ZYLORIC™ Tablets
Allopurinol
PRESENTATION :
Each creamy white Tablet containing either 100 mg allopuriol (coded U4A)
OR & 300 mg allopurinol {CODED (C 9B )
Indications :
Zyloric 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 01 malignancy potentialty 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;
– neopIastic disease and myel0proiiferative disease wi1h high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic thetapy;
– certain enzyme dsorders which lead to overproduction of urate for example :
* hypoxanthine guanine phosphoribosyltransferase including lesch nyhan syndrome
* glucose 6 phosphatase including glycogen storage disease
* phosphoribosylphosphate synthethetase
* phosphoribosylphosphate amidotransferase;
* adenine phosphoribosyltransferase.
Zyloric is Indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficienl activity of adenine
phosphoribosyhranferase.
Zyloric 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.
Dosage and Administration :
The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Zyloric 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 dose regimen may be appropriate.
• Adults
Zyloric 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 (586 Dosage and Adninistntm – Renal impakmenl and warnings and precautions
The following dosage schedules are suggested :
100 to 200 mg daiy n mid contitions,
300 to 600 mg daiy in moderatety severe conditions,
700 to 9OOmgdailynS8Y8re conditions.
if dosage on a mg/kg bodyweight basis Is required, 2 to 10 mg/kg bodyweight/day should be used. Where available Zyloric granules should be used in preference to the halving of tablets.
• Children (uncler 15 years)
10 to 20 mg/kg bodyweight/day up to a maximum 0f 400 mg daily Use In children is rarely indicated, except In malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch -Nyhan syndrome.
• Elderly
In the absence 01 specific data, the lowest dosage which produces salistactory urate redx:tion should be used Particular attention should be paid to advice in “Dosage and Administratiorl • Renal impairmed’ and • warnings and Precautions”.
• Renal impairment
Since allopurinol and Its metaboites are exaeted 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 t0 use single doses 01100 mg allonger intervals than one day.
if facilities are available to monitor plasma oxipurinol concentrations , the dose should be adjusted to maintm plasma oxipurinol levels below 100 micromol/litre (15.2 mg/liter).
AIopuriloI and its metaboites are removed by renal daIysis.” daIysIs is required two to three times a week consideration should be givin to an altemalive dosage schedule 0f 300 to 400 mg allopuriol invnedately aner each (iat,’sis WIth none in the interim.
• Hepatic Impairment
Reduced doses should be used in patients with hepatic impairmenl
Periodic liver function tests are recommended during the earty stages of therapy.
• Treatment ot High Urate Tumover Conditions e.g. Neoplasia, Lesch-Nyhan Syndrome
It is advisable 10 correct existing hyperuricaemia and/or hyperuricosuria with ZYLORIC before starting cytotoxic therapy. Adequate hydralion is importanllo maintain optimum diuresis and alkalinisation 01 the urine Is advisable 10 increase solubility of urinary urate/uric acid. Dosage of ZYLORIC shoold be at the IaNer end 01 the recommended dosage schedule. urate nephropathy or other pathology has compromised renal bnction. the advice ~ in dosage and ActnRstration· should be 1oIowed. These slaps may reduce the risk of xanthine and/or oxiprinol deposition complicating the cinicaI situation (see interactions and Adverse Reaaions).
Contraindications :
Zyloric tablets and cisperstie granutes should not be administered to intividuals known to be hypersensitive to allopurinol or to any of the
components of the fomulation.
Warnings and Precautions :
Zyloric should be withdrawn IMMEDIATELY when askin rash or 0ther evidence of sensitivity occurs. Reduced doses should be used in patients with hepatic or renal impaifmenl Patients under treatment ilf ITfpertension or cardac ilsufficiency, tor example with diuretics or ACE mtitOfS, may have some concomitant irf1lainnenl of renaJ hKlcbon ancIlYlORIC should be used with care in this
hyperuricaerria per se is generaIy not considered an ideation br use of lYlORIC. Fknd and dietary modification with management of the under1ying cause may correct the condition.
Acute gouty attacks :
Zyloric treatment shoutd 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 Zyloric ,as with uricosuric agents an acute attack of gouty arthritis may be precipitated Therefore it is advisable to give prophy!axis with a Suitable anti inflammatory agent or colchicine for a few months.. The literature should be consulted for detais of appropriate dosage and precautions and warmgs. if acute attacks develop in patients receiving Zyloric treatment. should contine at the same dosage while the acute attack is treated With asuitable anti inflammatory agent
Xanthine deposition :
In conditions where the rate of urate formation is geatly increased (e.g. maignant disease and is treatment, Lesch-nyhan syndrome) the absolute concentration 0f xanthine in urine could, in rare cases. rise SlA’tiaentIyto aklwdeposition lithe uMary tract. llis risk may be nrirised by adequate hydration to achieYe optinaI Lme riIution.
Impaction of uricacid renal stones :
Adequate thet with Zyloric will lead to dissolution of large uric acid renal pelvic: stones, with the remote possibility in the ureter.
Interactions :
6-mercapto9urine and azathloprtne
Azathioprine is metabolised to 6-mercaptopume wtictI is ilactiYated by the action of xanthine oxidase. When 6-mercaplopurine or azalhioprine is given concurrently with Zyloric only one-quartef of the usual dose of &men:apIopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong !heir activity.
Vidarabine (adenine arabinoside)
Evidence suggests that the plasma half-life 01 VicIara.t*le is ncreased in the presence of allopurinol. When the two products are used concomitantly extra vigtlance Is necessary, 10 recognise enhanced toxic etfects.
Salicylate! and uricosuric agents Inconsistent style
0xipurin0I, the majOf metabolite d allopurinol and itseI1 therapeutically actiYe, is excreted by the kidney in a similar vr.rr to urate. Hence, drugs with uricosuric activity such as probenecid Of large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of allopurinol, but the significance needs to be assessed in each case.
Chlorpropamide
If ZYWRJC is given concomitanlly with chlorpropamide when reoallunction is poor, there may be an increased risk of prolonged hypoglycaemic activity because allopurinol and chlorpropamide may compete !or excretion in the reoaltubula.
Coumarin anticoagulants
There have been rare reports artncreased eHecI 01 war1arin and other coomarin anticoagulants when cc-acminerered with lYLORIC, therefore, al\ patients receiving anticoagulants must be carefully monitored.
Phenytoin
Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
Theophylline
Inhibition 0f the metabolism 01 theophylline has been reported. The mecha.wn of the interaction may be explained by xanthine oxidase being involved in the biotransformation 01 theophyltine in man. Theophylline levels should be monitored in patients starting Of increasing Zyloric therapy.
Ampicillin/Amoxicillin
An increase in the frequency 01 skin rash has been reported among patients receiving ampiciIin Of amoxiciIlin concurrently with ZYLORC compared to patients who are no! receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving ZVLORJC an alternative to ampiciIIWl Of amoxicillin is used where available.
Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamlne
EManced bone marrow suppression by cydophosphamide and other cytotOXic agents has been reported among patients with neopIastic disease (other than leukaemia) in the presence of allopurirlol. However, in a wekontroIIed study of patients treated with cydophosphamide, doxorubicin. bleomycin, procarbame ~Of rnedlIoroethamine (roostine hydrochloride) mORIC rid not appear to increase the toxic reaction of these cytotoxic agents.
Cyclosporin
Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with ZYLORC. The possibilty of enhanced cycIosporin toxicity shcdl be considered if the drugs are co-administered
Didanosine
In healthy volunteers and HIV patients receiving didanosine, plasma ddanoSIne Cmax and AUC values we«! approxiTIateJy doubled with concomitant ZYLORC treatment (300 mgdaily) with out effecting half life therefor dose reduction of didanosine may be
when used concortitantIy with ZYLORC
Pregnancy and lactation
(see Pre clinical safety Data)
There is Ndequate evidence of safety of ZYLORC in human~, alIhough it has been in wide use kif many years without apparent I
consequence. Use in pregw there is no safer ahematrve and when !he (isease itself carries risks klr!he rnoIher or oobom child.
Reports in<icale that aIoplmoI and ~ are exaeted in human breast rhIk. Concentralioos of 1.41f91i1re aIk:lpuMoI and 53.7 rJ91iIre
CJq)UrinoI have been demonstrated in breast rriIk from a woman taking aIopurinoIJOO mgIday. However, then! are no data concermg the effects 0f aIopuriloI Of its metaboites on the breast-led baby.
Effects on Ability to Drive and Use Machines
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving ZYLORC patients shoJd exercise caution beIore driving, using or participating in dangerous actMties until they are reasonably certain that mORIC does !’leX adwrsety
alfectper1ormance.
Advefse Reactions
For this product there is no modem clinical documentation which can be used as support for determining the frequency of undesirable effects.
Overdose :
Ingestion 01 up to 22.5 9 allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizzioess have been reported in a patient who ingested 20 g allopurinol. Recovery followed general supportive measures. Massive absorption 01 allopurinol may lead to considerable inhibition 01 xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with s-mercaptopunne andIor azathioprioo. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metaboees. U considered necessary haemodialysis may be used.
PHARMACOLOGICAL PROPERTIES :
Pharmacodynamics
Allopurinol is axanthine -oxidase inhibitor Of.
Allopurinol and its main metabolite oxipuronol lower the level of uric: acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine 10 xanthine and xanthine to uric acid. addition 10 the inhibition of purine catabolism, in some but nol all hyperuricaemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine.guanine phosphoribosyltransferase.
Pharmacokinetics
Absorption
Allopurinol is active when given orally and is rapidly absorbed from the upper gastrolntestinal tract. Studies have detected aKopurinol in the blood 30 10 60 min after dosing. Estimates of bioavailabilily vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 h after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 h. Peak plasma levels of oxipurinol generally occur after 3 to 5 h aner oral administration of allopurinol and are much more sustained.
Distribution
Allopurinol is negligibly bound by plasma prolelns and therelore variations in protetl binding are nolthought 10 slgniflCarltly alter ceererce. The apparent YOIume 01 distribution of allopurinol is approximalety 1.6Iitrelk.g, ‘Nhich suggests relatively extensive uptake by tissues.concentrations of allopurinol have not been reported in humans, but It is likety that allopurinol and oKipurinol will be present In the highest concentrations in the liver and intestinal mucosa where Kanthine oxoase activity is high.
Metabolism
The main metabolite of allopurinol is oxipurinol. Other metaboiites 01 allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
Elimination
Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainty by metabolic conversion to oxipurinol by xanthine oxidase and aldehyOO oxidase, with less than 10% of the unchanged drug excreted in the urine Allopurinol has a plasma halt-life of abou\ 0.5 to 1.5h. Oxipurinol is a less polent inhibitor of xanthine oxidase Ihan allopurinol, bullhe plasma half-life of oxipurinol is far more prolonged. Estimates range from 13to 30 h.in man. rterejoe effective inhibition of xanthine oxkIase. is maintained over a 24 h period ~tha sin~e daity allopurinol. Patients with normal renal h.nction will gradually accumulate oxipunnol u~lil a steacy-state plasma OKJpun”?i concentration IS reached.
Such patients, laking 300 mg of allopuri”lol per day will generalty ~ plasma ~nnol concentrations of 510 10 m!}is eliminated unchanged in the urine but has a long elimlnallOfl hall because it undergoes tubutar reabsorption. Reported values lot \he elimination halt-Jife range from 13.6jl.to 29 h. The large discrepancies in these-values may be accounted Ior by variations In study design and/or creatilline clearance in the patients.
Special Patlen! Populations :
• Renal Impairment
Allopuriool and oxipurinol clearance is ~ealfy reduced in patients with poor renal fuoction resulting in higher plasma levels i’I chronic therapy. Patents with reoallmpairmenl, where creatinine clearance values were between 10 and 20 mVmin, showed plasma oxipuriflol corcennancns 01 approximatety 30 mgllitre after prolonged treatment with 300 mg allopurinol per day. This is approximatety the concentration which would be achieved by doses of 600 mwday in those with nctnet renal function. A reduction in the dose of allopurinol is therefore required in patienls wilh renal impairment.
• Elderly
The kinetics of the drug are not likely 10 be altered other than due to deterioration in renal function (see Pharmacokinetics – Renal impairment).
Pre-clinical Safety Data :
Cytogenetic studies show that allopurinol does nol induce chromosome aberrations in human blood cells in vitro et concentrations up to 100 microgramJml and in vivo at doses up to 600 m!}’day for a mean period 0140 moolhs. Allopurinol does not produce nnrosc compounds in vitro or affect tymphocyte transformation in vitro. Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of !he cell cycle and is not mutagenic. No evidence of carcinogenicity has been jouno in mice and rats treated with aJlopurinollor up 10 2 years. One study in mice receiving intraperitoneal doses of 50 or 100 m!}’1<.g on days 10 or 13 of gestation resulted in foetal abnonnalities, however in a
similar study in rats at 120 m!}’1<.g on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up 10100 m!}’1<.glday, rats up to 200 mQI1<glday and rabbits up to 150 mglkglday 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 allopurinol would not be expected 10 cause embryoloxicity without also causing maternal toxicity.
Special precauucns for Storage :
store :ZYLORC tablets below 25 c and keep dry
package : ZYLORC tablets 100 mg and 300 mg
Manufactured by:
GlaxoSmithKline S.A.E. El Salam City, Cairo, A.R.E.
