Generic Name
diclofenac sodium

Drug Description
The active ingredient is diclofenac sodium [sodium-(o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate)]. Each 2 ml vial contains 75 mg of diclofenac sodium.

Presentation
Solution for Injection

Indications
Intramuscular use: Dyloject 75 mg/2 ml Solution for Injection is effective in acute forms of pain, including renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute trauma and fractures, and post-operative pain.Intravenous use: For treatment or prevention of post-operative pain in supervised healthcare settings.

Adult Dosage
Instructions on using the vial1. Remove the green flip cap2. Aseptically withdraw the appropriate amount (not more than 2 ml) for either IV use or deep IM injection. As with all parenteral products, Dyloject should be inspected visually for particulate matter or discoloration prior to administration.AdultsUndesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.Dyloject 75 mg/2 ml Solution for Injection should not be given for more than two days.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 vial once (or in severe cases twice) daily, intramuscularly by deep intragluteal injection into the upper outer quadrant of the buttock. If two injections daily are required, it is advised that the alternative buttock be used for the second injection.Recommended IM injection procedure1. The patient may lie down or stand, whichever is more comfortable.2. The exposed buttocks should be inspected to find the most suitable injection site. Avoid scars and lumps and choose the buttock which is free from any problems. If more than one injection needs to be given, the other buttock should be used.3. The injection site should be thoroughly disinfected, e.g. with alcohol, and allowed to dry.4. To ensure deep intramuscular injection, give high into upper outer quadrant of the buttock, taking particular care to avoid the sciatic nerve and blood vessels. Avoid injecting into an area where resistance is felt. N.B. In obese patients, avoid deposition of the drug into the subcutaneous fatty tissue. In small thin patients with little muscle bulk, be especially aware of the sciatic nerve, which may be quite superficial.5. Prior to injection of solution, draw back to ensure that no blood vessel has been penetrated. If blood is drawn, withdraw the needle to another site and check again.Renal colic: One 75 mg dose intramuscularly. A further dose may be administered after 30 minutes if necessary. The recommended maximum daily dose of Dyloject is 150 mg.Intravenous use: Dyloject 75 mg/2 ml Solution for Injection may be given as an intravenous bolus injection. Two alternative regimens are recommended for bolus injection.• For the treatment of moderate to severe post-operative pain, 75 mg should be injected intravenously. If necessary, treatment may be repeated after 4 to 6 hours, not exceeding 150 mg within any period of 24 hours.• For the prevention of post-operative pain, a loading dose of 25 mg to 50 mg administered as a 5 to 60 second intravenous bolus after surgery, followed by additional injections up to a maximum daily dosage of 150 mg. If necessary, treatment may be repeated after 4 to 6 hours, not exceeding 150 mg within any period of 24 hours.Phlebitis: Intravenous drug administration has been associated with the occurrence of Thrombophlebitis. Clinical studies comparing Dyloject 75 mg/2 ml Solution for Injection to Voltarol® Ampoules have demonstrated reduced severity and one fourth the incidence of phlebitis (p=0.0032).Children: Dyloject 75 mg/2 ml Solution for Injection is not recommended for use in children.Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. The recommended maximum daily dose of Dyloject 75 mg/2 ml Solution for Injection is 150 mg.Patients with renal impairment: Hydroxypropylbetadex (HPβCD), when administered intravenously, is predominantly eliminated through glomerular filtration. Therefore, patients with severe renal impairment defined as creatinine clearance below 30 ml/min should not be treated with Dyloject 75 mg/2 ml Solution for Injection.

Contra Indications
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).Severe heart failure, renal failure, and hepatic failure.During the last trimester of pregnancy.History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or rhinitis) in response to ibuprofen, aspirin or other NSAIDS.Hypersensitivity to diclofenac sodium, or to any of the excipients.The excipient HPβCD is predominantly eliminated through the kidney by glomerular filtration. Therefore, Dyloject 75 mg/2 ml Solution for Injection is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min).Specifically for IV useConcomitant NSAID including cyclooxygenase-2 selective inhibitors or anticoagulant use (including low dose heparin).A 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.

Special Precautions
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.The use of Dyloject 75 mg/2 ml Solution for Injection with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided. Concomitant use during IV use is contraindicated.Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs. They can occur at any time during treatment, with or without warning symptoms or a previous history of serious 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, 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.Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.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. Concomitant use with anticoagulants during IV treatment is contraindicated.When gastrointestinal bleeding or ulceration occurs in patients receiving Dyloject 75 mg/2 ml Solution for Injection, the drug should be withdrawn.NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.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. Patients appear to be at highest risk for 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. Dyloject 75 mg/2 ml Solution for Injection should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.Hepatic: Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.Hypersensitivity reactions: As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.Like other NSAIDs, Dyloject 75 mg/2 ml Solution for Injection may mask the signs and symptoms of infection due to its pharmacodynamic properties.Renal impairment: HPβCD, when administered intravenously, is predominantly eliminated through the kidney by glomerular filtration. Therefore, patients with renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for Injection.PrecautionsCardiovascular, Renal and Hepatic Impairment: The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics or those recovering from major surgery and the elderly. Renal function should be monitored in these patients.Renal impairment: HPβCD, when administered intravenously, is predominantly eliminated through the kidney by glomerular filtration. Therefore, patients with renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for Injection.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, etc.), Dyloject 75 mg/2 ml Solution for Injection should be discontinued. Hepatitis may occur without prodromal symptoms.Use of Dyloject 75 mg/2 ml Solution for Injection in patients with hepatic porphyria may trigger an attack.Haematological: Dyloject 75 mg/2 ml Solution for Injection may reversibly inhibit platelet aggregation. Patients with defect of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.Long-term treatment: Dyloject 75 mg/2 ml Solution for Injection is not recommended for long term use. Prescribers should select follow-on treatment based on prescribing information for the specific product selected. All patients who are receiving non-steroidal anti-inflammatory agents long term, 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: Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients. IV use in patients with history of asthma is contraindicated.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.Clinical trial and epidemiological data suggest that use of diclofenac, particularly 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).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, smoking).Impaired female fertility: The use of Dyloject 75 mg/2 ml Solution for Injection may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Dyloject 75 mg/2 ml Solution for Injection should be considered.

Interactions
Lithium and digoxin: Decreased elimination of lithium and digoxin.Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin.Antidiabetic agents: Clinical studies have shown that diclofenac 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.Ciclosporin: Increased risk of nephrotoxicity.Methotrexate: Decreased the elimination of methotrexate.Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.Other analgesics including cyclooxygenase-2 selective inhibitors and corticosteroids: Avoid concomitant use of two or more NSAIDs (including aspirin) or corticosteroids as this may increase the risk of adverse effects.Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma glycoside and HPβCD levels.Mifepristone: NSAIDs should not be used for 8 to 12 days after mifepristone administration, as NSAIDs can reduce the effect of mifepristone.Anti-hypertensives: Reduced anti-hypertensive effect.Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Adverse Reactions
Side effects observed following parenteral diclofenac administrationIf serious side effects occur, Dyloject 75 mg/2 ml Solution for Injection should be withdrawn. Frequency estimate: frequent: >10%; occasional: > 1 to 10%; rare: > 0.001 to 1%; isolated cases: < 0.001%.Gastrointestinal tractOccasional: epigastric pain, other gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, dyspepsia, flatulence, anorexia).Rare: gastrointestinal bleeding (haematemesis, melaena, bloody diarrhoea), abdominal pain/tenderness, gastrointestinal ulcers with or without bleeding or perforation, mouth ulcerations, tooth and tongue disorders or dysphagia.In isolated cases: aphthous stomatitis, glossitis, esophageal lesions, lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations or ulcerative colitis or Crohn's proctocolitis, colonic damage and stricture formation), pancreatitis, or constipation.Central nervous systemOccasional: headache, dizziness or vertigo.Rare: drowsiness, tiredness, dysgeusia, paraesthesia, balance impairment, aponia, hypoaesthesia, migraine, speech disorder, or trismus.In isolated cases: disturbances of sensation, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, or aseptic meningitis.General disordersRare: pain, chest pain, chest tightness, malaise, rigors, bloody discharge, feeling abnormal, feeling hot, or pyrexia.Musculoskeletal and connective tissue disordersOccasional: pain in jaw.Rare: facial pain, joint stiffness, myalgia, back pain, chest wall pain, neck pain, muscle cramp, or muscle tightness.Special sensesRare: eyelid oedema, eyelid pruritus, increased lacrimation, or eye pain.In isolated cases: disturbances of vision (blurred vision, diplopia), impaired hearing, tinnitus, or taste disturbances.SkinOccasional: rashes or skin eruptions.Rare: urticaria, pruritus, or sweating increased.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, or purpura including allergic purpura.KidneyRare: oedema, renal pain.In isolated cases: acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, or papillary necrosis.LiverOccasional: elevation of serum aminotransferase enzymes (ALT, AST).Rare: liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice, or increased lipase.BloodRare: neutrophilia.In isolated cases: thrombocytopenia, leucopenia, agranulocytosis, hemolytic anaemia, or aplastic anaemia.HypersensitivityRare: hypersensitivity reactions (e.g. bronchospasm, anaphylactic/anaphylactoid systemic reactions including hypotension), respiratory disorder NOS, or rhinorrhoea.In isolated cases: vasculitis, or pneumonitis.Cardiovascular and cerebrovascularOccasional: haemorrhageRare: phlebitis, hypotension, bradycardia, or flushing.In isolated cases: palpitations, chest pain, hypertension, or congestive heart failure.Laboratory abnormalitiesRare: elevated creatine phosphokinase, ketonuria, haematuria, or bilirubin in urine.Other organ systemsIn isolated cases: impotence.Reactions to the intramuscular injectionOccasional: reactions such as local pain and induration.In isolated cases: abscesses and local necrosis at the injection site.Reactions to the intravenous injectionOccasional: thrombophlebitis.Rare: cannula site reaction, infusion site discomfort or burning, injection site stinging, or pyrexia.Additional adverse events have been documented following diclofenac administrationCardiovascular and cerebrovascular: Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).Additional adverse reactions have been documented following non-selective NSAIDs therapyHypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising 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 necrolysis and erythema multiforme).Other adverse reactions reported less commonly include:Renal: Renal failure.Neurological and special senses: Optic neuritis, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Manufacturer
Therabel Pharma UK Limited

Drug Availability
POM – Prescription Only Medicine

Updated
18 August 2010