Allopurinol Tablets Bp 300mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Allopurinol Tablets 300 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Allopurinol 300 mg per tablet.
For excipients, see 6.1.
3. PHARMACEUTICAL FORM
Allopurinol Tablets 300 mg are presented as white, normal convex tablets engraved with the company logo on one side and A330 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Allopurinol is indicated for reducing urate/uric acid formation in conditions where urate/uric acid deposition has already occurred or is a predictable clinical risk eg.
1. For prophylaxis of gout, gouty arthritis, skin tophi, nephrolithiasis.
2. Hyperuricaemia associated with leukaemia, radiotherapy, antineoplastic agents and during therapy with diuretics of the thiazide or similar type.
3. Prophylaxis of uric acid and calcium oxalate renal stones.
4. Certain enzyme disorders which lead to over production of urate for example Lesch-Nyhan syndrome.
4.2 Posology and method of administration Adults:
Chronic gout and gouty arthritis. prophylaxis of uric acid and calcium oxalate renal stones, hyperuricaemia - diuretic therapy of thiazide or similar type.
Initial dose: 100 mg daily increased by 100 mg at weekly intervals until the desired concentration of uric acid is reached. Doses in excess of 300 mg should be administered in divided doses. In the early stage of treatment with allopurinol, an acute attack of gouty arthritis may be precipitated. It is advisable to give a prophylactic dose of colchicine or an anti-inflammatory analgesic for about one month.
Usual maintenance dose: 200 - 600 mg per day.
In severe conditions: 700 - 900 mg per day
Hyperuricaemia associated with leukaemia, radiotherapy or antineoplastic agents: Therapy should commence 2 - 3 days prior to initiation of chemotherapy or radiotherapy.
Initial dose: 200 mg three times daily and adjusted as required to a usual maintenance dose of 300 - 400 mg daily.
Children under 15 years: : 10 - 20 mg/kg bodyweight/day up to a maximum of 400 mg daily. Use in children is rarely indicated except in malignant conditions especially leukaemia and certain enzyme disorders such as Lesch-Nyhan syndrome
Elderly: Maintenance dose should be the minimum required to maintain serum and urinary urate levels normal.
Dose recommendation in impaired renal function in adults:
If creatinine clearance exceeds 20 ml/minute - give standard dose.
If creatinine clearance is between 20 and 10 ml/minute - give 100 - 200 mg/day.
If creatine clearance is less than 10 ml/min - give 100 mg/day or at longer intervals.
Dose recommendations in renal dialysis:
300 - 400 mg after each dialysis with none in the interim.
Dosage in hepatic impairment:
Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.
Treatment of high urate turnover conditions, eg. Neoplasia, Lesch-Nyhan syndrome:
It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with allopurinol before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum diuresis and to attempt alkalinisation of urine to increase solubility or urinary urate/uric acid. Dosage of allopurinol should be at the lower end of the recommended dosage schedule.
Route of administration: Oral. May be taken once daily after a meal.
Hypersensitivity to allopurinol or to any of the excipients.
Allopurinol is contraindicated as a treatment for the acute attack of gout.
4.4 Special warnings and precautions for use
Acute gouty attacks: Treatment with allopurinol should not be started during an attack of gout or unless completely subsided, as further attacks may be precipitated.
In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for at least one month. 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 acute attack is treated with a suitable anti-inflammatory agent.
Allopurinol potentiates the effects of 6-mercaptopurine or azathioprine.
It has been suggested that iron salts and allopurinol should not be given concomitantly to patients with idiopathic haemochromatosis and that allopurinol should not be given to the immediate relatives of such patients. Alcohol, antineoplastic agents, cytotoxic drugs, diazoxide, etacrynic acid, furosemide, mecamylamine or pyrazinamide may increase serum uric acid concentrations, therefore, dosage of allopurinol needs to be adjusted accordingly. Ampicillin, when concurrently administered with allopurinol may increase the possibility of skin rash.
Cyclophosphamide and possibly other antineoplastic agents when administered concurrently with allopurinol increase the risk of bone marrow depression.
Care should be taken when administering allopurinol and thiazide diuretics concurrently in patients with known or possible renal impairment as there is possibility of a severe hypersensitivity reaction to allopurinol.
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.
Drugs that acidify urine may increase the possibility of xanthine kidney stones when used concurrently with allopurinol.
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.
When vidarabine is used concurrently with allopurinol it increases the risk of neurotoxicity and other side effects such as anaemia, nausea, pain and pruritus.
Hypersensitivity syndrome, SJS and TEN
Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and life threatening cutaneous reactions, Stevens Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN). These reactions are clinical diagnoses, and their clinical presentations remain the basis for decision making. 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 weeks of treatment. If such reactions (e.g progressive skin rash often with blisters or mucosal lesions) occur at any time during treatment, allopurinol should be withdrawn immediately. Early withdrawal is associated with a better prognosis. Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
If the patient has developed SJS or TEN with the use of allopurinol, allopurinol must not be restarted in this patient at any time.
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).
Chronic renal impairment
Patients with chronic renal impairment may be at increased risk of developing hypersensitivity reactions including SJS/TEN associated with allopurinol. Extra vigilance for the signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately and permanently at the first appearance of symptoms (see section 4.8).
Hepatic or renal impairment
A reduction in dosage should be considered in the presence of renal and/or hepatic disorders (see section 4.2). 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
6-Mercaptopurine or Azathioprine: Allopurinol potentiates the effects of 6-mercaptopurine or azathioprine when given concurrently with allopurinol. Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given concurrently with allopurinol, only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.
The manufacturer of capecitabine (prodrug of fluorouracil) advises that concurrent use should be avoided
Coumarin anticoagulants: When administering anticoagulants of coumarin-derivatives (eg. warfarin), the anticoagulant effects may be potentiated when used concurrently with allopurinol because of inhibition of enzymatic metabolism of the anticoagulant, therefore, all patients receiving anticoagulants must be carefully monitored.
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.
Chlorpropamide: There may be a risk of prolonged hypoglycaemic activity when a patient on chlorpropamide is given allopurinol, as allopurinol and chlorpropamide may compete for excretion in the renal tubule.
When allopurinol and sulfinpyrazone are taken concomitantly there is an additive antihyperuricemic effect.
Theophylline: Concurrent administration of large dose (600mg/day) of allopurinol with xanthines may decrease theophylline clearance resulting in an increase in serum theophylline concentration. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man. Therefore, serum concentration should be monitored and theophylline dosage adjusted as required.
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.
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.
Didanosine: 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.
ACE Inhibitors and Angiotensin-II Antagonists: There is an increased risk of toxicity with captopril, especially in patients with renal impairment.
Ciclosporin: When taken concomitantly with allopurinol, the plasma
ciclosporin concentration is possibly increased; the possibility of enhanced ciclosporin toxicity which increases the risk of nephrotoxicity, should be considered if the drugs are co-administered.
4.6 Pregnancy and lactation
There is no evidence to suggest that allopurinol taken orally causes foetal abnormalities in humans, it has been in wide use for many years without apparent ill consequence. High dose intraperitoneal allopurinol has been associated with foetal abnormalities in mice. Extensive studies in animals with oral allopurinol, however, have shown none. Nevertheless, risk-benefit must be considered because the effect of xanthine oxidase inhibition on the human foetus is not known. As with all drugs, due caution should be exercised in the use of allopurinol in pregnancy and used only when there is no safer alternative and when the disease itself carries risk for the mother or unborn child.
Allopurinol is excreted in breast milk. It is therefore recommended that caution should be exercised if breast-feeding when undergoing treatment with allopurinol. Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from woman taking allopurinol 300 mg/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.
4.8 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:
Very common >1/10 ( >10%)
Common >1/100 and <1/10 ( >1% and <10%)
Uncommon >1/1000 and <1/100 ( >0.1% and <1%)
Rare >1/10,000 and <1/1000 ( >0.01% and <0.1%)
Very rare <1/10,000 (<0.01%)
Adverse reactions in association with allopurinol are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.
Infections and infestations
Very rare: Furunculosis
Blood and lymphatic system disorders
Rare: Blood dyscrasias
Very rare: Agranulocytosis, aplastic anaemia, thrombocytopenia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
Immune system disorders
Uncommon: Hypersensitivity reactions
Very rare: Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
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 rarely acute anaphylactic shock has been reported.
Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
Metabolism and nutrition disorders
Very rare: Diabetes mellitus, hyperlipidaemia
Psychiatric disorders
Very rare: Depression Nervous system disorders
Rare : Peripheral neuritis
Very rare: Coma, paralysis, ataxia, neuropathy, paraesthesiae, somnolence, headache, taste perversion.
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
Respiratory, thoracic and mediastinal disorders
Rare: Sore throat
Gastrointestinal disorders
Uncommon: Vomiting, nausea Rare : Diarrhoea
Very rare: Recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit
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: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).
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, sometimes purpuric and rarely exfoliative, such as Stevens- Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).
Allopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions, allopurinol may, if desired, be reintroduced at a small dose (e.g. 50mg/day) and gradually increased. If the rash recurs, Allopurinol should be permanently withdrawn as more severe hypersensitivity may occur (see Immune system disorders).
Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.
Musculoskeletal and connective tissue disorders
Rare: Loin pain, aches and pains in muscles Renal and urinary disorders
Rare: dysuria.
Very rare: Haematuria, uraemia
Reproductive system and breast disorders
Very rare: Male infertility, erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Rare: chills.
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).
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
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20g allopurinol. Recovery followed general supportive measures.There are no reports of overdosage or acute intoxication but the most likely reaction would be gastrointestinal intolerance. Massive absorption of allopurinol leads to considerable inhibition of xanthine oxidase activity which should have no untoward effects unless 6-mercaptopurine and/or azathioprine is being taken concomitantly. There is increased activity of these drugs. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites.
Dialysis may be performed if considered necessary.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Allopurinol and its metabolite oxypurinol decrease the production of uric acid from mono and di substitutes purine by inhibiting the action of xanthine oxidase. Xanthine oxidase is the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Serum levels of hypoxanthine and xanthine, however, remain low because of their high renal clearance rates and because of their re-entry into purine metabolic processes. Hypoxanthine and xanthine may be re-utilised for nucleotide and nucleic acid synthesis via an action involving the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPR tase). The resultant increase in nucleotide concentration leads to feedback inhibition of purine biosynthesis. Allopurinol thereby decreases uric acid concentration in both serum and urine and maintains a normal level in blood as long as the therapy is continued regularly. Acute attacks of gout may precipitate in the early stages of treatment especially if the drug is started in full dosage. After a few months of therapy, attacks become infrequent and/or finally stop altogether.
Allopurinol prevents or decreases urate deposition thereby preventing the occurrence/progression of gouty arthritis and urate nephropathy. In patients with chronic gout, allopurinol may prevent or decrease tophi formation and chronic joint changes promote resolution of existing urate crystals and deposits and reduce the risk of uric acid calculi.
Reduction in urine urate concentration prevents or decreases the formation of uric acid or calculi thereby reducing the incidence of urinary calculi and preventing damage to the kidneys.
Allopurinol should be administered with care to patients with renal impairment and in advanced renal failure where uricosuric agents may become ineffective. Allopurinol may be used for the prevention of uric acid nephropathy due to excessive nucleoprotein catabolism disease especially during treatment with x-rays or cytotoxic drugs. Allopurinol may be combined with uricosuric agents if an adequate serum level cannot be maintained.
5.2 Pharmacokinetic properties
Allopurinol is absorbed from the gastrointestinal tract. About 80-90% is absorbed, following a single 300 mg oral dose. Allopurinol is primarily metabolised in the liver. About 70% of the dose is metabolised to the active metabolite oxypurinol.
Half-life of allopurinol is 1-3 hours compared with oxypurinol which is 12-30 hours (average being 15 hours). Half-life may be greatly prolonged in patients with renal impairment. Plasma levels after a 300 mg oral dose approach 2 mcg/ml. The long half-life of oxypurinol enables the once daily allopurinol regimen feasible since oxypurinol itself is a potent xanthine oxidase inhibitor.
A significant reduction in serum uric acid concentration usually occurs within 2-3 days. In some patients especially with severe tophaceous deposits or those who are underexcretors of uric acid, significant reduction of serum and urine uric acid concentrations may be delayed, possibly because of mobilisation of urate from existing tissue deposits.
Peak serum concentrations of allopurinol and oxypurinol are attained after 0.52 hours and 4.5-5 hours respectively following a single 300 mg dose.
Peak serum concentrations following a single 300 mg dose for allopurinol is about 2 mcg/ml and for oxypurinol is 5 mcg/ml and this may increase to 30 -40 mcg/ml in patients with renal impairment.
The serum uric acid concentration usually returns to the pretreatment value after 1-2 weeks of discontinuation of therapy.
Both allopurinol and oxypurinol are distributed into total body fluid. Allopurinol and oxypurinol are not bound to serum proteins and are excreted mainly in urine. Allopurinol is cleared by glomerular filtration, oxypurinol undergoes tubular reabsorption, resulting in lower oxypurinol levels and hence less xanthine oxidase inhibition.
Patients with impaired renal function require lower than normal doses of allopurinol. Allopurinol and oxypurinol are dialyzable, therefore can be administered to patients undergoing haemodialysis.
About ten per cent of allopurinol is excreted unchanged by the kidneys and 70% as oxypurinol. The remainder may be excreted by unidentified routes as other metabolites or in the faeces probably as unabsorbed allopurinol.
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 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.
An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Sodium starch glycollate Povidone
Magnesium stearate
6.2 Incompatibilities
None reported
6.3 Shelf life
|
Opaque plastic containers: |
3 years |
|
Aluminium/opaque PVC blisters: |
2 years |
6.4 Special precautions for storage
Store in container provided. Do not store above 25°C.
6.5 Nature and contents of container
Opaque plastic containers composed of polypropylene tubes and polyethylene tamper-evident closures for pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000 tablets. Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000) with packing inclusion of polyether foam or polyethylene or polypropylene filler.
Blister packs of aluminium/opaque PVC blister packs. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 42, 56, 84 and 112.
Not all pack sizes may be marketed.
6.6 Instructions for use/handling
No special instructions for use/handling.
MARKETING AUTHORISATION HOLDER
7.
Crescent Pharma limited Units 3 and 4
Quidhampton Business Units
Polhampton Lane
Overton
Hants
RG25 3ED
UK
8. MARKETING AUTHORISATION NUMBER
PL 20416 / 0003
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29 March 2004
10 DATE OF REVISION OF THE TEXT
22/03/2015