SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Allopurinol Tablets 100mg Uricto 100mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains allopurinol BP 100mg

3    PHARMACEUTICAL FORM

White, circular, biconvex, uncoated tablets with “A1” embossed on one side. Diameter 9.5mm

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Gout. Primary hyperuricaemia. Secondary hyperuricaemia. Prophylaxis of uric acid and calcium oxalate stones.

4.2 Posology and method of administration

Adults:

The initial dose is 100mg to 200mg. The maintenance dose is 200mg to 600mg daily. Maximum single dose 300mg. It has rarely been found necessary to exceed 900mg per day. The dose should be adjusted by monitoring serum uric acid and/or urinary uric acid levels at appropriate intervals until the desired effect is attained, which may take 1 to 3 weeks.

Elderly patients:

The dose should be maintained at the minimum necessary to maintain normal serum and urinary urate levels.

Children:

10mg to 20mg/kg body weight/day. Use in children is mainly indicated in malignant conditions, especially leukaemia and certain enzyme disorders, for example Lesch-Nyhan syndrome.

Patients with hepatic disease:

The dosage of allopurinol should be reduced in patients with hepatic disease.

Dose recommendations in impaired renal function:

Allopurinol and its metabolites are excreted via the kidney. Impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action.

The amount and frequency of the dosage may require reduction as indicated by monitoring serum uric acid levels. The following schedule is provided for guidance in adults.

Creatinine Clearance	Dose
Greater than 20ml/minute 10ml to 20ml/minute 2ml to 10ml/minute	Standard dose 100mg to 200mg/day 100mg/day or at longer intervals

Dose recommendations in renal dialysis:

Allopurinol and its metabolites are removed by renal dialysis. If frequent dialysis is required an alternative schedule of 300mg to 400mg allopurinol after each dialysis with none in the interim should be considered.

Initiation of therapy:

In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore, it is advisable to give a prophylactic dose of a suitable anti-inflammatory agent or colchicine (0.5mg, 3 times a day) for at least 1 month.

Use with uricosurics:

Allopurinol does not interfere with the action of uricosuric agents. When changing from uricosuric therapy to allopurinol, 1 to 3 weeks overlap of treatment is recommended to ensure a continuous hypouricaemic effect.

Use in neoplasia:

When giving allopurinol to prevent uric acid nephropathy in neoplastic conditions, it is advisable to start treatment with Allopurinol before cytotoxic therapy.

Method of administration: Oral

4.3    Contraindications

Acute gout. Known hypersensitivity to Allopurinol or to any of the components of the formulation.

Treatment for an acute attack of gout; prophylactic therapy may be commenced when the acute attack has completely subsided, provided antiinflammatory agents are also taken.

4.4    Special warnings and precautions for use

Use in the elderly: the dose should be maintained at the minimum necessary to maintain serum and urinary urate levels.

Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see section 4.8).

A reduction in dosage should be considered in the presence of severe renal or hepatic disorders.

Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported with the use of allopurinol.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first week of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, allopurinol treatment should be discontinued.

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has also been reported with the use of allopurinol. DRESS is characterised by fever, eosinophilia, atypical circulating lymphocites, lymphadenopathy and hepatitis.

Hypersensitivity syndrome, SJS and TEN

Allopurinol 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, allopurinol 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 allopurinol 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, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the patient is a known carrier of HLA-B*5801, the use of allopurinol may be considered if 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 (see section 4.8).

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

Asymptomatic hyperuricaemia per se is generally not considered an indication for use of allopurinol. Fluid and dietary modification with management of the underlying cause may correct the condition.

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

In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicines 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 allopurinol, treatment should continue at the same dosage while the attack is treated with a suitable antiinflammatory 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 allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Lactose intolerance: Allopurinol tablets contain lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

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

ACE Inhibitors: increased risk of toxicity when allopurinol is given with captopril especially in renal impairment. Concurrent use of allopurinol and ACE inhibitors may lead to an increased risk of haematological reactions such as leucopenia, especially if there is pre-existing renal failure.

Ampicillin/Amoxicillin: An increase in frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol an alternative to ampicillin or amoxicillin is used where available

Coumarin anticoagulants: There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with allopurinol, therefore, all patients receiving anticoagulants must be carefully monitored. Although there is no evidence that an interaction between allopurinol and the coumarins seen under experimental conditions has any clinical significance, this possibility should be borne in mind when a patient on oral anticoagulants is given allopurinol.

Didanosin: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half-life. Co-administration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.

Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are coadministered.

Cytotoxics: allopurinol enhances effects and increase toxicity of azathioprine and mercaptopurine (reduce dose of azathioprine and mercaptopurine) avoidance of allopurinol advised by the manufacturer of capecitabine. Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given oxidase will prolong their activity.

Diuretics: Increased risk of hypersensitivity when allopurinol is given with thiazides and related diuretics especially in renal impairment.

Theophylline: Inhibition of the metabolism of theophylline has been reported. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man. Theophylline levels should be monitored in patients starting or increasing allopurinol therapy

Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of vidarabine is increased in the presence of allopurinol. When the two products are used concomitantly extra vigilance is necessary, to recognise enhanced toxic effects.

Salicylates and uricosuric agents: Oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity such as probenecid or 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.

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

Cyclophosphamide,    doxorubicin,    bleomycin,    procarbazine,

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

6-mercaptopurine and azathioprine: If azathioprine or 6-mercaptopurine is given concurrently with allopurinol, the dose of these agents should only be one quarter of that usually given as inhibition of xanthine oxidase will prolong their activity.

Antacids: Allopurinol may fail to reduce the blood-uric-acid concentrations when given at the same time as aluminium hydroxide. Intake of antacids and allopurinol should not separated by 3 hours.

4.6    Fertility, pregnancy and lactation

High dose intraperitoneal allopurinol in mice has been associated with foetal abnormalities but extensive animal studies with oral allopurinol have shown none. In human pregnancy, there is no evidence that allopurinol taken orally causes foetal abnormalities; however, as with all drugs, caution should be exercised in the use of allopurinol during pregnancy.

There is inadequate evidence of safety of allopurinol in human pregnancy, although it has been in wide use for many years without apparent ill consequence.

Use in pregnancy only when there is no safer alternative and when the disease itself carries risk for the mother or unborn child.

Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7mg/litre oxipurinol have been demonstrated in breast milk from woman taking allopurinol 300mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

4.7    Effects on ability to drive and use machines

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

Undesirable effects

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 through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency:

>1/10 (> 10%)

>1/100 and <1/10 (>1% and <10%)

>1/1000 and <1/100 (>0.1% and <1%) >1/10,000 and <1/1000 (>0.01% and <0.1%) <1/10,000 (<0.01%)

Adverse reactions in association with allopurinol are usually rare and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorders.

Infections and infestations Very rare: furunculosis

Blood and lymphatic system disorders

Very rare: agranulocytosis, aplastic anaemia, thrombocytopenia

Frequency not known: leucopenia, eosinophilia, haemolytic anaemia

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.

Reports of transient reduction in the number of circulating formed elements of the blood are usually in association with a renal and/or hepatic disorder reinforcing the need for particular care in this group of patients.

Immune system disorders Uncommon: hypersensitivity reactions

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). If such reactions do occur, it may be at any time during treatment, allopurinol should be withdrawn immediately and permanently.

When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal (see section 4.4).

Very rare: Angioimmunoblastic lymphadenopathy

Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.

Frequency not known: arthralgia

Associated vasculitis and tissue response may be manifested in various ways including hepatitis, interstitial nephritis and, very rarely, epilepsy. Corticosteroids may be beneficial in overcoming them. When generalised hypersensitivity reactions have occurred, a renal and/or hepatic disorder has usually been present, particularly when the outcome has been fatal.

Metabolism and Nutritional disorders:

Very rare: diabetes mellitus, hyperlipaemia Frequency not known: exacerbation of gouty attacks

Psychiatric disorders:

Very rare: depression

Nervous system disorders:

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

Frequency not known: dizziness Eye disorders:

Very rare: cataract, visual disorder, macular changes Ear and labyrinth disorders:

Very rare: vertigo

Cardiac disorders

Very rare: angina, bradycardia

Vascular disorders Very rare: hypertension

Frequency not known: vasculitis

Gastrointestinal disorders Uncommon: vomiting nausea

Very rare: recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit.

Frequency not known: diarrhoea, abdominal pain.

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 allopurinol after meals.

Hepatobiliary disorders

Uncommon: asymptomatic increases in liver function tests

Rare: hepatitis (including hepatic necrosis and granulomatous hepatitis)

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

Skin and subcutaneous tissue disorders Common: rash

Rare: Stevens Johnson syndrome/toxic epidermal necrolysis

Very rare: angioedema, fixed drug eruption, alopecia, discoloured hair

Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly or purpuric and rarely exfoliative such as Stevens Johnson syndrome and toxic epidermal necrolysis.

Allopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions allopurinol may, if desired, be reintroduced at a low dose (e.g. 50mg/day) which may be gradually increased. If the rash recurs, allopurinol should be permanently withdrawn.

Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN) have been reported.

Frequency not known: skin reaction associated with eosinophilia, urticaria.

Drug Rash with Eosinophilia and Systemic Symptoms has been reported. Some cases have had a fatal outcome.

The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.

Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction

If desired, after recovery from mild reactions, allopurinol may be reintroduced at a low dose (e.g. 50mg/day) which may be gradually increased. If the rash recurs, allopurinol should be permanently withdrawn.

The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers. However, the use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established.

Renal and urinary disorders:

Very rare: haematuria, uraemia

Frequency not known: nephrolithiasis

Reproductive system and breast disorders:

Very rare: male infertility, erectile dysfunction, gynaecomastia,

Frequency not known: nocturnal emissions

General disorders and administration site conditions:

Very rare: oedema, general malaise, asthenia, fever

Fever has been reported to occur with and without signs and symptoms of a more generalised allopurinol hypersensitivity reaction (see immune system disorders)

Miscellaneous: exacerbation of acute gouty attacks may occur in the early stages of hypouricaemic therapy, see sub-section 4.2 Posology and Method of Administration. In those conditions where the body’s miscible urate pool is greatly increased (e.g. malignant disease and its treatment; Lesch-Nyhan syndrome), the rise in the xanthine concentration resulting from the action of allopurinol may lead to tissue deposits of xanthine. Fluid intake should ensure adequate urinary output. Xanthine crystals have been seen in the muscle tissue of patients receiving allopurinol, but this appears to have no clinical significance.

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.

4.9 Overdose

No reports of overdosage or acute intoxication are available. The most likely reaction would be gastro-intestinal tolerance. Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless 6-mercaptopurine, adenine, arabinoside, and/or azathioprine is being taken concurrently. In this case, the risk of increased activity of these drugs must be recognised. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Dialysis may be resorted to if considered necessary.

Symptoms

Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and abdominal pain. Rarely, there may be renal insufficiency and hepatitis.

Treatment

The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50g for adults; 1g/kg for children) if the patient presents within 1 hour of ingestion of more than 50mg/kg. If more than 50mg/kg has been ingested check U&Es and LFTs.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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

5.2    Pharmacokinetic properties

Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after 3-5 hours after oral administration of allopurinol and are much more sustained.

Allopurinol 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 allopurinol is approximately 1.6 litre/kg which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.

Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol 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. Allopurinol has a plasma half-life of about 1 to 2 hours.

Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, 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 allopurinol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10mg/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.

Allopurinol 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 20ml/min, showed plasma oxipurinol concentrations of approximately 30mg/litre after prolonged treatment with 300mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600mg/day in those with normal renal function. A reduction in the dose of allopurinol is therefore required in patients with renal impairment.

Pharmacokinetics in elderly patients.

The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see Pharmacokinetics in patients with renal impairment).

5.3 Preclinical safety data

A.    Mutagenicity

Cytogenetic studies show that allopurinol 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 mean period of 40 months.

Allopurinol does not produce nitraso compounds in vitro or affect lymphocyte transformation in vitro.

Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.

B.    Carcinogenicity

No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.

C.    Teratogenicity

One study in mice receiving intraperitoneal doses of 50 or 100mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up to 100mg/kg/day, rats up to 200mg/kg/day and rabbits up to 150mg/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 allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose, maize starch, povidone, magnesium stearate

6.2    Incompatibilities

None known.

6.3    Shelf life

60 months.

6.4    Special precautions for storage

Store in a cool, dry place and protect from light.

6.5    Nature and contents of container

Securitainer with polyethylene closures.

Blister strips comprising 250pm PVC film and 20pm Aluminium foil packed into an outer carton.

Pack sizes: 28, 30, 56, 60, 84, 90 and 250.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/10/2006

10 DATE OF REVISION OF THE TEXT

03/06/2014