Astellas Pharma Co. Ltd

Difene ampoules 75 mg/3 ml

Contains Diclofenac sodium.. 75 mg/3 ml.

Each ampoule contains 25mg/ml of diclofenac sodium.

For excipients, see section 6.1.

Solution for intramuscular injection or concentrate for solution for infusion.

A clear colourless solution.

Intramuscular use:

Difene can be used in the symptomatic management of acute exacerbation of rheumatoid arthritis and osteoarthritis, in acute back pain, acute gout, post operative pain, relief of pain in acute traumatic musculo-skeletal disorders and fractures and renal colic.

Intravenous infusion:

For treatment or prevention of post-operative pain in the hospital setting.

For intravenous infusion or intramuscular use only.

Adults:

Intravenous use:

One ampoule should be diluted in a minimum of 300 ml of normal saline and administered intravenously over a minimum of 30 minutes. A second dose may be administered 8 hours after the first infusion.

A maximum of two doses may be given intraveneously.

Intramuscular use:

One ampoule once (or in severe cases twice) daily intramuscularly by deep intragluteal injection into the upper outer quadrant. If two injections daily are required it is advised that the alternative buttock be used for the second injection.

Renal colic: One 75 mg ampoule intramuscularly. A further ampoule may be administered after 30 minutes if necessary.

As with oral Difene the total daily dose should not exceed 150 mg. Difene ampoules should not be given for more than 2 days; if necessary, treatment can be continued with capsules or suppositories.

Elderly: NSAIDS should be used with particular caution in elderly patients who are more prone to adverse events. The lowest dose compatible with adequate safe clinical control should be employed. See also Section 4.4.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

Children: Not suitable for children

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Patients with a history of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to diclofenac, aspirin, nonsteroidal anti-inflammatory drugs or any components of the preparation.

Severe heart failure.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The use of Difene Ampoules with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Warnings:

Gastro-intestinal: Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of previous GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5).

Patients with a history of GI toxicity especially when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

When GI bleeding or ulceration occurs in patients receiving DifeneAmpoules, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8 – undesirable effects).

Cardiovascular and cerebrovascular effects

Caution and appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg initiating daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before longer- term treatment of patient with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Hepatic: Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.

Hypersensitivity reactions: As with other nonsteroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Serious skin reaction, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 4.8). Patients appear to be at the highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Difene Ampoules should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The use of Difene Ampoules may impair the female fertility and is not recommended in women attempting to conceive. In woman who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Difene Ampoules should be considered.

Like other NSAIDs, Difene may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Precautions:

Renal: Patients with renal, cardiac or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDS may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored prior to the initiation of therapy and regularly thereafter.

The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of Difene.

Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Difene should be discontinued. Hepatitis may occur without prodromal symptoms. Use of Difene in patients with hepatic porphyria may trigger an attack.

Haematological: As with other NSAIDs, Difene may reversibly inhibit platelet aggregation (see anticoagulants in "drug interactions"). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Long-term treatment: All patients who are receiving non-steroidal anti-inflammatory agents should be monitored as a precautionary measure e.g. hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.

May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old..

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

Lithium and digoxin: Difene may increase plasma concentrations of lithium and digoxin.

Anti-coagulants: NSAIDSs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Antidiabetic agents: Clinical studies have shown that Difene can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.

Cyclosporin: Cases of nephrotoxicity have been reported in patients receiving concomitant cyclosporin and NSAIDS, including Difene. This might be mediated through combined renal antiprostaglandin effects of both the NSAID and cyclosporin.

Methotrexate: Cases of serious toxicity have been reported when methotrexate and NSAIDS are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDS. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

Other NSAIDS and steroids: Co-administration of Difene with other systemic NSAIDS and steroids may increase the frequency of unwanted effects. Concomitant therapy with aspirin lowers the plasma levels of each, although no clinical significance is known.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Diuretics: Various NSAIDS are liable to inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, hence serum potassium should be monitored. Diuretics can increase the risk of nephrotoxicity of NSAIDs

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

Anti-hypertensives: reduced anti-hypertensive effect.

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Probenecid: reduction in metabolism and elimination of NSAID and metabolites.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking Difene concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Although animal studies have not demonstrated teratogenic effects, Difene should not be used in pregnancy or lactation unless considered essential by the physician and if so the lowest effective dose should be used. Use of prostaglandin synthetase inhibitors in the third trimester may result in premature closure of the ductus arteriosus. Traces of drug are detectable in breast milk but are not clinically significant.

Isolated cases of disorientation and blurred vision have been reported with diclofenac sodium. If affected refrain from driving or operating machinery.

If serious side-effects occur, Difene should be withdrawn.

Gastrointestinal tract:

Occasional: epigastric pain, other gastrointestinal disorders (eg nausea, vomiting, diarrhoea, abdominal cramps/pain, dyspepsia, flatulence, anorexia, gastritis).

Rare: gastro-intestinal bleeding, peptic ulcer (with or without bleeding or perforation), bloody diarrhoea.

Isolated cases: lower gut disorders (eg non-specific haemorrhagic colitis and exacerbations of ulcerative colitis or Crohn's disease), pancreatitis, aphthous stomatitis, glossitis, oesophageal lesions, constipation.

Central Nervous System:

Occasional: headache, dizziness or vertigo.

Rare: drowsiness, tiredness.

Isolated cases: disturbances of sensation (paraesthesiae, memory disturbance, disorientation, disturbance of vision, blurred vision, diplopia), impaired hearing, tinnitus, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions. Taste alteration disorders.

Skin:

Occasional: injection site disorders eg local pain and induration, rashes or skin eruptions.

Rare: urticaria

Isolated cases: injection site abscesses and local necrosis have been reported with intramuscular use, bullous eruptions, eczema, erythema multiforme, StevensJohnson syndrome, lyell's syndrome, (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.

Kidney:

Isolated cases: acute renal insufficiency, urinary abnormalities (eg haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.

Liver:

Occasional: elevation of serum aminotransferase enzymes (SGOT, SGPT).

Rare: liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.

Blood:

Isolated cases: thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

Cardiovascular system:

Isolated cases: Oedema, palpitations, chest pain, hypertension, congestive heart failure.

Clinical and epidemiological data suggest that use of diclofenac, particularily at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Other organ systems:

Rare: oedema, hypersensitivity reactions (eg bronchospasm, anaphylactic/anaphylactoid systemic reactions including hypotension).

Isolated cases: impotence (association with Diclofenac sodium intake is doubtful), palpitation, chest pain, hypertension.

Management of acute poisoning with diclofenac and other non-steroidal anti-inflammatory drugs consists of supportive and symptomatic measures.

Therapeutic measures that can be taken include; supportive and symptomatic treatment for the complications of overdosage such as hypotension, renal failure, convulsions, gastro-intestinal irritation and respiratory depression; Forced diuresis or dialysis are probably of no help in eliminating diclofenac and other non-steroidal anti-inflammatory medicines due to their high rate of protein binding.

Diclofenac sodium is a phenylacetic acid derivative and a non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory and anti-pyretic properties. Diclofenac is an inhibitor of cyclo-oxygenase and therefore reduces prostaglandin synthesis. Reduction in prostaglandin levels reduces the inflammatory response by the body.

Absorption:

Absorption is complete but onset is delayed until passage through the stomach, which may be affected by food which delays stomach emptying. The mean peak plasma diclofenac concentrations reached at about 2 hours (50mg dose produces 1.48 ± 0.65g/ml (1.5g/ml 5mol/l)).

Bioavailability:

About half of the administered diclofenac is metabolised during its first passage through the liver ("first-pass" effect), the area under the concentrations curve (AUC) following oral administration is about half that following an equivalent parenteral dose.

Distribution:

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma, and remain higher for up to 12 hours.

Metabolism:

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites , most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination:

Total systemic clearance of diclofenac in plasma is 26356mL/min (mean value SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of <10mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

Animal studies have been carried out in a number of species to determine the toxicity of diclofenac sodium. Acute toxicity studies have been carried out in the rat and when administered orally an LD50 of 53 mg/kg produced behavioural effects and respiratory stimulation. Acute oral toxicity studies in the rabbit showed no toxic effect at a dose of 157 mg/kg.

Toxicity by the intravenous route has been measured in the rat, an administered dose of 117 mg/kg has been shown to have no adverse effect. Intraperitoneal studies have shown an no adverse effect level of 25 mg/kg in the rat, and subcutaneous toxicity in the rat shows a no toxic effect level of 83 mg/kg.

Reproductive toxicity has been studied in both the rat and the rabbit, a dose of 1 mg/kg/day for 21 days in rats has been shown to produce developmental abnormalities of the cardiovascular system. In the rabbit a dose of 10 mg/kg has been shown to reduce fertility.

Benzyl Alcohol

Propylene Glycol

Acetylcysteine

Mannitol

Sodium Hydroxide

Difene Ampoules for intramuscular use should not be mixed with other injection solutions.

Shelf life of the medicinal product as packaged for sale

3 years.

Shelf life after dilution for IV infusion

From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/ dilution (etc) has taken place in controlled and validated aseptic conditions.

Do not store above 25°C. Store in the original package.

Five colourless, Type I Ph.Eur. glass ampoules in an ampoule tray, one or two trays per box.

Pack size: 5 or 10 ampoules.

Not all pack sizes may be marketed.

Standard precautions for disposal of glass ampoules should be followed.

For single use only. Discard any unused injection.

Astellas Pharma Co. Ltd

25 The Courtyard

Kilcarbery Business Park

Clondalkin

Dublin 22

Ireland

P.A. 1241/12/6

28th August 1990/28th August 2005

February 2010