Allopurinol tablets 100 mg No. 50
Composition
active ingredient: allopurinol;
1 tablet contains allopurinol 100 mg or 300 mg;
Excipients: lactose monohydrate; corn starch; povidone; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: tablets of white or almost white color, round shape, with a flat surface, with a bevel and a score on one side.
Pharmacotherapeutic group
Drugs used for gout. Drugs that inhibit the formation of uric acid. Allopurinol.
ATX code M04A A01.
Pharmacological properties
Pharmacodynamics.
Allopurinol is a xanthine oxidase inhibitor. Allopurinol and its major metabolite oxypurinol lower plasma and urinary uric acid levels by inhibiting xanthine oxidase, the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to inhibiting purine catabolism in some, but not all, patients with hyperuricemia, de novo purine biosynthesis is inhibited through reversible inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol riboside and oxypurinol-7-riboside.
Pharmacokinetics.
Absorption. Allopurinol is active when administered orally and is rapidly absorbed from the upper gastrointestinal tract. After administration, allopurinol is detectable in the blood within 30–60 minutes. Bioavailability ranges from 67% to 90%. Peak plasma concentrations of allopurinol are usually reached about 1.5 hours after oral administration, but decline rapidly to barely detectable levels by 6 hours. Peak plasma concentrations of oxypurinol are usually reached 3–5 hours after oral administration and are more persistent.
Distribution. Allopurinol is not very protein bound, and therefore changes in protein binding are not expected to have a significant effect on clearance. The apparent volume of distribution of allopurinol is approximately 1.6 L/kg, indicating relatively extensive tissue absorption. Tissue concentrations of allopurinol in humans have not been studied, but it is likely that the highest concentrations of allopurinol and oxypurinol will be found in the liver and intestinal mucosa, where xanthine oxidase activity is high.
Biotransformation: The main metabolite of allopurinol is oxypurinol. Other metabolites include allopurinol riboside and oxypurinol-7-riboside.
Elimination: Approximately 20% of allopurinol administered orally is excreted in the faeces. Allopurinol is eliminated by metabolic conversion to oxypurinol by xanthine oxidase and aldehyde oxidase. Less than 10% of the drug is excreted unchanged in the urine. The elimination half-life is approximately 0.5 to 1.5 hours. Oxypurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but its elimination half-life in humans is significantly longer, from 13 to 30 hours. For this reason, effective inhibition of xanthine oxidase lasts for more than 24 hours after a single daily dose. Patients with normal renal function will gradually accumulate oxypurinol until steady-state plasma concentrations are reached. Such patients, taking 300 mg of allopurinol per day, will typically have plasma oxypurinol concentrations of 5–10 mg/L.
Oxypurinol is excreted in the urine but has a long half-life because it undergoes tubular reabsorption. The half-life studied ranges from 13.6 to 29 hours. The discrepancies in these values may be due to differences in study design and/or different creatinine clearances in patients.
Pharmacokinetics in patients with renal impairment. In patients with renal impairment, the clearance of allopurinol and oxypurinol is significantly reduced, leading to increased plasma concentrations during continuous treatment. In patients with renal impairment, whose creatinine clearance was 10 to 20 ml/min, plasma oxypurinol concentrations of approximately 30 mg/l were found after long-term treatment with allopurinol at a dose of 300 mg per day. This approximately corresponds to the concentration that would be achieved in a patient with normal renal function when taking 600 mg per day. In patients with renal impairment, the dose of the drug should be reduced.
Pharmacokinetics in the elderly: In elderly patients, changes in drug kinetics are unlikely, except in patients with renal impairment (see section “Pharmacokinetics in patients with renal impairment”).
Indication
The main clinical conditions in which the accumulation of uric acid and its salts may occur: idiopathic gout; urolithiasis (formation of uric acid stones); acute uric acid nephropathy; tumor and myeloproliferative diseases with a high rate of cell renewal, when the increase in urate levels occurs spontaneously or after cytotoxic therapy; some enzymopathies that lead to excessive formation of urate, for example: hypoxanthine-guanine phosphoribosyltransferase deficiency, in particular Lesch-Nyhan syndrome; glucose-6-phosphatase deficiency, in particular glycogenosis; impaired activity of phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate aminotransferase, adenine phosphoribosyltransferase.
The drug is indicated for the treatment of diseases caused by insufficient activity of adenine phosphoribosyltransferase and the formation of 2,8-dihydroxyadenine (2,8-DHA) kidney stones.
The drug is indicated for the treatment of recurrent formation of mixed calcium-oxalate kidney stones in hyperuricosuria, when diet, increased fluid intake, and similar measures have been ineffective.
Contraindication
Hypersensitivity to allopurinol or to any of the components of the drug.
Interaction with other medicinal products and other types of interactions
6-mercaptopurine and azathioprine. Azathioprine is metabolized to 6-mercaptopurine, which is inactivated by xanthine oxidase. When 6-mercaptopurine or azathioprine are used concomitantly with allopurinol, it is advisable to reduce the doses of the latter to a quarter of the usual dose, since inhibition of xanthine oxidase prolongs their effect.
Vidarabine (adenine arabinoside). Evidence suggests that the plasma half-life of vidarabine is increased in the presence of allopurinol. Additional monitoring for increased toxic effects is warranted when these drugs are used concomitantly.
Salicylates and uricosurics. Oxypurinol, the major metabolite of allopurinol with independent therapeutic activity, is excreted by the kidneys in a similar manner to uric acid salts. Therefore, drugs with uricosuric activity, such as probenecid or high doses of salicylates, may accelerate the excretion of oxypurinol. This may reduce the therapeutic activity of the drug, but this possibility should be evaluated on a case-by-case basis.
Chlorpropamide: Concomitant use of allopurinol with chlorpropamide in patients with impaired renal function increases the risk of prolonged hypoglycemia, since allopurinol and chlorpropamide may compete for elimination at the tubular excretion stage.
Coumarin anticoagulants: There have been isolated reports of increased effects of warfarin and other coumarin anticoagulants when used concomitantly with allopurinol, therefore careful monitoring of all patients receiving anticoagulants is necessary.
Phenytoin: Allopurinol may inhibit the hepatic oxidation of phenytoin, but the clinical significance of this interaction has not been proven.
Theophylline. Inhibition of theophylline metabolism has been reported. The mechanism of interaction may be due to the involvement of xanthine oxidase in the biotransformation of theophylline in the body. Plasma theophylline levels should be monitored when initiating allopurinol therapy or when the dose is increased.
Ampicillin/amoxicillin: A higher incidence of allergic skin reactions has been reported in patients receiving allopurinol concomitantly with ampicillin or amoxicillin compared to patients not receiving these drugs concomitantly. The reason for this interaction has not been determined. However, patients receiving allopurinol are advised to use other antibacterial agents.
Cytostatics: When allopurinol is used in combination with cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), blood dyscrasias have been observed more frequently than when these substances are used alone, therefore blood parameters should be regularly monitored in such patients.
Cyclosporine: When used simultaneously with allopurinol, an increase in the plasma concentration of cyclosporine is possible. The possibility of increased toxicity of cyclosporine should also be taken into account.
Didanosine. In healthy volunteers and HIV patients receiving didanosine concomitantly with allopurinol (300 mg daily), plasma Cmax and AUC values doubled without affecting the terminal half-life. Coadministration of these 2 drugs is generally not recommended. If concomitant use is necessary, a reduction in the didanosine dose may be necessary and patients should be closely monitored.
Diuretics: The interaction between allopurinol and furosemide leads to an increase in serum urate concentrations and plasma oxypurinol concentrations.
An increased risk of hypersensitivity has been reported when allopurinol is used with diuretics, particularly thiazides, especially in the presence of impaired renal function.
ACE inhibitors: An increased risk of hypersensitivity reactions has been reported when allopurinol is used with ACE inhibitors, especially in the presence of impaired renal function.
Aluminum hydroxide. The effect of allopurinol may be weakened when used simultaneously with aluminum hydroxide. An interval of at least 3 hours should be observed between taking these drugs.
Hypersensitivity syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions can manifest in a variety of ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis. These reactions are clinically significant and should inform treatment decisions. If such reactions occur during treatment, allopurinol should be discontinued immediately. Patients with hypersensitivity syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis should not be re-administered. Corticosteroids may be considered to manage skin reactions.
HLA-B *5801 allele. The presence of the HLA-B *5801 allele is associated with the risk of allopurinol hypersensitivity syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis. The frequency of this genetic marker varies considerably between ethnic groups (20% of Chinese, Han Chinese, 8-15% of Thais, 12% of Koreans, 1-2% of Japanese and Caucasians). Subgroups of patients likely to carry the HLA-B *5801 allele should be screened for before starting treatment with allopurinol. Chronic renal failure may also further increase the risk. If genotyping for HLA-B *5801 is not available for Han Chinese, Thai or Korean patients, the potential risks should be weighed against the expected benefits before starting treatment. If a patient is found to have the HLA-B *5801 allele, (especially those of Han Chinese, Thai or Korean origin), treatment with allopurinol is possible only if there are no other treatment options and the expected benefits outweigh the risks. Additional monitoring of patients is necessary for the development of signs of hypersensitivity syndrome, Stevens-Johnson syndrome or toxic epidermal necrolysis. The patient should be informed of the need to discontinue treatment at the first signs of hypersensitivity.
Stevens-Johnson syndrome and toxic epidermal necrolysis can occur even in patients who do not have the HLA-B *5801 allele, regardless of ethnic origin.
Chronic renal impairment. Patients with chronic renal impairment and concomitant use of diuretics, particularly thiazides, may be at increased risk of developing hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with allopurinol. Patients should be monitored closely for signs of hypersensitivity syndrome or Stevens-Johnson syndrome, and the patient should be informed of the need to discontinue treatment immediately and permanently at the first appearance of symptoms (see section 4.3).
Impaired hepatic or renal function. Patients with impaired hepatic or renal function should receive reduced doses of the drug (see section "Method of administration and dosage"). Patients taking drugs for the treatment of hypertension or heart failure, such as diuretics or ACE inhibitors, may have concomitant impaired renal function, and allopurinol should be used with caution in these patients.
Asymptomatic hyperuricemia. Asymptomatic hyperuricemia alone is not considered an indication for allopurinol. Increased fluid intake and dietary changes, combined with treatment of the underlying cause, may correct the condition.
Acute gouty attacks. In the presence of acute gouty attacks, treatment with allopurinol should not be started until they have completely resolved, as this may cause repeated attacks.
At the beginning of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may occur. Therefore, prophylaxis with an appropriate anti-inflammatory agent or colchicine for at least 1 month is advisable. Details of the appropriate dosages, precautions and warnings for their use should be consulted in the available literature.
If acute attacks develop in patients on allopurinol therapy, treatment should be continued at the same dosage, and the acute attack should be treated with an appropriate anti-inflammatory agent.
Xanthine deposition. In cases where the rate of urate formation is significantly increased (e.g., in the presence of malignant neoplasms and their treatment, Lesch-Nyhan syndrome), the absolute concentration of xanthine in the urine may, in rare cases, rise to levels sufficient for deposition in the urinary tract. This risk can be minimized by adequate hydration to achieve optimal urine dilution.
Effect on uric acid kidney stones. Adequate therapy with allopurinol leads to the dissolution of large uric acid kidney stones, which can subsequently lead to ureteral obstruction.
Thyroid disorders: During long-term treatment with allopurinol, 5.8% of patients experienced an increase in thyroid-stimulating hormone (TSH) values (> 5.5 μIU/ml). Caution is advised when using allopurinol in patients with thyroid disorders.
This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Pregnancy: There is insufficient evidence of the safety of allopurinol during pregnancy, although there is experience of its use for many years without apparent adverse effects.
Allopurinol should only be used during pregnancy when there is no safer alternative and when the disease itself poses risks to the mother or fetus.
Breastfeeding. Allopurinol and its metabolite oxypurinol are excreted in human milk. There is evidence that concentrations of 1.4 mg/l allopurinol and 53.7 mg/l oxypurinol were detected in the breast milk of a woman taking 300 mg of allopurinol per day. However, there is no data on the effects of allopurinol or its metabolites on the breastfed infant. Allopurinol is not recommended during breastfeeding.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Since patients receiving allopurinol may experience adverse reactions such as drowsiness, vertigo and ataxia, patients should be cautious when driving or operating machinery until it is known that allopurinol does not cause these adverse reactions.
Method of administration and doses
Doses.
Adults. The drug should be taken in small doses, for example 100 mg/day, in order to reduce the risk of adverse reactions, and the dose should be increased only if the serum urate concentration is unsatisfactory. Particular caution should be exercised in renal failure (see section "Method of administration and dosage. Renal failure").
The following dosage regimens are recommended:
When calculating the dose of the drug based on the patient's body weight, use doses of 2–10 mg/kg of body weight per day.
Children. Children under 15 years of age: 10 to 20 mg/kg body weight per day. Maximum daily dose is 400 mg. Allopurinol is rarely used in pediatric practice. Exceptions are malignant diseases (especially leukemia) and some enzymopathies (e.g., Lesch-Nyhan syndrome).
Elderly patients. In the absence of specific data, the lowest dosage that provides a satisfactory reduction in urate levels should be used. The possibility of decreased renal function should be taken into account (see sections “Method of administration and dosage. Renal insufficiency” and “Special precautions for use”).
Kidney failure.
Since allopurinol and its metabolites are excreted by the kidneys, impaired renal function may lead to accumulation of the drug and/or its metabolites with a prolonged plasma half-life. In severe renal impairment, it may be appropriate to use less than 100 mg per day or to administer single doses of 100 mg at intervals longer than one day. If monitoring of plasma oxypurinol concentrations is possible, the dose should be adjusted to maintain plasma oxypurinol concentrations below 100 μmol/liter (15.2 mg/L). Allopurinol and its metabolites are removed by hemodialysis. If dialysis is required 2–3 times per week, an alternative dosing regimen of 300–400 mg allopurinol should be considered immediately after each dialysis session without any intervening period.
Hepatic impairment: Lower doses should be administered to patients with impaired liver function. Periodic monitoring of liver function tests is recommended at the beginning of treatment.
Treatment of conditions with high urate metabolism, such as neoplasia, Lesch-Nyhan syndrome. It is advisable to correct existing hyperuricemia and/or hyperuricosuria with allopurinol before starting cytotoxic therapy. It is important to ensure proper hydration to maintain optimal diuresis, as well as to alkalinize the urine to increase the solubility of uric acid and its salts. The dosage of allopurinol should be at the lower end of the recommended dosage.
If urate nephropathy or other renal dysfunction is diagnosed, the recommendations given in the section "Method of administration and dosage. Renal failure" should be followed.
These measures may reduce the risk of xanthine and/or oxypurinol accumulation, which complicates the clinical situation (see also sections “Interaction with other medicinal products and other types of interactions” and “Adverse reactions”).
Monitoring advice: Doses should be adjusted by monitoring serum urate concentrations and urinary uric acid and its salts at appropriate intervals.
Method of administration. The drug is taken orally once a day after meals. It is well tolerated, especially when taken after meals. If the daily dose exceeds 300 mg and symptoms of gastrointestinal intolerance occur, it may be advisable to divide the doses.
Children. Children under 15 years of age. Allopurinol is rarely used in pediatric practice. Exceptions are malignant diseases (especially leukemia) and some enzymopathies (e.g., Lesch-Nyhan syndrome).
Oral administration of up to 22.5 g of allopurinol has been reported without adverse effects in one patient. In another patient, nausea, vomiting, diarrhea, and dizziness were observed after oral administration of 20 g of allopurinol. General supportive measures were used to facilitate recovery. Absorption of large doses of allopurinol may result in significant inhibition of xanthine oxidase, which does not cause undesirable effects, except when used concomitantly with other drugs, especially 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimal diuresis helps to eliminate allopurinol and its metabolites. Hemodialysis may be performed if necessary.
Side effects
There are no current clinical data for the drug that can be used to determine the frequency of adverse effects. The frequency of adverse effects may vary depending on the dose and when administered simultaneously with other drugs.
The estimated frequency categories of adverse reactions are given: for most reactions, suitable data for calculating incidence are not available. Adverse reactions identified through post-marketing surveillance are considered rare or very rare. The frequency of adverse reactions was estimated as follows:
Very often | ≥1/10 |
Often | ≥1/100 to <1/10 |
Infrequently | ≥1/1000 to <1/100 |
Rarely | ≥1/10,000 to <1/1000 |
Very rare | <1/10,000 |
Unknown | cannot be estimated from available data |
Adverse reactions associated with allopurinol are rare and minor in most populations. Their incidence is higher in the presence of renal and/or hepatic pathology.
Organ classes and systems | Frequency | Adverse reaction |
Infections and infestations | Very rare | Furunculosis |
Blood and lymphatic system disorders | Very rare | Agranulocytosis1 Aplastic anemia1 Thrombocytopenia1 |
On the part of the immune system | Infrequently | Hypersensitivity2 |
Very rare | Angioimmunoblastic T-cell lymphoma3 Anaphylactic shock |
Metabolism and nutrition | Very rare | Diabetes mellitus Hyperlipidemia |
From the psyche | Very rare | Depression |
From the nervous system | Very rare | Coma Paralysis Ataxia Peripheral neuropathy Paresthesia Drowsiness Dysgeusia Headache |
Unknown | Aseptic meningitis |
From the organs of vision | Very rare | Cataract Vision impairment Maculopathy |
From the side of the organs of hearing and labyrinth | Very rare | Vertigo |
From the heart | Very rare | Angina pectoris Bradycardia |
From the vascular side | Very rare | Hypertension |
Gastrointestinal tract | Infrequently | Vomiting4 Nausea4 Diarrhea |
Very rare | Hematemesis Steatorrhea Stomatitis Bowel dysfunction |
Liver | Infrequently | Pathological change in liver function tests5 |
Rarely | Hepatitis (including hepatic necrosis and granulomatous hepatitis) |
Skin and subcutaneous tissue disorders | Often | Rash |
Rarely | Stevens-Johnson syndrome6 Toxic epidermal necrolysis6 |
Very rare | Angioedema7 Drug-induced dermatitis Alopecia Hair bleaching |
From the urinary system | Very rare | Hematuria Azotemia |
Reproductive system and breast disorders | Very rare | Male infertility Erectile dysfunction Gynecomastia |
General disorders and administration site conditions | Very rare | Swelling Malaise Asthenia Pyrexia 8 |
Laboratory studies | Often | Increased TSH levels in the blood9 |
1 There have been very rare reports of thrombocytopenia, agranulocytosis and aplastic anemia, especially in individuals with renal and/or hepatic impairment, which requires close monitoring of such patients.
Allopurinol should not be re-administered if hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, occur. Corticosteroids may be used to manage cutaneous hypersensitivity reactions. Renal and/or hepatic involvement is usually present in generalised hypersensitivity reactions, particularly in fatal cases.
3 Angioimmunoblastic T-cell lymphoma has been reported very rarely following biopsy of generalized lymphadenopathy. This condition was reversible upon discontinuation of allopurinol.
4 Nausea and vomiting were reported in early clinical trials. This problem can be avoided by taking allopurinol after meals.
5 Liver dysfunction has been reported without the occurrence of a generalized hypersensitivity reaction.
6 Cutaneous reactions are the most common and may occur at any time during treatment. These reactions may present as pruritus, maculopapular rash, occasionally as exfoliative, purpuric rash, and rarely as exfoliative rashes (such as Stevens-Johnson syndrome and toxic epidermal necrolysis). The greatest risk of Stevens-Johnson syndrome and toxic epidermal necrolysis or other serious hypersensitivity reactions occurs during the first weeks of treatment. Early diagnosis and immediate discontinuation of any suspected drug provide the best outcome in managing such reactions. Allopurinol should be discontinued immediately if such reactions occur. After recovery from mild reactions, allopurinol may be re-initiated at a low dose (e.g. 50 mg/day) with gradual titration if necessary. The presence of the HLA-B *5801 allele has been shown to be associated with a risk of developing hypersensitivity reactions and the development of Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the use of genotyping as a screening tool for deciding on allopurinol treatment has not been proven. If rashes recur during treatment with allopurinol, the drug should be discontinued immediately, as more serious hypersensitivity may develop (see section "Adverse reactions. Immune system disorders"). If the development of Stevens-Johnson syndrome and toxic epidermal necrolysis or other serious hypersensitivity reactions cannot be excluded, allopurinol should not be re-administered, as this may lead to serious or even fatal consequences. The clinical diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis is the basis for decisions on further treatment with allopurinol. If such reactions occur at any time during treatment, allopurinol should be immediately and permanently discontinued.
7 Angioedema with or without signs and symptoms of a generalised hypersensitivity reaction has been reported.
8 Fever with or without signs and symptoms of a generalized hypersensitivity reaction has been reported.
9 The detection of elevated TSH levels in relevant studies does not indicate any effect on free T4 levels, or this TSH level indicates subclinical hypothyroidism.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
Tablets of 100 mg No. 50 (10×5) in a blister in a box or 300 mg No. 10 (10×1), No. 50 (10×5) in a blister in a box.
Vacation category
According to the recipe.
Producer
Limited Liability Company "Pharmaceutical Company "Zdorovya".
Location of the manufacturer and address of the place of its activity. Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, building 22.
