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Allopurinol Hypersensitivity Syndrome: Allopurinol should be withdrawn immediately at the first sign of a skin rash or if other evidence of allergic reaction or hypersensitivity occurs. It should be withdrawn immediately and permanently at the first sign of intolerance.
Allopurinol may cause a rare but potentially life-threatening allopurinol hypersensitivity syndrome (AHS) which consists of an erythematous maculopapular rash with desquamation, fever, nephritis, eosinophilia, and worsening of renal function.
Severe hypersensitivity reactions (e.g., exfoliative, urticarial and purpuric lesions) as well as severe cutaneous adverse reactions [e.g., Stevens-Johnson Syndrome (SJS) or erythema multiforme exudativum, Toxic Epidermal Necrolysis (TEN) or Lyell's Syndrome, and/or generalized vasculitis], which may be fatal (deaths associated with allopurinol have been rare and almost always as a result of generalized hypersensitivity), have been reported following the appearance of skin rash. Very rarely, acute anaphylactic shock has been reported. If such reactions occur, which may be at any time during treatment, allopurinol should be withdrawn immediately and permanently. When generalized hypersensitivity reactions occur and a renal and/or hepatic disorder is present, the outcome could be fatal.
HLA-B*5801 Allele: The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol-related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese population, about 12% in the Korean population and 1 to 2% in individuals of Japanese or European origin. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the patient is a known carrier of HLA-B*5801, the use of allopurinol may be considered if the benefits are thought to exceed risks. Close monitoring for signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately at the first appearance of symptoms.
Skin and Subcutaneous Reactions: Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric, and rarely exfoliative. Allopurinol should be withdrawn immediately should such reactions occur.
Angioedema has been reported to occur with and without signs and symptoms of a more generalized hypersensitivity reaction.
Asymptomatic hyperuricemia: Allopurinol is not indicated for the treatment of asymptomatic hyperuricemia. Adequate fluid intake (two liters per day), dietary modification, and management of the underlying cause may treat the condition.
In the general population, asymptomatic hyperuricemia should not be routinely treated with allopurinol. Well-known associated risk factors of hyperuricemia such as dyslipidemia, obesity, metabolic syndrome, psoriasis, malignancies and congestive heart failure should be addressed.
Lifestyle changes are recommended which include appropriate diet and exercise.
Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.
As with other uricosuric agents, acute gouty attacks may be precipitated during the first six to 12 months of allopurinol treatment in new patients, and these may persist even when normal or subnormal serum uric acid levels have been attained. The mobilization of urates from tissue deposits, which cause fluctuations in the serum uric acid levels, is thought to be the mechanism of these episodes.
In the absence of contraindications (i.e., gastrointestinal ulcers or renal impairment), colchicine or a suitable anti-inflammatory agent (e.g., nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors) may be used as prophylaxis for the first three to six months, especially in new patients and in those who had high previous attack rate. Although acute attacks may still occur, these are reported to be shorter in duration and less severe after several months of treatment. Acute gouty attacks may also be prevented by slowly introducing allopurinol treatment (see Dosage & Administration). If acute gouty attacks develop in patients currently taking allopurinol, treatment should proceed with the same dosage while the acute attack is treated with an appropriate anti-inflammatory agent. Ice compress may also be given in combination with pharmacologic agents for relief of joint pain and swelling of acute gouty arthritis.
Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g., neoplastic disease and its treatment; Lesch-Nyhan Syndrome), the absolute concentration of xanthine in urine may rise sufficiently in rare cases and allow deposition of xanthine stones in the urinary tract. This risk may be minimized by adequate hydration to achieve optimal urine dilution.
Impaction of uric acid renal stones: Adequate therapy with allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Bone marrow depression: There have been reports of bone marrow depression, particularly in patients receiving concomitant drugs which have the potential to cause the reaction (see Interactions). This may occur as early as six weeks to as long as six years after initiation of allopurinol therapy. In patients receiving allopurinol alone, varying degrees of bone marrow depression, affecting one or more cell lines may be observed rarely.
Hepatic Insufficiency: There have been a few cases of reversible clinical hepatotoxicity and asymptomatic increase in serum alkaline phosphatase or serum transaminase observed in patients receiving allopurinol. If patients receiving allopurinol develop anorexia, weight loss, or pruritus, assessment of liver function should be included in the diagnostic evaluation. Periodic liver function tests and complete blood counts are recommended during the early stages of therapy in patients with pre-existing liver disease.
Renal Insufficiency: Since allopurinol and its metabolites are excreted by the kidneys, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of their plasma half-lives.
Some patients with pre-existing renal disease or poor urate clearance have shown a rise in blood urea nitrogen (BUN) during allopurinol administration. Patients with impaired renal function must be carefully observed while taking allopurinol (particularly during the early stages of therapy) and the dosage decreased or the drug discontinued if evidence of deterioration in renal function occurs and persists.
Renal failure associated with allopurinol use has been reported in patients with hyperuricemia secondary to neoplastic diseases. Concomitant illnesses such as multiple myeloma and congestive myocardial disease were seen in patients whose renal dysfunction increased after allopurinol was started. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with allopurinol. Albuminuria has been reported in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.
Particular care should also be taken in the elderly where renal function may be reduced thus leading to retention of the drug and its metabolites with consequent prolongation of action. Renal function tests should be performed before starting allopurinol therapy.
Renal function tests, particularly BUN, serum creatinine, or creatinine clearance, should be periodically assessed in patients with decreased renal function or those with co-morbidities that may affect renal function (e.g., hypertension, diabetes). Dosage should be reassessed in these patients.
Cardiovascular Disorders: Allopurinol should be used with caution in patients under treatment for hypertension or cardiac insufficiency, such as with diuretics or angiotensin-converting-enzyme (ACE) inhibitors, since such patients may have some concomitant impairment of kidney function.
Thyroid disorders: In a long-term open-label extension study, increases in thyroid-stimulating hormones (TSH) levels have been observed in patients during allopurinol therapy. Thus, allopurinol should be used with caution in patients with impaired thyroid function.
Hemachromatosis: A study revealed that reversible rises in serum iron levels and reduction in total iron binding capacity occurred in patients receiving 500 to 600 mg of allopurinol daily. These effects returned to normal when dosage was reduced to 300 mg daily.
Caution should be exercised in the administration of allopurinol to patients with abnormal iron storage, including hemochromatosis.
Information to Patients: Patients undergoing allopurinol treatment should be informed of the following: Allopurinol should be discontinued immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes or swelling of the lips or mouth. Patients should also be advised to consult their physician immediately if such reactions occur; Fluid intake (2 liters/day) during therapy is recommended to prevent renal stones; If a single dose of allopurinol is occasionally missed, there is no need to double the dose at the next scheduled time; Patients should be reminded that there may be certain risks associated with the concomitant use of allopurinol and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, or thiazide diuretics; Allopurinol can cause drowsiness and can affect coordination. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are sure that allopurinol does not adversely affect performance; In order to minimize gastric irritation, patients should take allopurinol after a meal; Patients should not take allopurinol without the advice of a physician. Regular follow-up with a physician is recommended.
Effects on Ability to Drive or Use Machines: Allopurinol may cause somnolence, dizziness, ataxia, and vertigo. Since allopurinol has the potential to impair their ability to perform activities requiring mental alertness, patients should be cautioned about operating hazardous machinery and during motor vehicles.
Use in Children: It is generally recommended that the use of allopurinol be restricted to children with hyperuricemia secondary to neoplastic disease, cancer chemotherapy, or genetic disorders of purine metabolism (i.e., Lesch-Nyhan syndrome).
Use in Elderly: Appropriate dosage of allopurinol in geriatric patients should be selected with caution because of the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease and drug therapy in these patients.
