Zyloric - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Allopurinol

ZYLORIC 100 mg Tablets
ZYLORIC 300 mg Tab

Why is Zyloric used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

Antigout - preparations inhibiting the formation of uric acid.

THERAPEUTIC INDICATIONS

ZYLORIC is indicated for the main clinical manifestations of uric acid / urate deposition. These include: joint gout, tophi and / or renal involvement due to crystal precipitation or urolithiasis. These situations occur in gout, in uratic lithiasis and in acute uric acid nephropathy, in neoplastic and myeloproliferative diseases with high cell turnover, in which there are high levels of urate, either spontaneously or as a consequence of cytotoxic therapy and in certain enzymatic disorders. (especially Lesch-Nyhan syndrome).

ZYLORIC is also indicated for the prevention and treatment of oxalocalcic lithiasis in the presence of hyperuricemia and / or hyperuricuria.

Contraindications When Zyloric should not be used

Hypersensitivity to allopurinol or to any of the excipients. ZYLORIC is contraindicated in the treatment of acute gout attacks.

Precautions for use What you need to know before taking Zyloric

Zyloric should be discontinued immediately when skin rash or other signs and symptoms of hypersensitivity occur. Zyloric must be discontinued immediately and permanently at the first signs of intolerance.

Treatment with ZYLORIC (allopurinol) should be stopped immediately as soon as skin reactions or other signs that may indicate an allergic reaction appear.

Serious skin reactions (hypersensitivity syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with the use of allopurinol. and conjunctivitis (red and swollen eyes). These severe skin reactions are often preceded by flu-like symptoms such as fever, headache, widespread aches. The rash may progress to the appearance of diffuse blisters or peeling of the skin.

These severe skin reactions may be more common in individuals of Han Chinese and Thai descent. If you develop rash or these skin symptoms, you should stop taking allopurinol and contact your doctor immediately. The highest risk of severe skin reactions occurs within the first 8 weeks of treatment.

If Stevens-Johnson syndrome or toxic epidermal necrolysis has occurred with the use of ZYLORIC, this drug should no longer be used.

In rare cases, the allergic reaction manifests itself as a delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, vasculitis, lymphadenopathy, pseudo-lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and intrahepatic bile duct disappearance syndrome, in various combinations. Other organs (e.g. liver, lungs, kidneys, pancreas, myocardium and colon) may also be involved. In patients with pre-existing liver disease it is recommended to perform periodic liver function tests and to adopt appropriately reduced doses of the drug.

Hypersensitivity reactions may occur more easily in patients with renal function disorders who are taking ZYLORIC and thiazides at the same time. Therefore, in this clinical setting, the above combination should be administered with caution and patients should be kept under close observation.

Asymptomatic hyperuricaemia is generally not considered in itself an indication for the use of ZYLORIC. Dietary and fluid changes, along with treatment of the underlying condition, can correct uricaemia.

Allopurinol treatment should not be started until a previous acute attack of gout has completely ended, since treatment with allopurinol may induce further attacks. If an acute attack develops in patients treated with allopurinol, therapy should continue with the same dosage, while the acute attack should be treated with an appropriate anti-inflammatory drug.

In case of muscle pain, it is advisable to undertake a measurement of the levels of CPK and other indicators of muscle damage. The alteration of these parameters involves the suspension of the therapy.

At the beginning of treatment with ZYLORIC, an acute attack of gout may occur even in subjects with normal uricemia. It is therefore advisable, at the beginning of treatment, to administer maintenance doses of colchicine prophylactically. It is also advisable to start treatment with a low dose (100 mg / day) and increase it by 100 mg at weekly intervals until a uricaemia of 6 mg / 100 ml is reached and without exceeding the maximum recommended dose (800 mg / day). The use of colchicine or other anti-inflammatory drugs may be necessary in some cases to suppress gout attacks. The attacks usually become shorter and less severe after a few months of therapy. The mobilization of urate from tissue deposits causing the level to fluctuate. blood uric acid may be a possible explanation for these episodes Even with adequate therapy with ZYLORIC, it may take several months to achieve control of acute attacks.

It is advisable to maintain a fluid intake such as to determine a daily urine volume of at least 2 liters, with neutral or slightly alkaline urine to avoid the theoretical possibility of formation of xanthine stones and to help prevent the precipitation of urate in patients taking concomitant uricosuric therapy. Adequate therapy with ZYLORIC involves the dissolution of uric acid kidney stones with the remote risk of blocking them in the ureter.

In some patients with pre-existing renal disease or with low urate clearance, an elevation of azotemia has been found during therapy with ZYLORIC. Although the mechanism responsible for this has not been identified, patients with impaired renal function should be carefully observed at " initiation of ZYLORIC administration.

If the disturbance of renal function increases, the dosage of the drug should be reduced or its administration discontinued.

Among patients whose renal dysfunction increased after initiation of ZYLORIC therapy, there were concomitant diseases such as multiple myeloma or congestive heart failure. Renal failure is also frequently associated with gouty nephropathy and rarely with associated hypersensitivity reactions. to ZYLORIC. Allopurinol and its primary active metabolite oxipurinol are cleared by the kidney. For this reason alterations in renal function have profound effects on dosage. Bone marrow depression has been reported in patients taking ZYLORIC. Most of these patients were taking concomitant therapies. capable of producing this effect.

This occurred between 6 weeks and 6 years after the start of ZYLORIC therapy.

Rarely, individual patients treated with ZYLORIC alone may develop bone marrow depression of varying degrees, affecting one or more cell lines.

A reduced dosage should be used in patients with impaired hepatic or renal function. Patients being treated for hypertension or heart failure, eg with diuretics or ACE inhibitors, may have concomitant renal insufficiency and therefore allopurinol should be used with caution in this patient group.

In patients with decreased renal function or with concomitant diseases that can affect renal function such as hypertension or diabetes mellitus, renal function should be periodically monitored, in particular blood urea nitrogen and creatinine or creatinine clearance and possibly readjusted the dosage of ZYLORIC.

Interactions Which drugs or foods can change the effect of Zyloric

6-mercaptopurine and azathioprine

Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. In patients receiving 6-mercaptopurine or azathioprine the concomitant administration of 300-600 mg of ZYLORIC per day necessitates a reduction of the 6-mercaptopurine or azathioprine dose to a quarter of the usual dose. This is because the inhibition of xanthine oxidase determines a prolongation of the activity of these drugs.

The dose of mercaptopurine or azathioprine will subsequently be adjusted based on the assessment of the therapeutic response and the appearance of toxic effects.

Vidarabine (adenine arabinoside)

In the presence of allopurinol, the plasma half-life of adenine arabinoside is increased. Particular care must be exercised when the two products are used concomitantly in order to highlight an increase in toxic effects.

Salicylates and uricosurics

Oxipurinol, the main metabolite of allopurinol, which is also therapeutically active, is excreted by the kidney in the same way as urates.

Therefore agents with uricosuric activity (such as probenecid or high doses of salicylates) may accelerate the excretion of oxypurinol. This may result in a decrease in the therapeutic activity of ZYLORIC but the clinical significance of this must be assessed on a case-by-case basis.

Concomitant administration of uricosuric agents and ZYLORIC was associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in the excretion of uric acid compared to those observed with ZYLORIC alone.

Although to date there are no clinical demonstrations of renal precipitation of oxypurines in patients receiving ZYLORIC, alone or in combination with uricosuric drugs, this possibility should be kept in mind on a case-by-case basis.

Chlorpropamide

If ZYLORIC is administered concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged blood glucose lowering activity as allopurinol and chlorpropamide may compete for excretion into the renal tubule.

Coumarin anticoagulants

There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when administered concomitantly with allopurinol. Therefore all patients taking anticoagulants should be closely monitored.

Phenytoin

Allopurinol may inhibit the hepatic oxidation of phenytoin but the clinical significance of this is unclear.

Theophylline

Inhibition of theophylline metabolism has been reported. The mechanism of interaction can be explained by the fact that xanthine oxidase is involved in the metabolism of theophylline in humans.

Theophylline levels should be monitored in patients starting allopurinol therapy or taking higher doses.

Ampicillin / Amoxicillin

An increased frequency of skin reactions has been reported in patients taking ampicillin or amoxicillin together with ZYLORIC compared to patients not receiving either drug. The cause of this association is unknown.

However, it is recommended that an alternative therapy to ampicillin or amoxicillin is used in patients receiving allopurinol when available.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mecloroetamine

In patients with neoplastic diseases, except leukemia, an increase in bone marrow depression due to cyclophosphamide and other cytotoxics has been described in the presence of ZYLORIC, however in a controlled study in patients on combined therapy.

ZYLORIC did not increase bone marrow toxicity of cyclophosphamide, doxorubicin, bleomycin, procarbazine and / or mechloretamine (mustine hydrochloride).

Cyclosporine

Some reports suggest that the plasma concentration of cyclosporine may be increased during concomitant treatment with allopurinol.

Therefore, in case of simultaneous administration of the two drugs, the possibility of an increase in cyclosporine toxicity should be taken into account.

Didanosine

In healthy volunteers and in HIV infected patients administered didanosine, plasma Cmax and AUC values ​​of didanosine were approximately doubled with concomitant allopurinol (300 mg daily) without affecting the terminal half-life. dose reductions of didanosine may be required when used concomitantly with allupurinol.

Thiazide diuretics

Reports that concomitant use of ZYLORIC and thiazide diuretics may contribute to increased allopurinol toxicity in some patients have been reviewed in an attempt to establish the mechanism and cause-and-effect relationship.

Review of case descriptions indicates that most patients were receiving thiazide diuretics for hypertension and that evaluations that excluded renal impairment secondary to hypertensive nephropathy were often not performed.

In patients in whom renal insufficiency was documented, however, the recommendation to decrease the dose of ZYLORIC was not observed.

Although a mechanism or cause-and-effect relationship has not been established, renal function should be monitored in patients receiving ZYLORIC and thiazide diuretics, even in the absence of renal insufficiency, and the dosage should be further decreased in patients on combination therapy if detects decreased kidney function.

Tolbutamide

The conversion of tolbutamide to inactive metabolites has been shown to be catalysed by rat liver xanthine oxidase. The possible clinical relevance of these observations is not known.

Warnings It is important to know that:

ZYLORIC contains lactose: in case of ascertained intolerance to sugars, contact your doctor before taking the medicine.

Teratogenesis

A study in mice treated with intraperitoneal doses of 50 or 100 mg / kg on the 10th or 13th day of gestation revealed fetal abnormalities, however in a similar study in rats treated with 120 mg / kg on the 12th day of gestation no abnormalities were observed. . Large studies with high oral doses of allopurinol in mice up to 100 mg / kg / day, in rats up to 200 mg / kg / day and in rabbits up to 150 mg / kg / day from the eighth to the sixteenth day of gestation did not evidenced teratogenicity.

An in vitro study using cultured mouse fetal salivary glands to detect embryotoxicity indicated that allopurinol is not expected to cause embryotoxicity without concomitant maternal toxicity.

Pregnancy and fertility

In a study conducted with high dose intraperitoneal allopurinol in mice, fetal abnormalities were observed, but in further studies with oral allopurinol in rats and rabbits, no abnormalities were observed. There is insufficient evidence available regarding the safety of ZYLORIC in human pregnancy, although it has been widely used for many years with no apparent adverse consequences.

Use in pregnancy is only recommended when there is no safer alternative and when the disease itself poses a risk to the mother or fetus.

Feeding time

The data indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4 mg / liter of allopurinol and 53.7 mg / liter of oxypurinol were found in the milk of a woman who took 300 mg of allopurinol daily.

As there are no data on the effects of allopurinol or its metabolites on the breastfed infant, administration of ZYLORIC to a nursing mother should be undertaken with caution.

Effects on ability to drive and use machines

Since adverse reactions such as somnolence, dizziness and ataxia have been reported in patients taking allopurinol, patients should exercise caution before driving, operating machinery or performing hazardous activities until they are reasonably certain that allopurinol does not has any negative influence on their performance.

Dosage and method of use How to use Zyloric: Dosage

In adults, the average daily dose is 300 mg once a day.

When high uric acid and / or uricuria values ​​make higher doses necessary, the doctor may increase the dose up to a maximum of 800 mg divided into 2-3 daily administrations after meals.

In order to reduce the possibility of acute gout attacks it is recommended to start treatment at low doses (100 mg) with weekly increments of 100 mg until the optimal maintenance dosage is achieved.

Normalization of the uricaemic rate is achieved in a period of 1-3 weeks. For the prevention of secondary uratic nephropathies, consequent to excessive nucleoprotein catabolism in neoplastic diseases, treatment with ZYLORIC should be practiced, when possible, before cytotoxic therapy in order to correct any pre-existing hyperuricemia and / or hyperuricuria.

ZYLORIC therapy can be maintained during antimitotic therapy and can also be continued indefinitely in the prophylaxis of hyperuricaemia which may arise during the natural crisis of the disease. In prolonged treatment a dose of 300-400 mg / day of allopurinol is usually sufficient to normalize the uricaemic level.

Since allopurinol and its metabolites are eliminated by the kidney, a prolongation of the plasma half-life of the drug can occur in case of poor function of this organ.

To avoid possible consequential risks, treatment can be started with a dose of 100 mg of allopurinol per day, increasing the dose only if the urinary or serum urate levels do not reduce adequately. As an alternative to the suggested treatment, the dosage can be based on creatinine clearance values, according to the following scheme:


Creatinine clearance Dose Above 20ml / min 300 mg / day Between 10 and 20 ml / min 100-200 mg / day Less than 10 ml / min 100 mg / day or at longer intervals

Allopurinol and its metabolites are eliminated by renal dialysis. In patients undergoing hemodialysis two or three times a week a dose of 300-400 mg of ZYLORIC is recommended immediately after each dialysis. No further administration should be given between sessions. dialysis and the other.

In elderly patients, particular attention should be paid to maintaining the dosage to the minimum necessary to maintain normal serum and urinary levels of uric acid.

In boys and children under the age of 15, the dose is 10-20 mg / kg of body weight per day, or 100-400 mg per day.

However, the indication in children is rare (leukemia and certain enzymatic disorders such as Lesch-Nyhan syndrome).

ZYLORIC should preferably always be taken at the same time of the day, after a meal.

Overdose What to do if you have taken too much Zyloric

Symptoms and signs

Intake of allopurinol up to 22.5 g without experiencing adverse effects has been reported. In one patient who ingested allopurinol 20 g, signs and symptoms including nausea, vomiting, diarrhea and dizziness were reported. he recovered following the adoption of general support measures.

Treatment

Massive absorption of allopurinol can lead to a considerable inhibition of xanthine oxidase activity which should have no undesirable effects, beyond the possible influence on concomitantly administered drugs, especially 6-mercaptopurine and / or azathioprine. Adequate hydration to maintain optimal diuresis facilitates the excretion of allopurinol and its metabolites. Dialysis may be used if deemed necessary.

Side Effects What are the side effects of Zyloric

The incidence of undesirable effects may vary according to the dose received and also to the possible concomitant administration of other therapeutic agents. The frequency categories assigned to the adverse drug reactions shown below are estimates: no data are available for most reactions. suitable for calculating the incidence. Adverse drug reactions identified through post-marketing monitoring are considered rare or very rare. The following convention was used for frequency classification:

  • Very common> 1/10 (> 10%)
  • Common> 1/100 and 1% e
  • Uncommon> 1 / 1,000 and 0.1% e
  • Rare> 1 / 10,000 and 0.01% e

Adverse reactions associated with allopurinol are rare in the overall treated population and are mostly mild in severity. The incidence is higher in the presence of renal and / or hepatic disorders. Infections and infestations

Very rare: furunculosis

Disorders of the blood and lymphatic system

Very rare: agranulocytosis, aplastic anemia, thrombocytopenia, leukocytosis, pancytopenia

Very rare cases of thrombocytopenia, agranulocytosis and aplastic anemia have been reported, particularly in subjects with renal and / or hepatic insufficiency; this determines the need to pay particular attention to this group of patients.

Disorders of the immune system

Rare: hypersensitivity reactions with fever and chills, headache, body aches (flu-like symptoms) and general malaise

Very rare: DRESS, angioimmunoblastic lymphadenopathy

A multi-organ hypersensitivity disorder (DRESS) has been reported, including fever, skin rash, joint pain, and changes in blood and liver function tests.

Anaphylactic shock has been reported very rarely. As such reactions can occur at any time during treatment, allopurinol should be discontinued IMMEDIATELY AND PERMANENTLY.

Angioimmunoblastic lymphadenopathy, which appears to be reversible after discontinuation of allopurinol, has been described very rarely following biopsy for generalized lymphadenopathy.

Metabolism and nutrition disorders

Very rare: diabetes mellitus, hyperlipidaemia

Psychiatric disorders

Very rare: depression

Nervous system disorders

Very rare: coma, paralysis, ataxia, neuropathy, paraesthesia, somnolence, headache, altered taste

Eye disorders

Very rare: cataracts, visual disturbances, macular changes

Ear and labyrinth disorders

Very rare: dizziness

Cardiac pathologies

Very rare: angina, bradycardia

Vascular pathologies

Very rare: hypertension

Gastrointestinal disorders

Uncommon: vomiting, nausea

Very rare: recurrent haematemesis, steatorrhea, stomatitis, alvus alterations, gastrointestinal haemorrhage.

In early clinical studies, cases of nausea and vomiting were reported. More recent data suggests that these reactions are not a significant problem and can be avoided by taking allopurinol after meals.

Hepatobiliary disorders

Uncommon: asymptomatic elevation of liver function test values ​​Rare: hepatitis (including hepatic necrosis and granulomatous hepatitis)

Hepatic dysfunction has been reported without overt evidence of more generalized hypersensitivity.

Skin and subcutaneous tissue disorders

Common: rash

Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, fixed drug eruption

Very rare: alopecia, hair discoloration. Skin reactions are the most common reactions and can occur at any time during treatment.

In severe skin reactions, the rash progresses to diffuse blistering and peeling of the skin, ulcers of the mouth, throat, nose, genitals and conjunctivitis. When these reactions occur, stop taking allopurinol immediately and inform your doctor immediately.

Angioedema has been observed to occur with and without signs and symptoms of a more generalized hypersensitivity reaction to allopurinol.

Renal and urinary disorders

Very rare: haematuria, uremia

Diseases of the reproductive system and breast

Very rare: male infertility, erectile dysfunction, gynaecomastia

General disorders and administration site conditions

Very rare: edema, general malaise, asthenia, fever

Fever has been observed to occur with and without signs and symptoms of a more generalized hypersensitivity reaction to allopurinol (see Immune system disorders).

Also reported: diarrhea, gastritis, dyspepsia, intermittent abdominal pain, hepatomegaly, jaundice, hyperbilirubinemia, neuritis, renal failure, myopathy, epistaxis, ecchymosis, necrotizing angiitis, pericarditis, peripheral vascular disorders, thrombophlebitis, vasodilatation, hypercalcemia, hypercalcemia haemorrhagic, salivary gland enlargement, tongue edema, anorexia, bronchospasm, asthma, pharyngitis, rhinitis, iritis, conjunctivitis, amblyopia, paralysis, optic neuritis, confusion, dizziness, lower limb paralysis, decreased libido, tinnitus, insomnia , nocturnal enuresis, nephritis.

Acute attacks of joint gout may occur during the initial phase of therapy with ZYLORIC, as with uricosurics.

Therefore a preventive treatment, for at least one month, with an anti-inflammatory or colchicine is recommended (see "Dose, Method and Time of Administration" and "Appropriate precautions for use").

When urate formation is increased (eg neoplasms and related therapy, Lesch-Nyhan syndrome) xanthine precipitation can occur in the urinary tract (see "Appropriate precautions for use").

Albuminuria has been observed in patients who developed clinical gout following chronic glomerulonephritis or chronic pyelonephritis. Fluid intake should be such as to ensure adequate urinary volume.

Xanthine crystals have been observed in the muscle tissue of patients receiving allopurinol, but this does not appear to have clinical significance.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

It is important to inform the doctor or pharmacist of any undesirable effect, even if not described in the package leaflet.

Expiry and Retention

Expiry: see the expiry date printed on the package.

Warning: do not use the medicine after the expiry date indicated on the package.

The expiry date refers to the product in intact packaging, correctly stored.

Conservation rules

Store in a dry place.

Composition and pharmaceutical form

COMPOSITION

ZYLORIC 100 mg Tablets

One tablet contains:

Active ingredient: allopurinol 100 mg

Excipients: lactose, corn starch, povidone, magnesium stearate.

ZYLORIC 300 mg Tablets

One tablet contains:

Active ingredient: allopurinol 300 mg

Excipients: lactose, corn starch, povidone, magnesium stearate.

PHARMACEUTICAL FORM AND CONTENT

ZYLORIC 100 mg Tablets: blister packs of 50 divisible tablets

ZYLORIC 300 mg Tablets: blister packs of 30 divisible tablets

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Zyloric can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZYLORIC TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

ZYLORIC 300 mg tablets

One tablet contains:

Active ingredient: allopurinol 300 mg

ZYLORIC 100 mg tablets

One tablet contains:

Active ingredient: allopurinol 100 mg

For the list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

ZYLORIC is indicated for the main clinical manifestations of uric acid / urate deposition. These include: joint gout, tophi and / or renal involvement due to crystal precipitation or urolithiasis.

These situations occur in gout, in uratic lithiasis and in acute uric acid nephropathy, in neoplastic and myeloproliferative diseases with high cell turnover, in which there are high levels of urate, either spontaneously or as a consequence of cytotoxic therapy and in certain enzymatic disorders. (especially Lesch-Nyhan syndrome).

ZYLORIC is also indicated for the prevention and treatment of oxalocalcic lithiasis in the presence of hyperuricemia and / or hyperuricuria.

04.2 Posology and method of administration

In adults, the average daily dose is 300 mg once a day.

When high uric acid and / or uricuria values ​​make higher doses necessary, the doctor may increase the dose up to a maximum of 800 mg divided into 2-3 daily administrations after meals.

In order to reduce the possibility of acute gout attacks it is recommended to start treatment at low doses (100 mg) with weekly increments of 100 mg until the optimal maintenance dosage is achieved.

Normalization of the uricaemic rate is achieved in a period of 1-3 weeks. For the prevention of secondary uratic nephropathies, consequent to excessive nucleoprotein catabolism in neoplastic diseases, treatment with ZYLORIC should be practiced, when possible, before cytotoxic therapy in order to correct any pre-existing hyperuricemia and / or hyperuricuria.

The therapy with ZYLORIC can be maintained during the antimitotic therapy and it can also be indefinitely prolonged in the prophylaxis of the hyperuricemia possibly arising during the natural crisis of the disease. In the prolonged treatment a dose of 300-400 mg / day of allopurinol is usually sufficient to normalize the uricaemic level. Since allopurinol and its metabolites are eliminated by the kidney, a prolongation of the plasma half-life of the drug may occur in case of poor function of this organ.

To avoid possible consequential risks, treatment can be started with a dose of 100 mg of allopurinol per day, increasing the dose only if the urinary or serum urate levels do not reduce adequately.

As an alternative to the suggested treatment, the dosage can be based on creatinine clearance values, according to the following scheme:


Creatinine clearance Dose above 20ml / min 300 mg / day between 10 and 20 ml / min 100-200 mg / day less than 10ml / min 100 mg / day or at longer intervals

Allopurinol and its metabolites are eliminated by renal dialysis. In patients undergoing hemodialysis two or three times a week a dose of 300-400 mg of ZYLORIC is recommended immediately after each dialysis. No further administration should be given between sessions. dialysis and the other.

In elderly patients, particular attention should be paid to maintaining the dosage to the minimum necessary to maintain normal serum and urinary levels of uric acid.

In boys and children under the age of 15, the dose is 10-20 mg / kg of body weight per day, or 100-400 mg per day. However, the indication in children is rare (leukemia and certain enzymatic disorders such as Lesch-Nyhan syndrome).

ZYLORIC should preferably always be taken at the same time of the day, after a meal.

04.3 Contraindications

Hypersensitivity to allopurinol or to any of the excipients.

ZYLORIC is contraindicated in the treatment of acute gout attacks.

04.4 Special warnings and appropriate precautions for use

Zyloric should be discontinued immediately when skin rash or other signs and symptoms of hypersensitivity occur. Zyloric must be discontinued immediately and permanently at the first signs of intolerance.

Hypersensitivity Syndrome, Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)

Hypersensitivity reactions to allopurinol can manifest in very different ways, including maculo-papular rash, hypersensitivity syndrome (also known as DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis (SSJ / TEN).

These reactions are clinical diagnoses; their appearance forms the basis for the clinical decision. If such reactions occur at any time during treatment, allopurinol should be discontinued immediately. Re-challenge should not be undertaken in patients with hypersensitivity syndrome and SSJ / TEN. Corticosteroids may be useful for overcome hypersensitivity skin reactions.

Patients should be informed of the signs and symptoms and monitored closely for skin reactions. The highest risk of developing SJS and TEN occurs in the first eight weeks of treatment.

If symptoms or signs of SJS or TEN occur (e.g. progressive skin rash often with blistering or mucosal lesions), treatment with ZYLORIC should be discontinued.

The best results in the management of SJS and TEN are obtained with an early diagnosis and immediate discontinuation of therapy with any suspect drug. Early discontinuation is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of ZYLORIC, ZYLORIC should no longer be used in this patient.

In rare cases, the allergic reaction manifests itself as a delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, vasculitis, lymphadenopathy, pseudo-lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and intrahepatic bile duct disappearance syndrome in various combinations. Other organs (e.g. liver, lungs, kidneys, pancreas, myocardium and colon) may also be involved. If anorexia, weight loss or pruritus occurs in patients receiving ZYLORIC, a liver function test should be included in the diagnostic evaluation.

In patients with pre-existing liver disease it is recommended to perform periodic liver function tests and to adopt appropriately reduced doses of the drug.

Hypersensitivity reactions may occur more easily in patients with renal function disorders who are taking ZYLORIC and thiazides at the same time.

Therefore, in this clinical setting, the above combination should be administered with caution and patients should be kept under close observation.

Allele HLA-B * 5801

The HLA-B * 5801 allele has been shown to be associated with the risk of developing allopurinol-related hypersensitivity syndrome and SJS / TEN. The frequency of the HLA-B * 5801 allele varies widely between ethnic groups: up to 20% in the Han Chinese population, about 12% in the Korean population, and 1-2% in individuals of Japanese or European descent. genotyping, as a screening tool for deciding whether or not to initiate allopurinol treatment, has not been established. If the patient is a known carrier of HLA-B * 5801, the use of allupurinol may be considered if the benefits are considered to outweigh the risks. Additional vigilance is required for signs of hypersensitivity syndrome or SJS / TEN and the patient should be informed of the need to stop treatment immediately at the first appearance of symptoms.

Asymptomatic hyperuricaemia is generally not considered in itself an indication for the use of ZYLORIC. Dietary and fluid changes, along with treatment of the underlying condition, can correct uricaemia.

Allopurinol treatment should not be started until a previous acute attack of gout has completely ended, since treatment with allopurinol may induce further attacks. If an acute attack develops in patients treated with allopurinol, therapy should continue with the same dosage, while the acute attack should be treated with an appropriate anti-inflammatory drug.

At the beginning of treatment with ZYLORIC an acute attack of gout may occur even in subjects with normal uricemia. It is therefore advisable to administer maintenance doses of colchicine prophylactically at the beginning of treatment. It is also advisable to start treatment with a low dose (100 mg / day) and increase it by 100 mg at weekly intervals until a uricaemia of 6 mg / 100 ml is reached and without exceeding the maximum recommended dose (800 mg / day). The use of colchicine or other anti-inflammatory drugs may be necessary in some cases to suppress gout attacks. Attacks usually become shorter and less severe after a few months of therapy. The mobilization of urates from tissue deposits causing blood level fluctuation of uric acid may be a possible explanation for these episodes.

Even with adequate therapy with ZYLORIC it can take many months to achieve control of acute attacks.

It is advisable to maintain a fluid intake such as to determine a daily urine volume of at least 2 liters, with neutral or slightly alkaline urine to avoid the theoretical possibility of formation of xanthine stones and to help prevent the precipitation of urate in patients taking concomitant uricosuric therapy.

Adequate therapy with ZYLORIC involves the dissolution of uric acid kidney stones with the remote risk of blocking them in the ureter.

Elevation of blood urea nitrogen has been reported in some patients with pre-existing kidney disease or low urate clearance during therapy with ZYLORIC.

Although the mechanism responsible for this has not been identified, patients with impaired renal function should be carefully observed at the start of administration of ZYLORIC. If the disturbance of renal function increases, the dosage of the drug should be reduced or discontinued.

Among patients whose renal dysfunction increased after initiation of ZYLORIC therapy, there were concomitant diseases such as multiple myeloma or congestive heart failure. Renal failure is also frequently associated with gouty nephropathy and rarely with associated hypersensitivity reactions. to ZYLORIC.

Allopurinol and its primary active metabolite oxipurinol are cleared by the kidney. For this reason, alterations in renal function have profound effects on dosage.

Bone marrow depression has been reported in patients receiving ZYLORIC. Most of these patients were taking concomitant therapies capable of producing this effect.

This occurred between 6 weeks and 6 years after the start of ZYLORIC therapy.

Rarely, individual patients treated with ZYLORIC alone may develop bone marrow depression of varying degrees, affecting one or more cell lines.

A reduced dosage should be used in patients with impaired hepatic or renal function. Patients being treated for hypertension or heart failure, eg with diuretics or ACE inhibitors, may have concomitant renal insufficiency and therefore allopurinol should be used with caution in this patient group.

In patients with decreased renal function or with concomitant diseases that can affect renal function such as hypertension or diabetes mellitus, renal function should be periodically monitored, in particular blood urea nitrogen and creatinine or creatinine clearance and possibly readjusted the dosage of ZYLORIC.

This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

In case of muscle distress, a measurement of CPK levels and other indicators of muscle damage should be undertaken. The alteration of these parameters involves the suspension of the therapy.

04.5 Interactions with other medicinal products and other forms of interaction

6-mercaptopurine and azathioprine

Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. In patients receiving 6-mercaptopurine or azathioprine the concomitant administration of 300-600 mg of ZYLORIC per day requires a reduction of the 6-mercaptopurine or azathioprine dose to approximately one third or one quarter of the usual dose. This is because the inhibition of xanthine oxidase determines a prolongation of the activity of these drugs.

The dose of mercaptopurine or azathioprine will subsequently be adjusted based on the evaluation of the therapeutic response and the appearance of toxic effects.

Vidarabine (Adenina Arabinoside)

In the presence of allopurinol, the plasma half-life of adenine arabinoside is increased. Particular care must be exercised when the two products are used concomitantly in order to highlight an increase in toxic effects.

Salicylates and uricosurics

Oxipurinol, the main metabolite of allopurinol, which is also therapeutically active, is excreted by the kidney in the same way as urates.

Therefore, uricosuric agents (such as probenecid or high doses of salicylates) may accelerate the excretion of oxypurinol. This may result in a decrease in the therapeutic activity of ZYLORIC but the clinical significance of this must be assessed on a case-by-case basis.

Concomitant administration of uricosuric agents and ZYLORIC was associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in the excretion of uric acid compared to those observed with ZYLORIC alone.

Although to date there are no clinical demonstrations of renal precipitation of oxypurines in patients receiving ZYLORIC, alone or in combination with uricosuric drugs, this possibility should be kept in mind on a case-by-case basis.

Chlorpropamide

If ZYLORIC is administered concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged blood glucose lowering activity as allopurinol and chlorpropamide may compete for excretion into the renal tubule.

Coumarin anticoagulants

There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when administered concomitantly with allopurinol. Therefore all patients taking anticoagulants should be closely monitored.

Phenytoin

Allopurinol may inhibit the hepatic oxidation of phenytoin but the clinical significance of this is unclear.

Theophylline

Inhibition of theophylline metabolism has been reported. The mechanism of interaction can be explained by the fact that xanthine oxidase is involved in the metabolism of theophylline in humans.

Theophylline levels should be monitored in patients starting allopurinol therapy or taking higher doses.

Ampicillin / Amoxicillin

An increased frequency of skin reactions has been reported in patients taking ampicillin or amoxicillin together with ZYLORIC compared to patients not receiving either drug. The cause of this association is unknown.

However, it is recommended that an alternative therapy to ampicillin or amoxicillin is used in patients receiving allopurinol when available.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mecloroetamine

In patients with neoplastic diseases other than leukemia, increased bone marrow depression from cyclophosphamide and other cytotoxics has been described in the presence of ZYLORIC, however in a controlled study in patients with lymphoma in combination therapy, ZYLORIC did not increase bone marrow toxicity. of cyclophosphamide, doxorubicin, bleomycin, procarbazine and / or mecloroetamine (mustine hydrochloride).

Cyclosporine

Some reports suggest that the plasma concentration of cyclosporine may be increased during concomitant treatment with allopurinol.Therefore, in case of simultaneous administration of the two drugs, the possibility of an increase in cyclosporine toxicity should be taken into account.

Didanosine

In healthy volunteers and in HIV infected patients administered didanosine, plasma Cmax and AUC values ​​of didanosine were approximately doubled with concomitant allopurinol (300 mg daily) without affecting the terminal half-life. dose reductions of didanosine may be required when used concomitantly with allupurinol.

Thiazide diuretics

Reports that concomitant use of ZYLORIC and thiazide diuretics may contribute to increased allopurinol toxicity in some patients have been reviewed in an attempt to establish the mechanism and cause-and-effect relationship.

Review of case descriptions indicates that most patients were receiving thiazide diuretics for hypertension and that evaluations that excluded renal impairment secondary to hypertensive nephropathy were often not performed.

In patients in whom renal insufficiency was documented, however, the recommendation to decrease the dose of ZYLORIC was not observed.

Although a mechanism or cause-and-effect relationship has not been established, renal function should be monitored in patients receiving ZYLORIC and thiazide diuretics, even in the absence of renal insufficiency, and the dosage should be further decreased in patients on combination therapy if detects decreased kidney function.

Tolbutamide

The conversion of tolbutamide to inactive metabolites has been shown to be catalysed by rat liver xanthine oxidase. The possible clinical relevance of these observations is not known.

04.6 Pregnancy and breastfeeding

Teratogenesis

A study in mice treated with intraperitoneal doses of 50 or 100 mg / kg on the 10th or 13th day of gestation revealed fetal abnormalities, however in a similar study in rats treated with 120 mg / kg on the 12th day of gestation no abnormalities were observed. . Large studies with high oral doses of allopurinol in mice up to 100 mg / kg / day, in rats up to 200 mg / kg / day and in rabbits up to 150 mg / kg / day from the eighth to the sixteenth day of gestation did not evidenced teratogenicity.A study in vitro performed using fetal salivary glands from cultured mice to detect embryotoxicity indicated that allopurinol is not expected to cause embryotoxicity without concomitant maternal toxicity.

Pregnancy and fertility

In a study conducted with high dose intraperitoneal allopurinol in mice, fetal abnormalities were observed, but in further studies with oral allopurinol in rats and rabbits, no abnormalities were observed. There is insufficient evidence available regarding the safety of ZYLORIC in human pregnancy, although it has been widely used for many years with no apparent adverse consequences.

Use in pregnancy is only recommended when there is no safer alternative and when the disease itself poses a risk to the mother or fetus.

Feeding time

The data indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4 mg / liter of allopurinol and 53.7 mg / liter of oxypurinol were found in the milk of a woman who took 300 mg of allopurinol daily.

As there are no data on the effects of allopurinol or its metabolites on the breastfed infant, administration of ZYLORIC to a nursing mother should be undertaken with caution.

04.7 Effects on ability to drive and use machines

Since adverse reactions such as somnolence, dizziness and ataxia have been reported in patients taking allopurinol, patients should exercise caution before driving, operating machinery or performing hazardous activities until they are reasonably certain that allopurinol does not has any negative influence on their performance.

04.8 Undesirable effects

The incidence of undesirable effects may vary according to the dose received and also to the possible concomitant administration of other therapeutic agents.

The frequency categories assigned to the adverse drug reactions below are estimates: for the majority of reactions no suitable data are available to calculate the incidence. Adverse drug reactions identified through post-marketing monitoring are to be considered rare or very rare. The following convention was used for frequency classification:

Very common ≥1 / 10 (≥10%)

Common ≥ 1/100 e

Uncommon ≥1 / 1,000 and

Rare ≥1 / 10,000 e

Very rare

Adverse reactions associated with allopurinol are rare in the overall treated population and are mostly mild in severity. The incidence is higher in the presence of renal and / or hepatic disorders.

Infections and infestations

Very rare: furunculosis

Disorders of the blood and lymphatic system

Very rare: agranulocytosis, aplastic anemia, thrombocytopenia, leukocytosis, pancytopenia

Very rare cases of thrombocytopenia, agranulocytosis and aplastic anemia have been reported, particularly in subjects with renal and / or hepatic insufficiency; this determines the need to pay particular attention to this group of patients.

Disorders of the immune system

Uncommon: hypersensitivity reactions

Very rare: Hypersensitivity syndrome or DRESS, angioimmunoblastic lymphadenopathy

Serious hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely (see Skin and subcutaneous tissue disorders).

A multi-organ delayed hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, rash, vasculitis, lymphadenopathy, pseudo-lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and disappearance syndrome intrahepatic bile ducts, manifests itself in various combinations. Other organs may also be involved (e.g. liver, lungs, kidneys,

pancreas, myocardium and colon). If such reactions occur at any time during treatment, allupyrinol treatment should be discontinued immediately and permanently.

When generalized hypersensitivity reactions occurred, renal and / or hepatic changes were generally present, particularly when the outcome was fatal.

Anaphylactic shock has been reported very rarely. Angioimmunoblastic lymphadenopathy, which appears to be reversible after discontinuation of allopurinol, has been described very rarely following biopsy for generalized lymphadenopathy.

Metabolism and nutrition disorders

Very rare: diabetes mellitus, hyperlipidaemia

Psychiatric disorders

Very rare: depression

Nervous system disorders

Very rare: coma, paralysis, ataxia, neuropathy, paraesthesia, somnolence, headache, altered taste

Eye disorders

Very rare: cataracts, visual disturbances, macular changes

Ear and labyrinth disorders

Very rare: dizziness

Cardiac pathologies

Very rare: angina, bradycardia

Vascular pathologies

Very rare: hypertension

Gastrointestinal disorders

Uncommon: vomiting, nausea

Very rare: recurrent haematemesis, steatorrhea, stomatitis, alvus alterations, gastrointestinal haemorrhage.

In early clinical studies, cases of nausea and vomiting were reported. More recent data suggests that these reactions are not a significant problem and can be avoided by taking allopurinol after meals.

Hepatobiliary disorders

Uncommon: asymptomatic increase in liver function test values

Rare: hepatitis (including hepatic necrosis and granulomatous hepatitis)

Hepatic dysfunction has been reported without overt evidence of more generalized hypersensitivity.

Skin and subcutaneous tissue disorders

Common: rash

Rare: Stevens-Johnston syndrome (SJS) and toxic epidermal necrolysis (TEN), angioedema, fixed drug eruption

Very rare: alopecia, hair discoloration.

Skin reactions are the most common reactions and can occur at any time during treatment. They can be itchy, maculopapular, sometimes scaly, sometimes purpuric, and rarely exfoliative. Allopurinol should be discontinued IMMEDIATELY when such reactions occur. After recovery from mild reactions, if desired, allopurinol can be re-introduced at a low dose (eg 50 mg / day) and gradually increased. If the rash recurs, allopurinol must be DEFINITELY discontinued as more severe hypersensitivity reactions may occur.

The risk of severe skin reactions such as SJS and TEN is not constant over time but appears to be limited to the first 8 weeks of treatment and is higher in patients taking 200 mg or more of allopurinol. In this period, the estimated excess risk of these severe skin reactions is 1.5 cases / week per million patients exposed to the drug.

Angioedema has been observed to occur with and without signs and symptoms of a more generalized hypersensitivity reaction to allopurinol.

Renal and urinary disorders

Very rare: haematuria, uremia

Diseases of the reproductive system and breast

Very rare: male infertility, erectile dysfunction, gynaecomastia

General disorders and administration site conditions

Very rare: edema, general malaise, asthenia, fever

Fever has been observed to occur with and without signs and symptoms of a more generalized hypersensitivity reaction to allopurinol (see Immune system disorders).

Also reported: diarrhea, gastritis, dyspepsia, intermittent abdominal pain, hepatomegaly, jaundice, hyperbilirubinemia, neuritis, renal failure, myopathy, epistaxis, ecchymosis, necrotizing angiitis, pericarditis, peripheral vascular disorders, thrombophlebitis, vasodilatation, hypercalcemia, hypercalcemia haemorrhagic, salivary gland enlargement, tongue edema, anorexia, bronchospasm, asthma, pharyngitis, rhinitis, iritis, conjunctivitis, amblyopia, paralysis, optic neuritis, confusion, dizziness, lower limb paralysis, decreased libido, tinnitus, insomnia , nocturnal enuresis, nephritis.

Acute attacks of joint gout may occur during the initial phase of therapy with ZYLORIC, as with uricosurics. Therefore a preventive treatment, for at least one month, with an anti-inflammatory or colchicine is recommended (see section 4.2 and section 4.4).

When urate formation is increased (e.g. neoplasms and related therapy, Lesch-Nyhan syndrome), precipitation of xanthine in the urinary tract may occur (see section 4.4).

Albuminuria has been observed in patients who developed clinical gout following chronic glomerulonephritis or chronic pyelonephritis. Fluid intake should be such as to ensure adequate urinary volume.

Xanthine crystals have been observed in the muscle tissue of patients receiving allopurinol, but this does not appear to have clinical significance.

04.9 Overdose

Symptoms and signs

Intake of allopurinol up to 22.5 g without experiencing adverse effects has been reported. In one patient who ingested allopurinol 20 g, signs and symptoms including nausea, vomiting, diarrhea and dizziness were reported. he recovered following the adoption of general support measures.

Treatment

Massive absorption of allopurinol can lead to a considerable inhibition of xanthine oxidase activity which should have no undesirable effects, beyond the possible influence on concomitantly administered drugs, especially 6-mercaptopurine and / or azathioprine. Adequate hydration to maintain optimal diuresis facilitates the excretion of allopurinol and its metabolites.

Dialysis may be used if deemed necessary.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout - preparations inhibiting the formation of uric acid.

ATC code: M04AA01.

Mechanism of action

Allopurinol inhibits xanthine oxidase.

Allopurinol and its main metabolite oxipurinol reduces the plasma and urinary level of uric acid by inhibiting xanthine oxidase, an enzyme that catalyzes the oxidation of hypoxanthine into xanthine and of the latter into uric acid.

Pharmacodynamic effects

In addition to the inhibition of purine catabolism, in some hyperuricaemic patients, but not in all, it causes a reduction in the synthesis de novo of purines by a mechanism of retroinhibition of hypoxanthine-guanine-phosphoribosyltransferase.

05.2 Pharmacokinetic properties

Absorption

Allopurinol is active for oral administration and is rapidly absorbed from the upper gastrointestinal tract. Allopuriniol was detected in the blood 30-60 minutes after administration. Estimates of bioavailability range from 67% to 90%. Peak plasma levels normally occur approximately 1.5 hours after oral administration of allopurinol but decrease rapidly and are hardly detectable after 6 hours. Peak plasma levels of oxypurinol generally occur 3 to 5 hours after oral administration of allopurinol and are much more sustained over time.

Distribution

Allopurinol is poorly bound to plasma proteins and therefore changes in protein binding are not thought to significantly alter clearance. The apparent volume of distribution is approximately 1.6 liters / kg, suggesting relatively large tissue absorption. Tissue concentrations of allopurinol have not been reported in humans but it is likely that both allopurinol and oxipurinol are present in higher concentrations in the liver and intestinal mucosa, where xanthine oxidase activity is elevated.

Metabolism

The major metabolite of allopurinol is oxipurinol. Other metabolites of allopurinol include allopurinol riboside and oxipurinol-7-riboside.

Elimination

Approximately 20% of the ingested dose of allopurinol is excreted in the faeces. Elimination of allopurinol occurs primarily by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase. Less than 10% of unchanged drug is excreted in the urine. Allopurinol has a plasma half-life ranging from 0.5 to 1 , About 5 hours.

Oxipurinol is a less potent xanthine oxidase inhibitor than allopurinol, but its plasma half-life is much longer. It is estimated to vary in humans from 13 to 30 hours. Thus, effective inhibition of xanthine oxidase for 24 hours is achieved with a single daily oral dose of allopurinol. Patients with normal renal function gradually accumulate oxypurinol until reaching steady-state plasma These patients, with the dose of 300 mg allopurinol per day, generally have plasma concentrations of oxypurinol of 5-10 mg / liter.

Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Values ​​from 13.6 hours to 29 hours of elimination half-life have been reported. The large variability in these values ​​can be explained by changes in study design and / or creatinine clearance in patients.

Special patient populations

Kidney failure

The clearance of allopurinol and oxipurinol is significantly reduced in patients with poor renal function: resulting in high plasma levels during chronic therapy. Patients with renal insufficiency (creatinine clearance values ​​of 10-20 ml / min) had plasma concentrations of oxypurinol of approximately 30 mg / liter after prolonged treatment with 300 mg of allopurinol per day. This concentration corresponds approximately to that which would be achieved in patients with normal renal function with doses of 600 mg / day. Therefore, a reduction in the dose of allopurinol is necessary in patients with renal insufficiency.

Senior citizens

Kinetic changes of the drug are not expected except due to deterioration of renal function (see pharmacokinetics in patients with renal insufficiency).

05.3 Preclinical safety data

Mutagenesis

Cytogenesis studies have shown that allopurinol does not induce chromosomal aberrations in human blood cells in vitro at concentrations up to 100 mcg / ml ed in vivo at doses up to 600 mg / day for an average period of 40 months.

Allopurinol does not produce nitrous compounds in vitro, nor does it negatively affect lymphocyte transformation in vitro. Evidence from biochemical and other cytological studies is strongly suggestive that allopurinol has no adverse effects on DNA at any stage of the cell cycle and is not mutagenic.

Carcinogenesis

No evidence of carcinogenicity was demonstrated in mice and rats treated with allopurinol for up to 2 years.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

lactose, corn starch, povidone, magnesium stearate

06.2 Incompatibility

Incompatibilities with other medicines are unknown.

06.3 Period of validity

5 years.

06.4 Special precautions for storage

Store in a dry place.

06.5 Nature of the immediate packaging and contents of the package

ZYLORIC 100 mg Tablets: Blister packs of 50 divisible tablets

ZYLORIC 300 mg Tablets: Blister packs of 30 divisible tablets

06.6 Instructions for use and handling

07.0 MARKETING AUTHORIZATION HOLDER

Teofarma S.r.l. - Via F.lli Cervi, 8 - 27010 Valle Salimbene (PV)

08.0 MARKETING AUTHORIZATION NUMBER

ZYLORIC 100 mg Tablets A.I.C .: 021259015

ZYLORIC 300 mg Tablets A.I.C .: 021259027

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

December 1968 / May 2010

10.0 DATE OF REVISION OF THE TEXT

AIFA determination of 10 February 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  liver-health drugs-hypertension medicinal-herbs