Milurit®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİLURIT® (MILURIT®)

Composition:

Active substance: allopurinol;

1 tablet contains allopurinol 150 mg or 200 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), gelatin, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

150 mg tablets: oval, white or greyish-white tablets with bevel and a line on one side and engraved stylized letter E and number 353 on the other side, odorless or nearly odorless;

200 mg tablets: oval, white or greyish-white tablets with bevel and the line "SNAP" on one side and engraved stylized letter E and number 354 on the other side, odorless or nearly odorless.

Tablets can be divided into equal doses.

Pharmacotherapeutic group.

Uric acid production inhibitors. ATC code M04A A01.

Pharmacological Properties

Pharmacodynamics

Allopurinol is a xanthine oxidase inhibitor. Allopurinol and its main metabolite, oxypurinol, interfere with the synthesis of uric acid and possess uricostatic properties primarily due to their ability to inhibit the enzyme xanthine oxidase, which catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, resulting in decreased uric acid concentration and promoting the dissolution of urates.

Pharmacokinetics

Allopurinol is rapidly absorbed in the upper gastrointestinal tract. After oral administration, allopurinol appears in blood plasma within 30–60 minutes. The bioavailability of the drug ranges from 67% to 90%.

Peak plasma concentrations of allopurinol and its metabolite oxypurinol are reached approximately 1.5 hours and 3–5 hours after administration, respectively. Allopurinol is minimally bound to plasma proteins. Its volume of distribution is approximately 1.3 L/kg.

Allopurinol is rapidly oxidized (plasma half-life is 1–2 hours) by xanthine oxidase and aldehyde oxidase to oxypurinol, which is also a potent xanthine oxidase inhibitor. However, the half-life of the metabolite ranges from 13 to 30 hours. Due to the prolonged half-life of oxypurinol, gradual accumulation may occur at the beginning of therapy until a steady-state plasma concentration is achieved. In patients with normal renal function, the average plasma concentration of oxypurinol typically reaches 5–10 mg/L after a single 300 mg dose of allopurinol.

Allopurinol is primarily excreted by the kidneys, with less than 10% excreted unchanged. Approximately 20% of allopurinol is excreted in feces. Oxypurinol is excreted unchanged in urine following tubular reabsorption.

Impaired renal function leads to prolonged half-life of oxypurinol; therefore, dosage recommendations must be followed in patients with renal insufficiency.

Clinical Characteristics.

Indications.

Adults:

• all forms of hyperuricemia not controlled by diet, including secondary hyperuricemia of various origins, and clinical complications of hyperuricemia, particularly gout, as well as dissolution and prevention of formation of uric acid crystals (kidney stones);
• treatment of recurrent, mixed calcium oxalate crystals associated with hyperuricemia, when fluid intake, dietary measures, and similar interventions are ineffective.

Children and adolescents:

• secondary hyperuricemia of various origins;
• urate nephropathy arising during leukemia treatment;
• congenital enzymatic deficiencies, particularly Lesch-Nyhan syndrome (partial or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase) and adenine phosphoribosyltransferase deficiency.

Contraindications.

Hypersensitivity to allopurinol or to any component of the drug. Severe impairment of renal function (creatinine clearance less than 2 ml/min) or hepatic function. Tablets of 300 mg should not be used when creatinine clearance is less than 20 ml/min.

Interaction with other medicinal products and other forms of interactions.

6-Mercaptopurine and azathioprine. When allopurinol is used concomitantly with 6-mercaptopurine or azathioprine, the doses of the latter should be reduced to 25% of the usual dose, as their metabolism is slowed due to inhibition of xanthine oxidase, resulting in prolonged effect.

Vidarabine (adenine arabinoside). When allopurinol is used concomitantly with vidarabine, the plasma half-life of the latter is prolonged; therefore, this combination should be used with caution to avoid potential enhancement of toxic effects.

Salicylates and uricosuric agents. The efficacy of allopurinol may be reduced when used concomitantly with drugs capable of promoting uric acid excretion (sulfinpyrazone, probenecid, benzbromarone, or salicylates).

Allopurinol slows the elimination of probenecid.

Chlorpropamide. In patients with impaired renal function, particularly when used concomitantly with allopurinol, the hypoglycemic effect of chlorpropamide may be prolonged, necessitating dose reduction.

Anticoagulants (coumarin derivatives). The effect of warfarin and other coumarin-derived anticoagulants may be enhanced; therefore, more frequent monitoring of blood coagulation and possible dose reduction of anticoagulants are required.

Phenytoin. Allopurinol may inhibit hepatic metabolism of phenytoin, although the clinical significance of this interaction has not been established.

Theophylline, caffeine. At high doses, allopurinol inhibits the metabolism and increases plasma concentrations of theophylline and caffeine. Plasma theophylline levels should be monitored at the beginning of allopurinol therapy or when its dose is increased.

Ampicillin/amoxicillin. When allopurinol is used concomitantly with ampicillin or amoxicillin, there is an increased likelihood of skin allergic reactions (exanthema); therefore, alternative antibiotics should be used in patients receiving allopurinol.

Cytostatic agents. When allopurinol is used with cytostatics (cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamine), enhanced suppression of bone marrow function has been observed; therefore, blood counts should be monitored at short intervals in such patients.

Cyclosporine. When used with allopurinol, cyclosporine plasma concentrations may increase, leading to increased toxicity.

Didanosine. In healthy volunteers and HIV patients receiving didanosine concomitantly with allopurinol (300 mg daily), Cmax and AUC in plasma doubled, without affecting terminal half-life. Concomitant use of these two drugs is generally not recommended. If co-administration is necessary, dose reduction of didanosine may be required, and careful patient monitoring is essential.

Captopril. Concomitant use of allopurinol and captopril may increase the risk of skin reactions, particularly in patients with chronic kidney disease.

Diuretics. Concomitant use of allopurinol and furosemide may increase plasma concentrations of urates and oxipurinol. An increased risk of hypersensitivity reactions has been reported with concomitant use of allopurinol and diuretics, particularly thiazides, especially in patients with impaired renal function.

ACE inhibitors. An increased risk of hypersensitivity reactions has been observed with concomitant use of allopurinol and ACE inhibitors, particularly in patients with impaired renal function.

Aluminum hydroxide. The effect of allopurinol may be reduced when used concomitantly with aluminum hydroxide. An interval of at least 3 hours should be maintained between administration of the two drugs.

Special precautions for use.

If hypersensitivity reactions occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and maculopapular exanthema, allopurinol should be discontinued immediately and must not be reintroduced.

The presence of the HLA-B*5801 allele (a genetic marker) in patients treated with allopurinol is associated with an increased risk of developing hypersensitivity reactions. The frequency of this genetic marker varies significantly among different ethnic groups (it is present in 20% of Han Chinese, 8–15% of Thais, 12% of Koreans, and 1–2% of Japanese and Caucasian populations). If a patient is known to carry the HLA-B*5801 allele, allopurinol should be considered for use only if the anticipated benefit outweighs the potential risks.

Such patients must be informed about the necessity to discontinue treatment immediately upon the first signs of a hypersensitivity syndrome.

Allopurinol is not recommended for use when plasma uric acid levels are below 535 µmol/L (9 mg/100 mL), provided dietary recommendations are followed and there is no kidney involvement. Avoid consumption of high-purine foods (e.g., organ meats such as kidneys, brain, liver, heart, and tongue; meat extracts, and alcohol, especially beer).

If hypersensitivity reactions (e.g., rashes) occur, allopurinol should be discontinued immediately.

Particular medical supervision is required in patients with impaired renal or hepatic function or pre-existing hematopoietic disorders. Dose recommendations appropriate for patients with impaired kidney or liver function must be observed. Allopurinol should be used with special caution in patients with arterial hypertension or heart failure who are receiving ACE inhibitors or diuretics.

During treatment of gout and uric acid nephrolithiasis, daily urine output should be at least 2 liters.

To prevent increases in serum or urinary uric acid concentration that may occur during radiotherapy or chemotherapy of tumors, as well as in Lesch-Nyhan syndrome, in addition to allopurinol, patients should drink large amounts of fluids to maintain adequate diuresis. Furthermore, urine alkalinization may be performed to enhance the solubility and excretion of urates/uric acid.

If urate nephropathy or other pathological changes have already impaired renal function, the dose should be adjusted according to renal function parameters.

Allopurinol treatment should not be initiated during acute gout attacks until the attacks have completely subsided. Acute gout attacks may be exacerbated at the beginning of allopurinol therapy due to mobilization of large amounts of uric acid. Therefore, concomitant use of analgesics or colchicine is recommended during the first 4 weeks of treatment.

In patients with large uric acid kidney stones, it cannot be excluded that during allopurinol treatment some stones may dissolve and pass into the bladder, potentially causing ureteral obstruction.

Thyroid dysfunction, specifically elevated thyroid-stimulating hormone (TSH) levels (>5.5 µIU/mL), has been observed during long-term allopurinol therapy in 5.8% of patients. Caution is advised when administering allopurinol to patients with pre-existing thyroid dysfunction.

Use during pregnancy or breastfeeding.

There are insufficient data on the use of allopurinol during pregnancy. Since allopurinol affects purine metabolism and the potential risk to the human fetus is unknown, allopurinol is not recommended during pregnancy.

Allopurinol passes into breast milk; therefore, the drug should not be used during breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

Until individual response to allopurinol is established, caution is advised when driving or operating machinery due to the potential occurrence of dizziness, somnolence, and ataxia.

Dosage and Administration

Dosage

Adults. The medicinal product should be initiated at low doses, for example 100 mg/day, in order to minimize the risk of adverse reactions, and the dose should be increased only if serum urate concentrations remain unsatisfactory. Particular caution should be exercised in patients with renal impairment (see section "Dosage and Administration. Renal Impairment"). The following dosage regimens are recommended:

• In mild conditions: 100–200 mg per day;
• In moderate conditions: 300–600 mg per day;
• In severe conditions: 700–900 mg per day.

When calculating the dose based on body weight, administer 2–10 mg/kg body weight per day.

Children. Children under 15 years of age: 10–20 mg/kg body weight per day. Maximum daily dose: 400 mg. Allopurinol is rarely used in pediatric practice. Exceptions include malignant diseases (especially leukemia) and certain enzyme disorders (e.g., Lesch-Nyhan syndrome).

Elderly Patients. Due to the lack of specific data, the lowest effective dose that achieves adequate urate reduction should be used. Possible reduction in renal function should be taken into account (see sections "Dosage and Administration. Renal Impairment" and "Special Warnings and Precautions for Use").

Renal Impairment.

Since allopurinol and its metabolites are excreted by the kidneys, renal dysfunction may lead to accumulation of the drug and/or its metabolites, with prolonged plasma half-life. In severe renal impairment, it may be appropriate to administer less than 100 mg per day or to use single doses of 100 mg at intervals longer than 24 hours. If monitoring of plasma oxypurinol concentration is possible, the dose should be adjusted to maintain plasma oxypurinol levels below 100 µmol/L (15.2 mg/L). Allopurinol and its metabolites are removed by hemodialysis. In patients requiring dialysis 2–3 times per week, an alternative dosing regimen should be considered: 300–400 mg of allopurinol immediately after each dialysis session, without any intervening doses.

Hepatic Impairment. Lower doses should be prescribed to patients with impaired liver function. Periodic monitoring of liver function tests is recommended at the beginning of treatment.

Treatment under conditions of high urate turnover, e.g., neoplasia, Lesch-Nyhan syndrome. It is advisable to correct pre-existing hyperuricemia and/or hyperuricosuria with allopurinol prior to initiating cytotoxic therapy. Adequate hydration should be ensured to maintain optimal diuresis, and urine should be alkalinized to enhance the solubility of uric acid and its salts. Allopurinol dosage should be at the lower end of the recommended range.

If urate nephropathy or other renal dysfunction is present, recommendations provided in the section "Dosage and Administration. Renal Impairment" should be followed.

These measures may reduce the risk of xanthine and/or oxypurinol accumulation, which may complicate the clinical picture (see also sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Adverse Reactions").

Monitoring Recommendations. Doses should be adjusted based on periodic monitoring of serum urate concentrations and urinary uric acid and its salt levels at appropriate intervals.

Administration

The medicinal product is taken orally once daily after food. It is well tolerated, especially when taken after meals. If the daily dose exceeds 300 mg and gastrointestinal intolerance symptoms occur, dose splitting may be considered.

Children. Children under 15 years of age. Allopurinol is rarely used in pediatric practice. Exceptions include malignant diseases (especially leukemia) and certain enzyme disorders (e.g., Lesch-Nyhan syndrome).

Overdose.

Symptoms. After a single dose of 20 g, one patient experienced nausea, vomiting, diarrhea, and dizziness; another patient showed no adverse effects after ingesting 22.5 g of allopurinol. With prolonged use of 200–400 mg allopurinol per day in patients with impaired renal function, severe intoxication symptoms have been reported (skin reactions, fever, hepatitis, eosinophilia, and exacerbation of renal failure). In cases of allopurinol overdose, xanthine oxidase activity is significantly inhibited; however, clinically significant adverse effects occur primarily when allopurinol is co-administered with 6-mercaptopurine or azathioprine.

In suspected overdose, especially with concomitant intake of 6-mercaptopurine or azathioprine, gastric lavage, induction of emesis, or administration of activated charcoal and sodium phosphate may be considered if less than 1 hour has passed since drug ingestion.

Treatment. Treatment is symptomatic. Hemodialysis may be necessary if indicated. No specific antidote is known.

Adverse reactions.

There are no current clinical data available for the product that can be used to determine the frequency of adverse effects. The frequency of adverse effects may vary depending on the dose, as well as when administered concomitantly with other medicinal products.

The following estimated frequency categories for adverse reactions are provided: for most reactions, appropriate data for calculating incidence are lacking. Adverse reactions identified through post-marketing surveillance are considered rare or very rare. The frequency of adverse reactions was assessed as follows:

Adverse reactions associated with allopurinol are rare and insignificant in most of the population. Their incidence is higher in the presence of renal and/or hepatic pathology.

1 Very rare cases of thrombocytopenia, agranulocytosis, and aplastic anemia have been reported, particularly in patients with impaired renal and/or hepatic function, requiring special attention to such patients.

2 Delayed-type hypersensitivity reactions (DRESS syndrome) with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilic hepatomegaly, liver function disorders, including destruction and disappearance of intrahepatic bile ducts, may occur in various combinations. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, and colon). If such reactions occur, allopurinol should be discontinued immediately and must not be prescribed again. Allopurinol must not be re-administered in case of hypersensitivity reactions, including SJS/TEN. Corticosteroids may be used to manage hypersensitivity skin reactions. Generalized hypersensitivity reactions are usually associated with renal and/or hepatic disorders, especially in fatal cases.

3 Very rare cases of angioimmunoblastic T-cell lymphoma have been reported following biopsy of generalized lymphadenopathy. This condition has been shown to be reversible upon discontinuation of allopurinol.

4 Nausea and vomiting were reported in early clinical trials during allopurinol treatment. This problem can be avoided by taking allopurinol after meals.

5 Cases of liver dysfunction without occurrence of generalized hypersensitivity reactions have been reported.

6 Skin reactions are the most common and may occur at any time during treatment. These reactions may present as purpuric, maculopapular, squamous, or exfoliative rash (SJS/TEN). The highest risk of developing SJS/TEN or other serious hypersensitivity reactions occurs during the first weeks of treatment. Early diagnosis and immediate discontinuation of any suspected drug can prevent more serious consequences. If such reactions occur, allopurinol should be discontinued immediately. After recovery, if restarting allopurinol treatment, it is recommended to begin with a low dose (e.g., 50 mg/day) and gradually increase it. The HLA-B*5801 allele has been associated with an increased risk of hypersensitivity reactions and SJS/TEN during allopurinol treatment. However, the use of genotyping as a screening tool for decisions on allopurinol therapy has not been established. If rash recurs during allopurinol treatment, the drug should be discontinued immediately, as more severe hypersensitivity may develop. Allopurinol should not be re-administered if SJS/TEN or other serious hypersensitivity reactions cannot be ruled out, as this may lead to severe or even fatal reactions. Clinical diagnosis of SJS/TEN remains the primary basis for decision-making. If such reactions occur during treatment, allopurinol should be discontinued immediately.

7 Cases of angioneurotic edema with or without signs and symptoms of generalized hypersensitivity reactions have been reported.

8 Cases of fever with or without signs and symptoms of generalized hypersensitivity reactions have been reported.

9 Elevated TSH levels detected in appropriate tests do not necessarily indicate any effect on free T4 levels, or such TSH levels may indicate subclinical hypothyroidism.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

30, 50, 60, 70, 80, 90, 100, or 120 tablets in a brown glass bottle closed with a polyethylene plastic cap with tamper-evident function;

1 bottle per cardboard box and 10 tablets in a blister; 3, 4, 5, 6, 7, 8, 9, 10, or 12 blisters in cardboard packaging with the instruction for medical use.

Prescription category. Prescription only.

Manufacturer.

EGIS Pharmaceuticals Ltd., Hungary.

Manufacturer's location and address of business activity.

65 Matyas Kiraly str., 9900 Kermend, Hungary.

118-120 Bekenyfoldi str., 1165 Budapest, Hungary.