemia) and certain enzymatic disorders (for example, Lesch-Nychen syndrome). Elderly patients In the absence of specific data, the minimum effective dose should be used to ensure a sufficient reduction in serum urate concentrations. Particular attention should be paid to recommendations for selecting the dose of the drug for patients with impaired renal function and certain other conditions (see subsection “Patients with impaired renal function” and section “Precautions”). Patients with Impaired Renal Function Since allopurinol and its metabolites are excreted by the kidneys, impaired renal function may result in retention of the drug and/or its metabolites with subsequent prolongation of their plasma half-life. In case of severe renal failure, it is advisable to use Allopurinol in a dose of less than 100 mg per day or use single doses of 100 mg at intervals of more than one day. If it is possible to control the concentration of oxypurinol in the blood plasma, then the dose of Allopurinol should be adjusted so as to maintain the level of oxypurinol in the blood plasma below 100 µmol/l (15.2 mg/l). Allopurinol and its metabolites are removed from the body by hemodialysis. If hemodialysis is required 2-3 times a week, then an alternative treatment regimen should be considered - taking 300-400 mg of Allopurinol immediately after completion of each hemodialysis session (the drug is not taken between temodialysis sessions). Patients with impaired liver function In patients with impaired liver function, reduced doses should be used. In the early stages of therapy, it is recommended to periodically monitor laboratory parameters of liver function. Treatment of conditions with high urate metabolism, for example, neoplasia, Lesch-Nychen syndrome It is advisable to correct existing hyperuricemia and/or hyperuricosuria with Allopurinol before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimal diuresis and to alkalinize the urine to increase urate/uric acid solubility in urine. Allopurinol dosage should be at the lower end of the recommended dosage range. If renal function is compromised by the development of renal nephropathy OR other renal pathology, then treatment should be continued in accordance with the recommendations presented in the subsection "Patients with impaired renal function." These measures may reduce the risk of xanthine and/or uric acid deposits that complicate the disease. Recommendations for monitoring To establish the optimal dose of the drug, it is necessary to periodically monitor the concentration of urates in the blood serum, as well as the level of urates/uric acid in the urine.

Mode of application

Tablets for oral administration. Allopurinol can be taken once a day after meals. The drug is well tolerated, especially after meals. If the daily dose exceeds 300 mg and gastrointestinal disturbances occur, it is advisable to divide the dose into several doses.

Overdose

It was reported that 22.5 g of allopurinol was taken without adverse reactions. The occurrence of nausea, vomiting, diarrhea, and dizziness was observed in a patient who took allopurinol. To restore the condition, general supportive measures are taken. Massive absorption of allopurinol can lead to significant inhibition of xanthine oxidase activity, which should not cause any undesirable effects, except for the effect on concomitant therapy, especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimal diuresis promotes excretion of allopurinol and its metabolites. If necessary, hemodialysis is possible.

Side effect

The most common adverse reactions of allopurinol are skin rashes. Adverse effects may vary in frequency depending on the dose received, the disease, and when used in combination with other drugs. The frequency of adverse reactions increases with disorders of the kidneys and/or liver. At the beginning of treatment with allopurinol, reactive attacks of gout may occur due to the mobilization of uric acid from gouty nodules and other depots. Adverse reactions, information about which is given below, are classified by organs and systems and by the frequency of their occurrence: very often (? 10%); often (?1% and

• Thrombocytopenia, agranulocytosis and aplastic anemia have been reported very rarely, especially in patients with impaired renal and/or hepatic function, highlighting the need for special attention to this group of patients.
• Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, pseudopymphoma, arthralgia, leukopenia, and/or eosinophilia (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) occur rarely (see section 4.4). "Skin and subcutaneous tissue").

The vasculitis and tissue reactions associated with hypersensitivity reactions can have a variety of manifestations, including hepato-splenomegaly, hepatitis, biliary tract disappearance syndrome (destruction and disappearance of the intrahepatic bile ducts), renal failure and, very rarely, seizures. There may be disturbances in other organs (eg, liver, lungs, kidneys, pancreas, myocardium, colon). Acute anaphylactic shock has been reported very rarely. These reactions can occur at any time during treatment and if they occur, allopurinol should be discontinued IMMEDIATELY and PERMANENTLY. Resumption of use of the drug should not be carried out in patients with hypersensitivity syndrome, SJS/TEN. Corticosteroids may be effective in reversing cutaneous hypersensitivity reactions. Generalized hypersensitivity reactions, especially fatal ones, usually developed in patients with impaired renal and/or liver function.

• Angioimmunoblastic T-cell lymphoma is very rarely diagnosed after lymph node biopsy for generalized lymphadenopathy.
• Nausea and vomiting were reported in early clinical studies. Further observations have shown that these reactions are not a serious problem and can be avoided by taking Allopurinol after meals.
• Liver dysfunction (usually reversible with drug discontinuation) may occur without obvious signs of generalized hypersensitivity reactions.
• Skin reactions are the most common reactions and may occur at any time during treatment. These reactions may be accompanied by itching, the rash may be maculopapular, sometimes pityriasis-like, purpura may develop, and very rarely exfoliative dermatoses such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) may develop. The highest risk of developing SJS, TEN or other serious hypersensitivity reactions occurs in the first weeks of treatment. The best results in treating such reactions occur with early diagnosis and immediate discontinuation of any suspected drug. If such reactions develop, Allopurinol should be stopped immediately. If the skin reaction is mild, then after the symptoms disappear, the drug can be re-prescribed at a low dose (for example, 50 mg/day), gradually increasing it if necessary. If the skin rash reappears, the drug should be discontinued permanently, as severe generalized hypersensitivity reactions may occur. If SJS/TEN or other serious hypersensitivity reactions cannot be excluded, treatment with allopurinol should not be restarted due to the risk of severe or fatal reactions. The clinical diagnosis of SJS/TEN is the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be discontinued immediately and permanently.
• Cases of angioedema with and without symptoms of generalized hypersensitivity reactions have been reported.
• Cases of fever with and without symptoms of generalized hypersensitivity reactions have been reported.

Best before date

5 years Do not use the drug after the expiration date indicated on the package.

Storage conditions

In original packaging at a temperature not exceeding 25°C. Keep out of the reach of children.

Package

10 tablets in a blister made of polyvinyl chloride film and aluminum foil, coated on one side with thermovarnish and printed on the other side. 5 blisters, together with instructions for medical use of the drug or an insert, are placed in a cardboard pack.

Vacation conditions

On prescription.

Reviews about Allopurinol

Most of the patient reviews about the drug are positive. Consumers note the high effectiveness of the drug, rapid relief of symptoms of the disease, and a noticeable decrease in the level of uric acid in the blood according to test results. Patients also note that the drug works better as part of complex therapy and when following a diet.

However, there are also reviews of a different nature on the Internet, both neutral and negative. For some patients, Allopurinol either did not help or caused undesirable reactions, which served as a reason to cancel the course of treatment.

Allopurinol tab 300 mg N30 (Organic)

Azathioprine is metabolized to form 6-mercaptopurine, which is inactivated by the enzyme xanthine oxidase. When 6-mercaptopurine or azathioprine therapy is combined with allopurinol, patients should be given only one-fourth 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) The half-life of vidarabine is increased in the presence of allopurinol. When these drugs are used concomitantly, particular caution should be exercised regarding increased toxic effects of therapy. Salicylates and uricosurics The main active metabolite of allopurinol is oxypurinol, which is excreted by the kidneys in a manner similar to uric acid salts. Therefore, drugs with uricosuric activity, such as probenecid or high doses of salicylates, may increase the elimination of oxypurinol. In turn, increased 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 With the simultaneous use of allopurinol and chlorpropamide, in patients with impaired renal function, the risk of developing prolonged hypoglycemia increases, since allopurinol and chlorpropamide compete with each other at the stage of tubular excretion. Anticoagulants coumarin derivatives When used simultaneously with allopurinol, an increase in the effects of warfarin and other anticoagulants coumarin derivatives was observed. In this regard, it is necessary to carefully monitor the condition of patients receiving concomitant therapy with these drugs. Phenytoin Allopurinol is capable of inhibiting 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 participation of xanthine oxidase in the process of theophylline biotransformation in the human body. Serum theophylline concentrations should be monitored when initiating concomitant therapy with allopurinol, as well as when increasing the dose of the latter. Ampicillin and amoxicillin An increased incidence of skin reactions was reported in patients concomitantly receiving ampicillin or amoxicillin and allopurinol compared to patients who did not receive such concomitant therapy. The cause of this type of drug interaction has not been established. However, in patients receiving allopurinol, other antibacterial drugs are recommended instead of ampicillin and amoxicillin. 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, the concentration of cyclosporine in the blood plasma may increase during concomitant therapy with allopurinol. When using these drugs simultaneously, the possibility of increased toxicity of cyclosporine must be taken into account. Didanosine In healthy volunteers and HIV-infected patients receiving didanosine, during concomitant therapy with allopurinol (300 mg per day), an approximately two-fold increase in didanosine Cmax (maximum drug concentration in blood plasma) and AUC (area under the concentration-time curve) was observed. . The half-life of didanosine did not change. In general, simultaneous use of these drugs is not recommended. If concomitant therapy is unavoidable, a dose reduction of didanosine and careful monitoring of the patient may be necessary. ACE inhibitors Concomitant use of ACE inhibitors with allopurinol is accompanied by an increased risk of leukopenia, so these drugs should be combined with caution. Thiazide diuretics Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the risk of allopurinol-related hypersensitivity side effects, especially in patients with impaired renal function.

Main results

Between April 2010 and May 2021, 6198 patients were included in the study. Eight patients did not take a single tablet of the study drug, so the modified analysis, which was performed on the assumption that all patients took the prescribed treatment, included data on 6190 patients. There were no significant differences between groups in baseline characteristics.

In the febuxostat group, the final dose of study drug was 40 and 80 mg in 61 and 39% of patients, respectively. In the allopurinol group, 21.8, 44.6, 25.2, 4.3, and 4.1% of patients, respectively, took allopurinol doses of 200, 400, 300, 500, and 600 mg in accordance with the specific protocol for the CCR study.

Overall, 56.6% of patients persistently stopped taking the study drug: in the febuxostat group and allopurinol group 57.3 and 55.9%, respectively. The proportion of patients who did not visit the study center for the next scheduled examination generally reached 45%: in the febuxostat group and allopurinol group 45 and 44.9%, respectively. The median duration of treatment with febuxostat and allopurinol was 728 and 719 days, respectively. The median duration of follow-up in the febuxostat group and allopurinol group was 968 and 942 days, respectively.

The proportion of patients whose blood UA concentration was less than 360 μmol/L 2 weeks after the start of therapy was higher in the febuxostat group compared to the allopurinol group; After this, during the course of the study, more patients in the febuxostat group compared with the allopurinol group had blood sUA concentrations less than 360 μmol/L according to most tests, despite the fact that the differences between the groups were small. In addition, in the febuxostat group, compared with the allopurinol group, there was generally a higher proportion of patients with a blood sUA level less than 300 μmol/L during the study. The incidence of gout flares was similar in the febuxostat group and the allopurinol group, being 0.68 and 0.63 cases per person per year, respectively.

During the study, there were no statistically significant differences between the groups in blood concentrations of electrolytes, glucose and lipids, as well as blood pressure levels and the frequency of use of medications for the treatment of CVD.

After 624 adverse clinical outcomes occurred that led to study termination and before database closure, additional adverse clinical outcomes occurred. The results of the full analysis showed a similar incidence of adverse outcomes included in the main outcome: such outcomes in the febuxostat group and the allopurinol group occurred in 10.8 and 10.4% of patients, respectively, during a median follow-up of 32 months (risk ratio 1 .03 with the upper limit of one-sided 98.5% CI 1.23; p=0.002 for the analysis performed to test the hypothesis of non-inferiority of febuxostat compared to allopurinol). When additional rates of nonfatal adverse events were analyzed, the risk ratios were similar to those in the study as a whole.

However, the risk of death from any cause and the risk of death from complications of CVD were higher in the febuxostat group compared with the allopurinol group. In the febuxostat group and allopurinol group, 7.8 and 6.4% of patients died from any cause, respectively (risk ratio 1.22 with 95% CI from 1.01 to 1.47; p = 0.04), and from complications of CVD - 4.3 and 3.2% of patients, respectively (risk ratio 1.34 with 95% CI from 1.03 to 1.73; p = 0.03). Among the causes of death from complications of CVD, the most common was sudden death from complications of heart disease: this cause of death in the febuxostat group and allopurinol group was observed in 2.7 and 1.8% of patients, respectively. The rates of hospitalization for heart failure and hospitalization for non-ischemic arrhythmias, as well as the incidence of thromboembolic complications and hospitalization for transient cerebrovascular accident were similar in the two groups.

The results of the analysis of the main indicator in the subgroups indicated the absence of heterogeneity in the subgroups of patients with certain baseline characteristics. For CVD mortality, there was an interaction between NSAID use and no low-dose aspirin use (unstandardized p < 0.05 for both comparisons).

According to a planned analysis of the incidence of adverse outcomes included in the main outcome that developed while taking the study drug or within 30 days after discontinuation of therapy, such outcomes in the febuxostat group and allopurinol group occurred in 7.8 and 7.7% of patients, respectively. (hazard ratio 1.00 with upper limit of one-sided 98.5% CI 1.22). This analysis found that mortality from CVD complications was statistically significantly higher in the febuxostat group compared with the allopurinol group (risk ratio 1.49; 95% CI 1.01 to 2.22; p=0.047).

The results of a secondary analysis of the incidence of adverse outcomes included in the main combined indicator that developed during the period of use of the study drugs indicated a similar incidence of such outcomes in the febuxostat group and the allopurinol group (such outcomes developed in 6.2 and 6.4% of patients, respectively; hazard ratio 0.94 with upper limit of one-sided 98.5% CI 1.17). The risk of death from any cause and the risk of death from complications of CVD were higher in the febuxostat group compared with the allopurinol group.