ANGUT

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COMPOSITION: Allopurinol .................................... 300 mg

                           Excipients q.s ............................... 1 tablet

(Pregelatinized starch (National 78-1551), orange E110, sodium lauryl sulfate, PVP K30, aerosil, magnesium stearate, croscarmellose sodium).

DOSAGE FORM: Tablet.

PRESENTATION: Box of 10 blisters x 10 tablets.

PHARMACODYNAMICS:

Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients, once more purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7 riboside.

PHARMACOKINETICS:

Allopurinol is rapidly absorbed from the gastrointestinal tract. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after 3-5 hours after oral administration. Allopurinol has a plasma half-life of about 1 to 2 hours. Approximately 20% of the ingested allopurinol is excreted in the faeces.

Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours.

INDICATIONS:

Reducing urate/uric acid formation in conditions where urate/uric acid deposition has already occurred (e.g. gouty arthritis, skin tophi, nephrolithiasis) or is a predictable clinical risk (e.g. treatment of malignancy potentially leading to acute uric acid nephropathy).

Management of 2, 8-dihydroxyadenine (2, 8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.

Management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

CONTRAINDICATIONS:

Hypersensitive to allopurinol or to any of the components of the drug.

PRECAUTIONS:

Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions, (including Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)), and hypersensitivity syndrome.

Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides, may be at increased risk of developing hypersensitivity reactions including SJS/TEN associated with allopurinol.

Reduced doses should be used in patients with hepatic or renal impairment. Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and allopurinol should be used with care in this group.

Asymptomatic hyperuricaemia is generally not considered an indication for use of allopurinol. Dietary modification with management of the underlying cause may correct the condition.

Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.

In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for at least one month.

If acute attacks develop in patients receiving allopurinol, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.

Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition 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.

PREGNANCY AND LACTATION:

There is inadequate evidence of safety of allopurinol in human pregnancy, although it has been in wide use for many years without apparent ill consequence. Use in pregnancy only when there is no safer alternative and when the disease itself carries risk for the mother or unborn child.

Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES:

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that allopurinol does not adversely affect performance.

INTERACTIONS:

Coumarin anticoagulants: There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when coadministered with allopurinol in certain cases.

Azathioprine or 6-mercaptopurine: When 6-mercaptopurine or azathioprine is given concurrently with allopurinol, only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.

Vidarabine (adenine arabinoside): The plasma half-life of vidarabine is increased in the presence of allopurinol.

Drugs with uricosuric activity such as sulfinpyrazone, probenecid or high dose of salicylates may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of allopurinol.

Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycaemic activity.

Theophylline: Their metabolism was shown to be inhibited by allopurinol, presumably through the inhibition of xanthine oxidase enzyme.

Ampicillin/ amoxicillin: An increase in the frequency of skin rash has been reported.

Ciclosporin: The plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are co-administered.

Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Didanosine: Co-administration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (mechloroethamine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.

ADVERSE EFFECTS:

Skin rashes are the most common reactions during treatment with allopurinol. They may be maculopapular or pruritic, sometimes purpuric, but more serious hypersensitivity reactions may occur and include exfoliative rashes, the Stevens-Johnson syndrome, and toxic epidermal necrolysis. It is therefore recommended that allopurinol be withdrawn immediately if a rash occurs. Further symptoms of hypersensitivity include fever and chills, lymphadenopathy, leucopenia or leucocytosis, eosinophilia, arthralgia, and vasculitis leading to renal and hepatic damage and, very rarely, seizures. These hypersensitivity reactions may be severe, even fatal, and patients with hepatic or renal impairment are at special risk. Hepatotoxicity and signs of altered liver function may also be found in patients not exhibiting hypersensitivity. Haematological effects include thrombocytopenia, aplastic anaemia, agranulocytosis, and haemolytic anaemia.

Common, ADR > 1/100

Skin reactions: rash, maculopapular rash, pruritus, exfoliative dermatitis, urticaria, erythema, eczema, bleeding.

Uncommon, 1/1000 < ADR < 1/100

Hepatic disorders: Increased alkaline phosphatase, AST, ALT, reversible hepatomegaly, hepatic cell damage, hepatitis, liver failure, hyperbilirubinemia, jaundice.

Rare, ADR < 1/1000

Body as a whole: Serious hypersensitivity reactions, fever, chills, sweating, irritability, exfoliation, lichen planus, facial edema, edema of skin, hair loss, nosebleeds.

Blood disorders: Leukopenia or leukocytosis, eosinophilia, agranulocytosis, thrombocytopenia, bleeding, bone marrow suppression, disseminated intravascular coagulation, lymphadenophathy, aplastic anemia, hemolytic anemia.

Gastrointestinal disorders: Nausea, vomiting, abdominal pain, diarrhea, constipation, flatulence, intestinal blockage, rectal inflammation, taste disturbances, stomatitis, dyspepsia, anorexia, gastritis, gastrointestinal bleeding, hemorrhagic pancreatitis, swollen salivary glands, tongue oedema.

Musculoskeletal disorders: Myalgia.

Eye disorders: Cataract, optic neuritis, and visual disturbances.

Nervous system disorders: Peripheral neuropathy, neuritis, paresthesia, headache, seizures, epilepsy, myoclonic, hypotonia, agitation, mental status changes, cerebral infarction, coma, dystonia, paralysis, tremors, drowsiness, dizziness, depression, confusion, insomnia, asthenia.

Endocrine disorders: Gynecomastia (male).

Cardiovascular disorders: Hypertension.

Urinary disorders: Kidney failure.

Inform your physician about any adverse effects occur during the treatment.

OVERDOSAGE:

Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20 g allopurinol. Recovery followed general supportive measures. Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary haemodialysis may be used.

DOSAGE & ADMINISTRATION:

Angut 300 may be taken orally once a day after a meal. It is well tolerated, especially after food. The daily dosage should not exceed 300 mg and gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.

Adults: Allopurinol should be introduced at low dosage e.g. 100 mg/day to reduce the risk of adverse reactions and increased only if the serum urate response is unsatisfactory.

The following dosage schedules are suggested:

- In mild conditions: Do not use this product because of difficulty in dose division.

- In moderately severe conditions: 300 to 600 mg daily.

- In severe conditions: 700 to 900 mg daily.

- If dosage on a mg/kg body-weight basis is required, 2 to 10 mg/kg body-weight/day should be used.

Paediatric population: Children under 15 years: 10 to 20 mg/kg body-weight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.

Older people: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used.

Patients with hepatic impairment: Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.

Patients with renal impairment: Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of plasma half-lives. In severe renal insufficiency, it may be advisable to use less than 100 mg per day or to use single doses of 100 mg at longer intervals than one day.

Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome: It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with allopurinol before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum diuresis and to attempt alkalinisation of urine to increase solubility of urinary urate/uric acid. Dosage of allopurinol should be at the lower end of the recommended dosage schedule. If urate nephropathy or other pathology has compromised renal function, the advice given in dosage in renal impairment should be followed.

Or as directed by the physician.

Read the directions carefully before use.

Consult the physician for more information.

This drug is for prescriptions only.

Shelf-life: 36 months from the manufacturing date.

Storage conditions: Store in dry places, not exceeding 30oC, protect from light.

Specifications: Manufacturer's.

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