Adults and Elderly:
Relief of all grades of pain and inflammation in a wide range of conditions, including:
-Arthritic conditions: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout.
-Acute musculo-skeletal disorders such as periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, bursitis.
-Other painful conditions resulting from trauma, including fracture, low back pain, sprains, strains, dislocations, orthopaedic, dental and other minor surgery, renal colic.
Ampoules used in intravenous infusion:
For treatment or prevention of post-operative pain in the hospital setting.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
EPIFENAC ampoules (given im or iv) should not be given for more than two days; if necessary, treatment can be continued with EPIFENAC tablets or suppositories.
Intramuscular injection:The following directions for intramuscular injection must be adhered to in order to avoid damage to a nerve or other tissue at the injection site.
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.Alternatively, one ampoule of 75 mg can be combined with other dosage forms of EPIFENAC (tablets or suppositories) up to the maximum daily dosage of 150 mg.

Renal colic: One 75 mg ampoule intramuscularly.A further ampoule may be administered after 30 minutes if necessary.The recommended maximum daily dose of EPIFENAC is 150 mg.
Intravenous Infusion: Immediately before initiating an intravenous infusion, EPIFENAC must be diluted with 100 - 500 ml of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5 ml 8.4% or 1 ml 4.2%). Only clear solutions should be used.
EPIFENAC must not be given as an intravenous bolus injection.
Two alternative regimens are recommended:
For the treatment of moderate to severe post-operative pain, 75 mg should be infused continuously over a period of 30 minutes to 2 hours.If necessary, treatment may be repeated after 4 - 6 hours, not exceeding 150 mg within any period of 24 hours.
For the prevention of post-operative pain, a loading dose of 25 - 50 mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approx.
5 mg per hour up to a maximum daily dosage of 150 mg.
Children:
EPIFENAC ampoules are not recommended for use in children.
Elderly: Although the pharmacokinetics of EPIFENAC are not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions.In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight and the patient should be monitored for GI bleeding during NSAID therapy.

-Hypersensitivity to the active substance or any of the excipients. -Patients with active, or a history of, gastrointestinal ulcers, bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding). -Patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) to ibuprofen, aspirin or other nonsteroidal anti-inflammatory drugs. -Severe hepatic, renal and heart failure (see Special warnings and precautions for use). -History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy. EPIFENAC is contraindicated in children less than 6 years. Diclofenac is now contraindicated in patients with established: - ischaemic heart disease - peripheral arterial disease - cerebrovascular disease - congestive heart failure (New York Heart Association [NYHA] classification II–IV) Specifically for iv use. -Concomitant NSAID or anticoagulant use (including low dose heparin). -History of haemorrhagic diathesis, a history of confirmed or suspected cerebrovascular bleeding. -Operations associated with a high risk of haemorrhage. -A history of asthma. -Moderate or severe renal impairment (serum creatinine >160 μmol/l). -Hypovolaemia or dehydration from any cause. Pregnancy, nursing mothers & pediatric use: Do not administer injections preserved with benzyl alcohol to premature infants, neonates, infants below 13 years, pregnant women, or nursing mothers.Benzyl alcohol has been associated with serious adverse events & death, particulary in pediatric patents (it may cause Gasping syndrome).Injections preservative free should be used in these population.

Warnings:
In all patients:
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
The use of EPIFENAC with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Diclofenac treatment should only be initiated after careful consideration for patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidaemia, diabetes mellitus, smoking).
As the cardiovascular risks of diclofenac may increasewith doseand duration of exposure, the lowest effective dose should be used for the shortest duration necessary to control symptoms. A patient’s need for symptomatic relief and response to treatment should be re-evaluated periodically.
Elderly: The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal.
Gastrointestinal: As with all NSAIDs, including diclofenac close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastric or intestinal ulceration, with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated.
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).
Gastrointestinal bleeding or ulceration/perforation: haematemesis melaena ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac. They can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. In the rare instances when gastrointestinal bleeding or ulceration occurs in patients receiving EPIFENAC, the drug should be withdrawn.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, 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, other drugs likely to increase gastrointestinal risk.
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 (SSRIs) or anti-platelet agents such as aspirin .
Hepatic: Close medical surveillance is also imperative in patients suffering from impairment of hepatic function.

Hypersensitivity reactions: As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylactic/ anaphylactoid reactions, can also occur without earlier exposure to the drug.
Like other NSAIDs, EPIFENAC may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Benzyl alcohol:This product contains benzyl alcohol which is potentially toxic when administered locally to neural tissue.
Precautions:
Cardiovascular Risk
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal.This risk may increase with duration of use.Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Gastrointestinal Risk
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.Elderly patients are at greater risk for serious gastrointestinal (GI) events.
Renal:Patients with renal, cardiac or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDs, including diclofenac may result in deterioration of renal function.The lowest effective dose should be used and renal function monitored.
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 EPIFENAC.
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), EPIFENAC should be discontinued.Hepatitis may occur with diclofenac without prodromal symptoms.
Use of EPIFENAC in patients with hepatic porphyria may trigger an attack.
Haematological:EPIFENAC may reversibly inhibit platelet aggregation.Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
Long term treatment:All patients who are receiving nonsteroidal anti-inflammatory agents should be monitored as a precautionary measure e.g.renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.
Respiratory disorders:Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.
Cardiovascular and cerebrovascular effects: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 including diclofenac.
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 initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).
SLE and mixed connective tissue disease:In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.
Dermatological:Serious skin reactions, 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, including EPIFENAC.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.EPIFENAC should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
Female fertility:The use of EPIFENAC may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of EPIFENAC should be considered.

Lithium and digoxin:Diclofenac sodium may increase plasma concentrations of lithium and digoxin.
Anticoagulants:Although clinical investigations do not appear to indicate that diclofenac sodium has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy.Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required.As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.
Antidiabetic agents:Clinical studies have shown that diclofenac sodium 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.
Methotrexate:Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac 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.
Potent CYP2C9 inhibitors:Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
Phenytoin:When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac sodium with aspirin or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration.Avoid concomitant use of two or more NSAIDs.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs, including diclofenac may cause increased risk of gastrointestinal bleeding.
Diuretics: Like other NSAIDs, diclofenac sodium may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.
Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Mifepristone: NSAIDs should not be used for 8 - 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Antihypertensives: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.
Ciclosporin and Tacrolimus: Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium.Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Pregnancy:
Pregnancy: Category C.
Congenital abnormalities have been reported in association with the administration of NSAIDs in man, however, these are low in frequency and do not appear to follow any discernible pattern.
In view of the known effects of NSAIDs, including diclofenac on the foetal cardiovascular system (e.g. a premature closure of the ductus arteriosus) and in causing uterine inertia, use in the last trimester of pregnancy is contraindicated.The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit outweighs the potential risk to foetus. The lowest effective dose should be used and duration kept as short as possible.
Lactation: Like other NSAIDs, diclofenac passes into breast milk in small amounts, therefore NSAIDs should if possible be avoided when breastfeeding.

Patients who experience dizziness, drowsiness, fatigue or visual disturbances, while taking NSAIDS should refrain from driving or operating machinery.

If serious side-effects occur, EPIFENAC should be withdrawn.
Frequency estimate: frequent: >10 %, occasional :>1 - 10 %, rare: >0.001 - 1 %, isolated cases: <0.001 %.
Gastrointestinal tract:
Occasional: Epigastric pain, other gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia).
Rare: Gastritis, gastrointestinal bleeding (haematemesis, melaena, and bloody diarrhoea), gastrointestinal ulcers with or without bleeding or perforation (sometimes fatal, particularly in the elderly) may occur.
In isolated cases:Aphthous stomatitis, glossitis, oesophageal lesions, lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations of ulcerative colitis or Crohn's proctocolitis, colonic damage and stricture formation), pancreatitis, constipation.
Central Nervous System disorders:
Occasional:Headache, dizziness, or vertigo.
Rare: Drowsiness, tiredness hypotension.
In isolated cases:Disturbances of sensation, paraesthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, confusion, hallucinations, malaise, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus and mixed tissue disease), with symptoms such as fever, stiff neck, headache, nausea and vomiting.

Special senses:
Isolated cases: Disturbances of vision (blurred vision, optic neuritis, diplopia), impaired hearing, tinnitus, taste disturbances.
Skin:
Occasional:Rashes or skin eruptions.
Rare: Urticaria.
In isolated cases:Bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.
Kidney:
Rare: Oedema.
In isolated cases:Acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.
Liver:
Occasional:Elevation of serum aminotransferase enzymes (ALT, AST).
Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.
Blood:
In isolated cases:Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.
Vascular:
Isolated cases:Vasculitus.
Respiratory:
Isolated cases:Pneumonitis.
Cardiovascular system:
Isolated cases:Palpitations, chest pain, hypertension, congestive heart failure.
Other organ systems:
Isolated cases:Impotence.
Reactions to the intramuscular injection:
Occasional:Reactions such as local pain and induration.
Isolated cases:Abscesses and local necrosis at the intramuscular injection site.
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with NSAIDs. These consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necroylsis and etheryma multiforme).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of benefit/risk balance of the medicinal product. Health care professionals are asked to report any suspected adverse reactions.

NPC Contact Information:

National pharmacovigilance & Drug safety centre (NPC):

Fax: +966-11-205-7662.
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000.
E-mail: npc.drug@sfda.gov.sa.
Website: www.sfda.gov.sa/npc.

Other GCC States:

Please contact the relevant competent authority.

Symptoms:Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally convulsions.In rare cases of significant poisoning acute renal failure and liver damage are possible.
Therapeutic measures:Patients should be treated symptomatically as required.Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered.Alternatively, in adults gastric lavage should be considered within one hour of ingestion of potentially toxic amounts.Frequent or prolonged convulsions should be treated with intravenous diazepam.Other measures may be indicated by the patients clinical condition.

Pharmacotherapeutic group:Nonsteroidal anti-inflammatory drugs (NSAIDs).
Mechanism of action:
EPIFENAC is a nonsteroidal agent with marked analgesic/anti- inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.When used concomitantly with opioids for the management of post-operative pain, EPIFENAC often reduces the need for opioids.

Absorption:
Ampoules:After administration of 75 mg diclofenac by intramuscular injection, absorption sets in immediately, and mean peak plasma concentrations of about 2.558 ± 0.968 μg/ml (2.5 μg/mL Ξ 8 μmol/L) are reached after about 20 minutes.The amount absorbed is in linear proportion to the size of the dose.
Intravenous infusion: When 75 mg diclofenac is administered as an intravenous infusion over 2 hours, mean peak plasma concentrations are about 1.875 ± 0.436 μg/ml (1.9 μg/ml Ξ 5.9 μmol/L).Shorter infusions result in higher peak plasma concentrations, while longer infusions give plateau concentrations proportional to the infusion rate after 3 to 4 hours.This is in contrast to the rapid decline in plasma concentrations seen after peak levels have been achieved with oral, rectal or i.m. administration.
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 and rectal administrations is about half that following an equivalent parenteral dose.

Pharmacokinetic behaviour does not change on repeated administration.Accumulation does not occur, provided the recommended dosage intervals are observed.
The plasma concentrations attained in children given equivalent doses (mg/kg, b.w.) are similar to those obtained in adults. (25 mg tablet, and 12.5 mg and 25 mg suppositories only)
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 phenol ic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.
Elimination:
The total systemic clearance of diclofenac in plasma is 263 ± 56 ml/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 in the form of 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 <10 mL/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.

None known.

Propylene glycol, sodium metabisulphite, benzyl alcohol, mannitol, sodium hydroxide, water for injection.

None known.

3 years (36 months).

Store at temperature not exceeding 30° C.

EPIFENAC Ampoules: Box of 3 amber glass ampoules.

No special instructions.