Allopurinol sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALOPURINOL SANDOZ® (ALLOPURINOL SANDOZ®)

Composition:

Active substance: allopurinol;

1 tablet contains allopurinol 100 mg or 300 mg;

Excipients: microcrystalline cellulose, povidone, macrogol 4000, crospovidone, talc, magnesium stearate, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

100 mg tablets – white, round, biconvex tablets with a score line on one side;

300 mg tablets – white or almost white, oblong, biconvex tablets with score lines on both sides and intact surface.

Pharmacotherapeutic group.

Uric acid synthesis inhibitors. ATC code M04A A01.

Pharmacological Properties

Pharmacodynamics

Allopurinol and its primary metabolite, oxypurinol, interfere with the synthesis of uric acid and possess uricostatic properties, primarily based on their ability to inhibit the enzyme xanthine oxidase, which catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. This leads to a reduction in uric acid concentration and promotes the dissolution of urates.

Pharmacokinetics

Allopurinol is rapidly absorbed in the upper gastrointestinal tract. After oral administration, allopurinol is detectable 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 inhibitor of xanthine oxidase. 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% of the drug 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.

Treatment of diseases caused by elevated levels of uric acid in the blood and formation of urate/oxalate stones (e.g., gout, acute urate nephropathy, and urate urolithiasis), as well as treatment of malignant tumors that potentially lead to exacerbation of all forms of hyperuricemia, particularly in various hemoblastoses (acute leukemia, chronic myeloid leukemia, lymphosarcoma), and urate nephropathy arising as a result of leukemia treatment.

Congenital enzyme deficiency, particularly Lesch-Nyhan syndrome (partial or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase) or adenine phosphoribosyltransferase deficiency.

Treatment of diseases caused by reduced activity of adenine phosphoribosyltransferase and formation of 2,8-dihydroxyadenine kidney stones.

Treatment of diseases caused by formation of mixed calcium-oxalate kidney stones associated with hyperuricosuria that is uncontrolled by diet.

Contraindications.

Hypersensitivity to allopurinol or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

6-Mercaptopurine and azathioprine. Azathioprine is metabolized to 6-mercaptopurine, which is inactivated by xanthine oxidase. When 6-mercaptopurine or azathioprine is administered concomitantly with allopurinol, an inhibitor of xanthine oxidase, the inhibition of xanthine oxidase prolongs their activity. Serum concentrations of 6-mercaptopurine or azathioprine may reach toxic levels, leading to life-threatening pancytopenia and myelosuppression when these drugs are used concomitantly with allopurinol. Therefore, concomitant use of allopurinol with 6-mercaptopurine or azathioprine should be avoided. If concomitant use with 6-mercaptopurine or azathioprine is considered clinically necessary, the dose should be reduced to one-quarter (25%) of the usual dose of 6-mercaptopurine or azathioprine, and frequent hematological monitoring should be ensured (see section "Special precautions for use").

Patients should be advised to report any signs or symptoms of bone marrow suppression (unexplained bruising or bleeding, sore throat, fever).

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).

Oxipurinol, the main metabolite of allopurinol with independent therapeutic activity, is excreted by the kidneys in a manner similar to uric acid salts. Therefore, drugs promoting uric acid excretion, such as probenecid or salicylates, in high doses may accelerate oxipurinol excretion. This may result in reduced therapeutic efficacy of allopurinol, although the clinical significance of this factor requires evaluation in each individual case.

Allopurinol slows the excretion of probenecid.

Chlorpropamide. In renal impairment, 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 potentiated; therefore, more frequent monitoring of blood coagulation and possible anticoagulant dose reduction are required.

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

Theophylline, caffeine. In 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.

Amoxicillin/ampicillin. When allopurinol is used concomitantly with ampicillin or amoxicillin, there is an increased risk of skin allergic reactions (exanthema); therefore, patients taking allopurinol should be prescribed alternative antibiotics.

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

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

Didanosine. Concomitant use with allopurinol is not recommended, as nearly a twofold increase in Cmax and AUC values for didanosine has been observed.

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 when allopurinol is used with diuretics, particularly thiazides, especially in patients with impaired renal function.

Angiotensin-converting enzyme (ACE) inhibitors.

An increased risk of hypersensitivity reactions has been reported when allopurinol is used concomitantly with 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 medicinal products.

Special precautions for use

If hypersensitivity reactions (DRESS syndrome), including Stevens-Johnson syndrome, toxic epidermal necrolysis, or maculopapular exanthema occur, allopurinol should be discontinued immediately and must not be reintroduced. Corticosteroids may help manage cutaneous hypersensitivity reactions.

The presence of the HLA-B*5801 allele (a genetic marker) in patients receiving 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, in 8–15% of Thais, in 12% of Koreans, and in 1–2% of Japanese and Caucasian populations). Allopurinol therapy should be considered in patients known to carry the HLA-B*5801 allele only if the expected benefit outweighs the potential risks.

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

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 renal involvement. Avoid consuming foods high in purines (e.g., organ meats: 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. Appropriate dose adjustments should be considered for patients with renal or hepatic impairment. 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 urolithiasis, daily urine output should be maintained at no less than 2 liters.

To prevent increased serum or urinary uric acid concentrations, which may occur during radiotherapy or chemotherapy of malignancies, as well as in Lesch-Nyhan syndrome, in addition to allopurinol, a high fluid intake should be maintained to ensure 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 caused 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. At the beginning of allopurinol therapy, acute gout attacks may be exacerbated 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 stones in the renal pelvis, it cannot be excluded that during allopurinol treatment some stones may dissolve and pass into the bladder, potentially causing ureteral obstruction.

During long-term allopurinol therapy, thyroid function disorders (5.8% of patients), particularly elevated thyroid-stimulating hormone (TSH) levels (>5.5 µIU/mL), have been observed. Caution is required when administering allopurinol to patients with pre-existing thyroid dysfunction.

Concomitant use of allopurinol with 6-mercaptopurine or azathioprine should be avoided, as fatal cases have been reported (see section "Interaction with other medicinal products and other forms of interaction").

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 humans 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 speed when 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.

Method of Administration and Dosage.

Adults. Allopurinol should be administered in low doses (100 mg daily) to reduce the risk of adverse reactions. The dose may be increased only if serum urate concentrations are unsatisfactory. Particular caution is required when administering the drug to patients with impaired renal function.

The following dosage regimens are recommended:

• for mild conditions – 100 to 200 mg daily;
• for moderate conditions – 300 to 600 mg daily;
• for severe conditions – 700 to 900 mg daily.

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

Children. For children aged 15 years and older, the daily dose of allopurinol is 10–20 mg/kg body weight. The maximum daily dose is 400 mg. Allopurinol is rarely prescribed to children, except in malignant conditions (particularly leukemias) and certain enzymatic disorders such as Lesch-Nyhan syndrome.

Elderly Patients. Due to the lack of specific data on allopurinol use in this patient group, the lowest therapeutically justified doses are recommended. Possible impairment of renal function in elderly patients should be taken into account.

Patients with Renal Impairment. Since allopurinol and its metabolites are excreted by the kidneys, improper dose adjustment may lead to overdosage in patients with impaired renal function.

In severe renal impairment, the maximum daily dose is 100 mg. A single dose of 100 mg may be administered at intervals longer than 24 hours (every 2–3 days).

If dose escalation is necessary, serum oxipurinol levels should be monitored and should not exceed 15.2 µg/mL.

During hemodialysis, administer 300–400 mg of allopurinol after each dialysis session (2–3 times per week).

Monitoring of serum urate concentrations and urinary uric acid levels at specified intervals is necessary for appropriate dose adjustment of allopurinol.

Patients with 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.

The 300 mg tablets should not be prescribed to these patients due to the high content of active substance.

The tablets should be taken after food, without chewing, with a large amount of liquid.

The duration of treatment depends on the course of the underlying disease. To prevent the formation of oxalate and urate stones, and in cases of primary hyperuricemia and gout, long-term therapy is required in most cases. In secondary hyperuricemia, short-term treatment is recommended, according to the duration of elevated uric acid levels.

Children.

To be used in children aged 15 years and older.

Allopurinol is rarely prescribed to children, except in malignant conditions (particularly leukemias) and certain enzymatic disorders such as Lesch-Nyhan syndrome.

Overdose.

Symptoms. After a single dose of 20 g, nausea, vomiting, diarrhea, and dizziness were observed in one patient. Another patient who ingested 22.5 g of allopurinol experienced no adverse effects. With prolonged use of 200–400 mg daily in patients with renal impairment, severe intoxication symptoms have been reported (skin reactions, fever, hepatitis, eosinophilia, and worsening of renal failure). Overdose of allopurinol significantly inhibits xanthine oxidase activity; however, clinically significant adverse effects occur only 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. Symptomatic therapy. Hemodialysis may be necessary if indicated. No specific antidote is known.

Adverse Reactions

The assessment of adverse effects is based on information regarding their frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Reactive gout attacks may occur at the beginning of allopurinol therapy.

Adverse reactions are most frequently observed in patients with renal and/or hepatic impairment or when allopurinol is used concomitantly with ampicillin or amoxicillin.

Blood and lymphatic system disorders:
Rare – severe bone marrow damage (thrombocytopenia^1, agranulocytosis^1, aplastic anemia^1), particularly in patients with renal impairment;
Very rare – blood count abnormalities (leukopenia, leukocytosis, granulocytosis, and eosinophilia), pure red cell aplasia.

Immune system disorders:
Rare – delayed-type hypersensitivity reactions^2, characterized by fever, skin rashes, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, and abnormal liver function tests (reversible elevation of transaminases and alkaline phosphatase); acute cholangitis and xanthine stones;
Very rare – anaphylactic reactions, including anaphylactic shock; angioimmunoblastic T-cell lymphoma^3.

Gastrointestinal disorders:
Rare – nausea^4, vomiting^4, diarrhea;
Very rare – hematemesis, steatorrhea, stomatitis, defecation disorders;
Frequency not known (cannot be estimated from available data): diarrhea.

Hepatobiliary disorders:
Rare – liver function abnormalities^5, ranging from asymptomatic elevation of liver function parameters to hepatitis (including liver necrosis and granulomatous hepatitis)^5.

Skin and subcutaneous tissue disorders:
Very rare – skin rashes, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)^6; alopecia, furunculosis, Quincke's edema^7, hair discoloration, dermatitis;
Frequency not known (cannot be estimated from available data): drug-induced lichenoid reaction.

Respiratory, thoracic and mediastinal disorders:
Very rare – angina pectoris.

Nervous system disorders:
Very rare – ataxia, peripheral neuritis, taste disturbances, coma, headache, neuropathy, paralysis, dizziness, somnolence, paresthesia;
Frequency not known (cannot be estimated from available data): aseptic meningitis.

Cardiac disorders:
Very rare – bradycardia, arterial hypertension.

Metabolism and nutrition disorders:
Very rare – diabetes mellitus, hyperlipidemia.

Psychiatric disorders:
Very rare – depression.

Reproductive system and breast disorders:
Very rare – gynecomastia, impotence, infertility.

Renal and urinary disorders:
Very rare – hematuria, uremia, azotemia.

Eye disorders:
Very rare – cataract, retinal degeneration, visual disturbances.

Musculoskeletal and connective tissue disorders:
Very rare – myalgia.

General disorders and administration site conditions:
Very rare – malaise, asthenia, edema, pyrexia^8.

Ear and labyrinth disorders:
Dizziness.

Investigations:
Increased blood TSH levels.

_______________________

^1 Very rare cases of thrombocytopenia, agranulocytosis, and aplastic anemia have been reported, particularly in patients with renal and/or hepatic impairment, requiring careful monitoring of such patients.

^2 Delayed-type hypersensitivity reactions (DRESS syndrome) with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilic hepatomegaly, and liver function abnormalities, 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 re-administered. Re-administration of allopurinol is contraindicated in cases of hypersensitivity reactions, including SJS/TEN. Corticosteroids may be used to manage skin hypersensitivity reactions. Generalized hypersensitivity reactions are usually associated with renal and/or hepatic dysfunction, 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. These adverse effects can be avoided by taking allopurinol after food.

^5 Liver dysfunction has been reported in the absence of generalized hypersensitivity reactions.

^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 SJS/TEN or other serious hypersensitivity reactions occurs during the first weeks of treatment. Early diagnosis and immediate discontinuation of any suspected drug are essential to prevent more severe outcomes. Allopurinol should be discontinued immediately if such reactions occur. If allopurinol is reintroduced after recovery, treatment should be initiated at a low dose (e.g., 50 mg/day) and gradually increased. The HLA-B*5801 allele has been associated with an increased risk of hypersensitivity reactions and SJS/TEN with allopurinol. However, the use of genotyping as a screening tool for allopurinol therapy decisions has not been established. Allopurinol should be discontinued immediately if recurrent rashes occur, as more severe hypersensitivity may develop. Re-administration of allopurinol should be avoided 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 cornerstone for decision-making. Allopurinol must be discontinued immediately if such reactions occur during treatment.

^7 Angioneurotic edema, with or without signs and symptoms of generalized hypersensitivity reaction, has been reported.

^8 Fever, with or without signs and symptoms of generalized hypersensitivity reaction, has been reported.

^9 Elevated TSH levels detected in laboratory tests do not necessarily indicate any effect on free T4 levels; such TSH elevation may indicate subclinical hypothyroidism.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.
Keep out of reach of children.

Packaging.

10 tablets in a blister; 5 blisters (10 × 5) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

SALUTAS Pharma GmbH, Germany (full-cycle manufacturing).

Manufacturer’s address and location of operations.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Or

Manufacturer.

LEK Pharmaceuticals d.d. (primary and secondary packaging, batch release).

Manufacturer’s address and location of operations.

Trimo, 2D, 9220 Lendava, Slovenia.