Allopurinol (Page 2 of 5)

CONTRAINDICATIONS

Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.

WARNINGS

ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irre- versible hepatotoxicity and on rare occasions death.

In patients receiving Purinethol® (mercaptopurine) or Imuran® (azathioprine), the concomitant administration of 300-600 mg of allopurinol per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects (see CLINICAL PHARMACOLOGY).

A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol, and in some patients asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.

Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.

The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

PRECAUTIONS

General:

An increase in acute attacks of gout has been reported during the early stages of allopurinol administration, even when normal or sub- normal serum uric acid levels have been attained. Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol is begun. In addition, it is recommended that the patient start with a low dose of allopurinol (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day). The use of colchicine or anti-inflammatory agents may be required to suppress gouty attacks in some cases. The attacks usually become shorter and less severe after several months of therapy. The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. Even with adequate allopurinol therapy, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least two liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of xanthine calculi under the influence of allopurinol therapy and (2) help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during allo- purinol administration. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of allopurinol administration and dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Renal failure in association with allopurinol administration has been observed among patients with hyper- uricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with allopurinol-associated hypersensitivity reactions. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.

Patients with decreased renal function require lower doses of allopurinol than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of allopurinol administration. In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels.

Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as six weeks to as long as six years after the initiation of allopurinol therapy. Rarely a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone.

Information for Patients: Patients should be informed of the following:

  1. They should be cautioned to discontinue allopurinol and to consult their physician 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.

  2. They should be reminded to continue drug therapy prescribed for gouty attacks, since optimal benefit of allopurinol may be delayed for two to six weeks.

  3. They should be encouraged to increase fluid intake during therapy to prevent renal stones.

  4. If a single dose of allopurinol is occasionally forgotten, there is no need to double the dose at the next scheduled time.

  5. There may be certain risks associated with the concomitant use of allopurinol and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin and thiazide diuretics, and they should follow the instructions of their physician.

  6. Due to the occasional occurrence of drowsiness, patients should take precautions when engaging in activities where alertness is mandatory.

  7. Patients may wish to take allopurinol after meals to minimize gastric irritation.

Laboratory Tests

The correct dosage and schedule for maintaining the serum uric acid within the normal range is best determined by using the serum uric acid as an index.

In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy (see WARNINGS).

Allopurinol and its primary active metabolite oxipurinol are eliminated by the kidneys; therefore, changes in renal function have a profound effect on dosage. In patients with decreased renal function or who have concurrent illnesses that can affect renal function such as hypertension and diabetes mellitus, periodic lab- oratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient’s allopurinol dosage reassessed.

The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are given allopurinol.

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