Ingestion of up to 22.5 g Sanfipurol 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 Sanfipurol. Recovery followed general supportive measures. Massive absorption of Sanfipurol may lead to considerable inhibition of xanthine oxidase activity which should have no untoward effect unless affecting concomitant medication, especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of Sanfipurol and its metabolites. If considered necessary haemodialysis may be used.
No major incompatibilities known.
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified though post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency:
| Very common Common Uncommon Rare Very rare | > 1/10 > 1/100 to <1/10 > 1/1,000 to < 1/100 > 1/10,000 to < 1/1,000 < 1/10,000 |
Adverse reactions in association with Sanfipurol are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.
| Table 1 Tabulated summary of adverse reactions | ||
| System Organ Class | Frequency | Adverse Reaction |
| Infections and infestations | Very rare | Furuncle |
| Blood and lymphatic system disorders | Very rare | Agranulocytosis1 Aplastic anaemia1 Thrombocytopenia1 |
| Not known | Haemolytic anaemia | |
| Immune system disorders | Uncommon | Hypersensitivity2 |
| Very rare | Angioimmunoblastic T-cell lymphoma3 | |
| Metabolism and nutrition disorders | Very rare | Diabetes mellitus Hyperlipidaemia |
| Psychiatric conditions | Very rare | Depression |
| Nervous system disorders | Very rare | Coma Paralysis Ataxia Neuropathy peripheral Paraesthesiae Somnolence Headache Dysgeusia |
| Eye disorders | Very rare | Cataract Visual impairment Maculopathy |
| Ear and labyrinth disorders | Very rare | Vertigo |
| Cardiac disorders | Very rare | Angina pectoris Bradycardia |
| Vascular disorders | Very rare | Hypertension |
| Gastrointestinal disorders | Uncommon | Vomiting4 Nausea4 |
| Very rare | Haematemesis Steatorrhoea Stomatitis Changed bowel habit | |
| Hepatobiliary disorders | Uncommon | Liver function test abnormal5 |
| Rare | Hepatitis (including hepatic necrosis and granulomatous hepatitis)5 | |
| Skin and subcutaneous tissue disorders | Common | Rash |
| Rare | Stevens-Johnson syndrome/toxic epidermal necrolysis6 | |
| Very rare | Angioedema7 Drug eruption Alopecia Hair colour changes | |
| Renal and urinary disorders | Very rare | Haematuria Azotaemia |
| Reproductive and breast disorders | Very rare | Infertility male Erectile dysfunction Gynaecomastia |
| General disorders and administration site conditions | Very rare | Oedema Malaise Asthenia Pyrexia8 |
| Not known | Chills | |
| Investigations | Common | Blood thyroid stimulating hormone increased9 |
1 Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
2 A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, rashes, vasculitis,lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia hepato-splenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium and colon). Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment. Sanfipurol should be withdrawn IMMEDIATELY AND PERMANENTLY.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
3 Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Sanfipurol.
4 In early clinical studies, nausea and vomiting were reported. Further reports suggest that this reaction is not a significant problem and can be avoided by taking Sanfipurol after meals.
5 Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.
6 Skin reactions are the most common reactions and may occur at any time during treatment.). If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce Sanfipurol due to the potential for a severe or even fatal reaction. The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, Sanfipurol should be withdrawn immediately and permanently
7 Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.
9 The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did not report any impact on free T4 levels or had TSH levels indicative of subclinical hypothyroidism.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Mutagenicity
Cytogenetic studies show that Sanfipurol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600 mg/day for a mean period of 40 months.
Sanfipurol does not produce nitroso compounds in vitro or affect lymphocyte transformation in vitro.
Evidence from biochemical and other cytological investigations strongly suggests that Sanfipurol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.
Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with Sanfipurol for up to 2 years.
Teratogenicity
One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of Sanfipurol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.
An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity indicated that Sanfipurol would not be expected to cause embryotoxicity without also causing maternal toxicity.
Sanfipurol is indicated for 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). The main clinical conditions where urate/uric acid deposition may occur are: idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage disease; phosphoribosylpyrophosphate synthetase, phosphoribosylpyrophosphate amidotransferase; adenine phosphoribosyltransferase.
Sanfipurol is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.
Sanfipurol is indicated for the management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.
Pharmacotherapeutic group: Preparations inhibiting uric acid production. ATC code: M04AA01.
Sanfipurol 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, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of Sanfipurol include Sanfipurol-riboside and oxipurinol-7-riboside.
Absorption
Sanfipurol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected Sanfipurol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of Sanfipurol generally occur approximately 1.5 hours after oral administration of Sanfipurol, but fall rapidly and are barely detectable after 6 hours. Peak plasma levels of oxipurinol generally occur after 3-5 hours after oral administration of Sanfipurol and are much more sustained.
Distribution
Sanfipurol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of Sanfipurol is approximately 1.6 litre/kg which, suggests relatively extensive uptake by tissues. Tissue concentrations of Sanfipurol have not been reported in humans, but it is likely that Sanfipurol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of Sanfipurol is oxipurinol. Other metabolites of Sanfipurol include Sanfipurol-riboside and oxipurinol-7-riboside.
Elimination
Approximately 20% of the ingested Sanfipurol is excreted in the faeces. Elimination of Sanfipurol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine. Sanfipurol has a plasma half-life of about 0.5 to 1.5 hours.
Oxipurinol is a less potent inhibitor of xanthine oxidase than Sanfipurol, but the plasma half-life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of Sanfipurol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300 mg of Sanfipurol per day will generally have plasma oxipurinol concentrations of 5-10 mg/litre.
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. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.
Pharmacokinetics in patients with renal impairment
Sanfipurol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20 ml/min, showed plasma oxipurinol concentrations of approximately 30 mg/litre after prolonged treatment with 300 mg Sanfipurol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of Sanfipurol is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients
Hypersensitivity syndrome, SJS and TEN
Sanfipurol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS / TEN. These reactions are clinical diagnoses, and their clinical presentations remain the basis for decision making. If such reactions occur at any time during treatment, Sanfipurol should be withdrawn immediately. Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
HLA-B*5801 allele
The HLA-B*5801 allele has been shown to be associated with the risk of developing Sanfipurol 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, 8-15% in the Thai, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. Screening for HLA-B*5801 should be considered before starting treatment with Sanfipurol in patient subgroups where the prevalence of this allele is known to be high. Chronic kidney disease may increase the risk in these patients additionally. In case that no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or Korean descent the benefits should be thoroughly assessed and considered outweigh the possible higher risks before starting therapy. The use of genotyping has not been established in other patient populations. If the patient is a known carrier of HLA-B*5801 (especially in those who are from Han Chinese, Thai or Korean descent),Sanfipurol should not be started unless there are no other reasonable therapeutic options and the benefits are thought to exceed risks. Extra vigilance 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.
SJS/TEN can still occur in patients who are found to be negative for HLA-B*5801 irrespective of their ethnic origin.
Chronic renal impairment
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 Sanfipurol. Extra vigilance for the signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately and permanently at the first appearance of symptoms.
Hepatic or renal impairment
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 Sanfipurol should be used with care in this group.
Asymptomatic hyperuricaemia
Asymptomatic hyperuricaemia per se is generally not considered an indication for use of Sanfipurol. Fluid and dietary modification with management of the underlying cause may correct the condition.
Acute gouty attacks
Sanfipurol 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 Sanfipurol, 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. The literature should be consulted for details of appropriate dosage and precautions and warnings.
If acute attacks develop in patients receiving Sanfipurol, 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 minimised by adequate hydration to achieve optimal urine dilution.
Impaction of uric acid renal stones
Adequate therapy with Sanfipurol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Thyroid disorders
Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with Sanfipurol (5.8%) in a long term open label extension study. Caution is required when Sanfipurol is used in patients with alteration of thyroid function.
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving Sanfipurol, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Sanfipurol does not adversely affect performance.
Posology
Adults
Sanfipurol 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. Extra caution should be exercised if renal function is poor. The following dosage schedules are suggested:
100 to 200 mg daily in mild conditions,
300 to 600 mg daily in moderately severe conditions,
700 to 900 mg daily in severe conditions.
If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be used.
Paediatric population
Children under 15 years: 10 to 20 mg/kg bodyweight/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.4.
Renal impairment
Since Sanfipurol 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. If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre). Sanfipurol and its metabolites are removed by renal dialysis. If dialysis is required two to three times a week consideration should be given to an alternative dosage schedule of 300-400 mg Sanfipurol immediately after each dialysis with none in the interim.
Hepatic impairment
Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.
Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome
It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with Sanfipurol 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 Sanfipurol should be at the lower end of the recommended dosage schedule.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation.8.
Monitoring Advice
The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Method of administration
Sanfipurol may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.
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