RiteMED Allopurinol

RiteMED Allopurinol





United Lab
Full Prescribing Info
RiteMED Allopurinol 100 mg: Each tablet contains 100 mg of Allopurinol.
RiteMED Allopurinol 300 mg: Each tablet contains 300 mg of Allopurinol.
Pharmacotherapeutic group: Hypoxanthine analogue, uricostatic, xanthine-oxidase inhibitor. ATC code: M04AA01.
Pharmacology: Pharmacodynamics: Allopurinol and its main metabolite oxypurinol reduce the formation of uric acid through inhibition of the enzyme xanthine oxidase, which plays an important role in the oxidation of hypoxanthine to uric acid. Consequently, uric acid and urate levels in body fluids and urine are lowered.
In addition to the inhibition of purine degradation, de novo purine biosynthesis can be suppressed in some patients via inhibition of hypoxanthine-guanine-phosphoribosyltransferase.
Furthermore, reduction in frequently increased purine biosynthesis to the normal physiological level is observed. Hypoxanthine increased during treatment with allopurinol is immediately transferred into inosine monophosphate and then to adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Elevated AMP and GMP concentrations effect a physiological feedback inhibition of PRPP amidotransferase, the first enzyme of purine biosynthesis.
In very small quantities (concentration in the liver <0.0001 mmol/L), allopurinol forms a ribonucleotide, the concentration of which is too small to be pharmacologically active.
Pharmacokinetics: Absorption and distribution: Allopurinol is rapidly absorbed from the gastrointestinal tract; following oral administration, the substance is detectable in plasma after 30-60 minutes.
About 1½ hours after intake of allopurinol, peak plasma concentrations of allopurinol are achieved, but fall rapidly and are barely detectable after approx. 6 hours. Oxypurinol plasma peak values are measured about 3-5 hours after oral intake of allopurinol. There is no gastric absorption; the most favorable conditions for absorption are in duodenum and upper jejunum. In the therapeutically usual dose of 300 mg in dependence on the extent and velocity of individual first-pass conversion into oxypurinol, the allopurinol peak serum values are between 1.0 μg/mL and 2.6 μg/mL, on average 1.8 μg/mL. The corresponding oxypurinol values are between 5 μg/mL and 11 μg/mL, on average 8.4 μg/mL.
Under standardized conditions with volunteers, mean peak plasma values of 5.24 μg oxypurinol/mL were measured after single administration of 300 mg allopurinol.
Twenty four (24) hours after single oral administration of 300 mg allopurinol, the mean concentration of oxypurinol in plasma was 3.78 μg/ml.
On account of the long half-life of oxypurinol, cumulation occurs during initiation of therapy. Balance is achieved after about one week. The plasma concentrations at the end of the dosage interval do not further increase in patients with normal renal function.
After chronic administration of 300 mg allopurinol to volunteers under standardized conditions, a balanced plasma level of oxypurinol was reached about 168 hours after starting intake of 300 mg allopurinol. The oxypurinol concentration in the volunteers was 9.98 μg/mL on average, but the interindividual variation of the plasma concentrations was very high.
The distribution volume of allopurinol is about 1.6 L/kg, suggesting a relatively high uptake into the tissue. Although no data is available in humans regarding tissue concentrations of allopurinol, the highest allopurinol and oxypurinol concentrations are to be expected in the liver and intestinal mucosa, as xanthine oxidase activity is very high in these tissues.
Metabolism and elimination: Allopurinol is rapidly (half-life approx. 2 hours) oxidated through xanthine oxidase and aldehyde oxidase to oxypurinol (alloxanthine), which is a similarly potent inhibitor of xanthine oxidase, but is more slowly bound to the enzyme.
Neither allopurinol nor its main metabolite oxypurinol have a pronounced binding affinity for plasma proteins. Excretion takes place predominantly via the kidneys with less than 10% of the medicinal product excreted in unchanged form. About 20% of the administered allopurinol is recovered in the feces after 48-72 hours. Oxypurinol is excreted with urine in unchanged form after tubular re-absorption.
The elimination half-life of oxypurinol is individually very different. It is 18-43 hours in healthy persons, in isolated cases, during purine-free diet, up to 70 hours. Renal impairment leads to a prolonged elimination half-life of oxypurinol.
In patients with creatinine clearance of 10-20 mL/min, oxypurinol plasma concentrations of 30 mg/mL were measured after administration of 300 mg allopurinol/day over a longer-term period. This is about the concentration reached in patients with normal renal function after administration of 600 mg allopurinol/day. When allopurinol is administered to patients with impaired renal function, the relevant dosage recommendations are therefore to be heeded (see Dosage & Administration).
The substance's long-term effect enables intake of allopurinol once daily.
Uric acid in the form of microcrystals or colloids can favor the crystallization of calcium oxalate from supersaturated solutions (heterogenous germ formation). Inhibitors of crystallization which inhibit the formation of calcium oxalate calculi and mainly consist of acid mucopolysaccharides are blocked as a consequence of their interference with uric acid (already at concentrations of 3 mmol/L). Reduction in uric acid excretion due to allopurinol prevents the formation of calcium oxalate calculi in these cases.
Bioavailability: The absolute bioavailability of 100 mg and 300 mg allopurinol is between 67% and 90%.
Toxicology: Preclinical safety data: Long-term use of allopurinol at high dosages in animal trials resulted in precipitation of xanthine precipitates which led to alterations in urinary duct organs.
In vitro and in vivo studies conducted to date have not yielded any evidence of a mutagenic or cancerogenic potential.
In animal experiments, teratogenic effects occurred in one in three animal species studied (mouse) at doses from 50 mg/kg bodyweight on day 10 of gestation.
Adults: All forms of hyperuricemia with uric acid values in serum in the range of 500 μmol/L (8.5 mg/100 mL) and above if not controllable by diet or clinical complications of hyperuricemic conditions, particularly manifest gout, urate nephropathy, dissolution and prevention of uric acid calculi, as well as to prevent the formation of calcium oxalate calculi in case of concurrent hyperuricemia; Secondary hyperuricemia of different genesis.
In addition for Allopurinol 100 mg: Children: Secondary hyperuricemia of different genesis; Uric acid nephropathy in leukemia treatment; Congenital enzyme deficiency diseases such as Lesch-Nyhan syndrome (partial or total defects of hypoxanthine-guanine-phosphoribosyl transferase) and adenine-phosphoribosyl transferase deficiency.
Dosage/Direction for Use
Allopurinol 100 mg: Adults: Depending on the current uric acid values in serum, 1-3 tablets of Allopurinol 100 mg (equivalent to 100-300 mg allopurinol) are taken per day.
In order to minimize the risk of adverse reactions, treatment should be initiated with 100 mg allopurinol daily. This dose may be increased only if the uric acid levels in serum are not sufficiently lowered. In isolated cases, the dose may be increased to 6-8 tablets of Allopurinol 100 mg (equivalent to 600-800 mg allopurinol) daily. In this case, the serum oxipurinol level is to be considered which should not exceed a value of 15 micrograms/mL (100 micromol). The dose should be administered divided over the day.
For better tolerability, a maximum of 3 tablets of Allopurinol 100 mg (equivalent to 300 mg allopurinol) should not be exceeded as single dose.
The maximum daily dose is 800 mg allopurinol.
Children: The daily dose is 10 mg allopurinol per kg bodyweight (up to a maximum of 400 mg/day), divided into 3 single doses.
Elderly patients: As no specific data is available regarding use of allopurinol in elderly patients, this patient group should be treated with the lowest therapeutically justifiable dose. In addition, impaired renal function is to be considered, particularly in elderly patients.
Impaired renal function: Impaired renal function without dose adjustment may lead to overdose, as allopurinol and its metabolites are excreted via the kidneys.
To reduce a possible risk, modification of the recommended dosage is indicated. In the presence of severe renal dysfunctions, a maximum of 100 mg allopurinol/day or single doses of 100 mg at longer intervals than one day should be administered. The relevant dose should be exceeded only if the effect is not sufficient. The serum oxypurinol level should not exceed a value of 15.2 μg/mL.
The following scheme provides guidance for dosing in renal insufficiency: See table.

Click on icon to see table/diagram/image

In hemodialysis, each treatment (i.e. 2 or 3 times per week) may be immediately followed by 300-400 mg allopurinol.
Impaired hepatic function: A procedure as in renal insufficiency is recommended in case of impaired hepatic function. Periodic liver function tests should be carried out during the early stages of therapy.
Allopurinol 300 mg: Adults: Depending on the current uric acid values in serum, 1 tablet of Allopurinol 300 mg (equivalent to 300 mg allopurinol) is taken per day.
In order to minimize the risk of adverse reactions, treatment should be initiated with 100 mg allopurinol daily. This dose may be increased only if the uric acid levels in serum are not sufficiently lowered.
Alternatively, 100-300 mg allopurinol can be given daily, with other strengths available for that.
In isolated cases, the dose may be increased to 2 tablets of Allopurinol 300 mg (equivalent to 600 mg allopurinol) daily. In this case, the serum oxypurinol level is to be considered which should not exceed a value of 15 μg/mL (100 μmol). Alternatively, the dose may be increased to 800 mg allopurinol in isolated cases. This dose should be administered divided over the day.
For better tolerability, a maximum of 1 tablet of Allopurinol 300 mg (equivalent to 300 mg allopurinol) should not be exceeded as single dose.
The maximum daily dose is 800 mg allopurinol.
Children, patients with impaired renal or hepatic function: Due to the high content of active substance, Allopurinol 300 mg is not suitable for children as well as patients with impaired renal or hepatic function.
In hemodialysis, each treatment (i.e. 2 or 3 limes per week) may be immediately followed by 300-400 mg allopurinol.
Elderly patients: As no specific data is available regarding use of allopurinol in elderly patients, this patient group should be treated with the lowest therapeutically justifiable dose. In addition, impaired renal function is to be considered, particularly in elderly patients.
Method and duration of use: The tablets are taken unchewed together with a generous quantity of liquid after a meal. If the total daily dose of 300 mg allopurinol is exceeded or if gastrointestinal intolerability occurs, the dose is to be administered divided over the day.
No specific antidote is known. After intake of a single dose of 20 g, one patient experienced symptoms such as nausea, vomiting, diarrhea, and vertigo. In another patient, intake of 22.5 g allopurinol did not result in adverse reactions. After chronic intake of 200-400 mg allopurinol daily in patients with impaired renal function, severe symptoms of intoxication have been described which involved skin reactions, fever, hepatitis, eosinophilia, and exacerbation in renal function.
If intoxication is suspected - particularly in case of co-medication with azathioprine or 6-mercaptopurine - measures reducing absorption or accelerating elimination such as generous supply of liquid or - if necessary - hemodialysis are indicated.
Hypersensitivity to allopurinol or to any of the other excipients.
In addition for Allopurinol 300 mg: Severe renal dysfunctions with creatinine clearance below 20 mL/min; Children.
Sudden lowering of serum uric acid may precipitate an acute attack of gout. Do not intake treatment with this drug during an acute attack of gout.
Special Precautions
According to more recent recommendations in literature, pharmaceutical therapy is superfluous in case of a serum uric acid level below 506 μmol/L, equivalent to 8.5 mg/100 mL, if dietary directions are kept and if there is no nephrotoxicity. Food with high content of purine (e.g. innards such as sweetbread, kidney, brain, liver, heart and tongue as well as meat extract) and alcohol (particularly beer, since guanosine, a ribonucleoside, is taken up thereby, which considerably increases the uric acid level) should be avoided.
If hypersensitivity reactions, e.g. exanthema, occur, allopurinol is to be discontinued immediately.
An especially careful medical monitoring is necessary in impaired renal function, hepatic function or pre-existing hematopoietic disorders. In patients with impaired renal or hepatic function, the relevant dosage recommendations are to be heeded (see Dosage & Administration). Particularly patients treated e.g. with ACE inhibitors or diuretics because of hypertension or cardiac insufficiency should receive allopurinol with caution, as renal function can be impaired in this patient group.
In the treatment of urate kidney and uric acid calculi, the urinary quantity should be at least 2 liters per day.
To avoid elevated uric acid concentrations in serum or urine - as they may occur e.g. in radiotherapy or chemotherapy of neoplasms as well as in the Lesch-Nyhan syndrome - generous supply of fluid is to be ensured in addition to administration of allopurinol in order to guarantee sufficient diuresis. In addition, alkalization of urine due to improved solubility of urate/uric acid may contribute to increased excretion of these substances with urine.
If urate nephropathy or other pathological alterations have already impaired renal function, the dose is to be adjusted according to renal function values (see Dosage & Administration).
In the presence of acute gouty attacks, treatment with allopurinol should not be started until they have completely subsided. In the early stage of treatment with allopurinol, acute gouty attacks may be precipitated through mobilization of larger uric acid depots. Coincident prophylactic administration of analgesics or colchicine should therefore be considered during the first 4 weeks of treatment.
If large uric acid calculi are present in the renal pelvis, it cannot be excluded that parts of the dissolved stones can settle in the ureter as a result of allopurinol treatment.
Allopurinol interacts with the metabolism of numerous medicinal products (see Interactions).
Effects on ability to drive and use machines: Since adverse reactions have been reported during treatment with allopurinol, such as somnolence, vertigo and ataxia, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that allopurinol does not adversely affect their performance.
Use In Pregnancy & Lactation
Pregnancy: No sufficient data is available regarding use of allopurinol in pregnant women. Experimental animal studies have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Since allopurinol interferes in the metabolism of purine and the potential risk for humans is not known, allopurinol should not be used during pregnancy unless definitely necessary.
Lactation: Allopurinol passes into human milk; it should therefore not be used during lactation.
Adverse Reactions
The following frequencies form the basis for the evaluation of adverse reactions: Very common: 10%; Common: 1%-<10%; Uncommon: 0.1%-<1%; Rare: 0.01%-<0.1%; Very rare: <0.01%, including isolated cases.
The incidence of adverse reactions is more common in the presence of renal and/or hepatic insufficiency or co-medication with ampicillin or amoxicillin.
Skin and hypersensitivity reactions: Skin reactions are the adverse reactions most commonly observed (approx. 4%); they can occur at any time during treatment and may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative.
Allopurinol is to be withdrawn immediately should such reactions occur. After recovery from mild symptoms, therapy may be resumed with a low dose (e.g. 50 mg/day). As required, this dose is to be increased gradually. If the skin rash recurs, the preparation should be permanently withdrawn, as severe generalised hypersensitivity reactions may occur.
Hypersensitivity reactions can manifest themselves as follows: Skin reactions accompanied by exfoliation, fever, lymphadenopathy, arthralgia and eosinophilia - such as Stevens-Johnson syndrome and Lyell's syndrome - rarely occur. Associated vasculitis and tissue reactions rarely occurring as well may be manifested in various ways, including hepatitis, interstitial nephritis and very rarely, seizures. If such reactions appear, it may be at any time during treatment, Allopurinol must be withdrawn immediately and permanently. Corticosteroids have proven beneficial for treatment.
In addition, the following observations have been made in isolated cases: Hypersensitivity reactions, which can manifest themselves - among others - as fever, skin reactions, chills and arthralgia, hepatic dysfunctions (reversible increase in transaminases and alkaline phosphatase), acute cholangitis and xanthine calculi.
If generalised hypersensitivity reactions have occurred, renal and/or hepatic dysfunctions were generally present particularly in lethal courses.
Very rarely, acute anaphylactic shock has been reported.
Angioimmunoblastic lymphadenopathy: Reversible angioimmunoblastic lymphadenopathy has very rarely been described after withdrawal of allopurinol.
Liver: Hepatic dysfunctions, ranging from asymptomatic increase in liver values lo hepatitis (including hepatic necrosis and granulomatous hepatitis) have rarely been reported.
Gastrointestinal tract: Nausea, vomiturition and diarrhea can occur. It should be paid attention to conscientious intake after meals together with sufficient liquid, particularly in patients with a sensitive stomach.
Blood and lymphatic system: Isolated cases of blood count alterations such as leukopenia, leukocytosis, granulocytosis and eosinophilia have been reported in isolated cases.
The occurrence of thrombocytopenia, agranulocytosis and aplastic anemia has uncommonly been reported, particularly in patients with renal dysfunctions. An especially careful monitoring of these patient groups is therefore necessary.
In addition, the following observations have been made in isolated cases: General malaise, alopecia, angina, asthenia, ataxia, peripheral neuritis, bradycardia, diabetes mellitus, depression, furunculosis, dysgeusia, gynecomastia, hematemesis, hematuria, hyperlipidemia, hypertension, impotence, infertility, cataract, coma, headache, macular degeneration, edema, myalgia, neuropathy, paralysis, paresthesia, Quincke's edema, vertigo, somnolence, dysopia, steatorrhea, stomatitis, discolored hair, uremia.
Drug Interactions
Allopurinol decelerates the elimination of probenecid.
The efficacy of allopurinol is reduced due to administration of the uricosuric medicinal products sulfinpyrazone, probenecid and benzbromarone or salicylates at high doses.
If allopurinol is taken concomitantly with 6-mercaptopurine or azathioprine, their dose must be reduced to 25% of the otherwise usual dose, since the metabolism of these active substances is decelerated in association with inhibition of xanthine oxidase, and thus their effect is prolonged.
The occurrence of allergic reactions (exanthema) due to ampicillin or amoxicillin is more frequently to be expected when allopurinol is administered concurrently. If possible, patients on allopurinol therapy should therefore receive other antibiotics.
Co-administration of allopurinol and captopril can increase the risk of skin reactions, particularly in association with chronic renal failure.
Anticoagulants of the coumarin type may be enhanced in their effect. More frequent monitoring of blood coagulation is therefore necessary, and appropriate dose reduction of the coumarin derivative is possibly necessitated.
Particularly in case of impaired renal function, the hypoglycemic effect of the antidiabetic chlorpropamide can be prolonged due to co-administration of allopurinol, which requires dose reduction.
At high dosage, allopurinol inhibits the theophylline metabolism. In the early stage of treatment with allopurinol or when increasing the dose of allopurinol, the theophylline plasma levels should therefore be determined.
If allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halogenides) are administered, blood count alterations more frequently occur than is the case in single administration of the active substances. The blood count is therefore to be monitored at short intervals.
The plasma half-life of vidarabine can be prolonged in the presence of allopurinol. Special attention is therefore necessary during concurrent use of these medicinal products in order to recognize possibly increased adverse reactions in good time.
The plasma concentration of ciclosporin can be increased during administration of allopurinol. It is to be considered that adverse reactions of ciclosporin can more commonly occur.
Allopurinol can impair the metabolization of phenytoin in the liver; it is not known to date whether these findings have clinical importance.
Store at temperatures not exceeding 25°C.
ATC Classification
M04AA01 - allopurinol ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.
Tab 100 mg x 100's. 300 mg x 100's.
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