Chemical Name:Diclofenac Sodium
Therapeutic Category:Anti-inflammatory drugs
Pharmacologic Category:Nonsteroidal anti-inflammatory drug
Composition:Diclofenac Sodium 75mg/3ml
DICLOFENAC – ELSAAD
Solution for IM Injection / Intravenous infution
Diclofenac Sodium 75mg/3ml
DICLOFENAC – ELSAAD :Each 3ml ampoule contains 75mg diclofenac sodium.
2- Pharmacological Properties:
Diclofenac injection 75mg/3ml is a non-steroidal agent with marked analgesic /anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclo-oxygenase)
3- Pharmacokinetic properties:
Diclofenac is absorbed after all form of administration . The plasma concentration of the agent is linearly proportional to the administered dose.
Diclofenac is 99.7% bound to serum proteins mainly albumin 99.4%.
The metabolism of diclofenac occurs quickly and almost completely.
The elimination of the active substance out of the plasma occurs with a systemic clearance of 263±56ml/min.
The terminal half-life is 1-2 hours .
Less than 1% of the active substance is renally eliminated in its unchanged form 60% of the administered amount are renally eliminated as metabolites ,the rest is eliminated with the feces.
- acute forms of pain ,including renal colic.
- exacerbations of osteo and rheumatoid arthritis.
- acute back pain.
- acute gout.
- acute trauma and fracture.
- post operative pain.
For the treatment or prevention of post-operative pain in the hospital setting.
- The drug do not given to children under 12 years.
- Hypersensitivity to diclofenac or to any of the excipients –mannitol , propylene glycol ,benzyl alcohol , sodium metabisulphite , sodium hydroxide.
- NSAIDs should not be administered to patients with active or a history of recurrent peptic ulcer / haemorrrhage.
- NSAIDs are contraindicated in patients who have previously shown hypersensitivity reaction (e.g asthma , rhinitis , angioedema or urticarial)
In response to ibuprofen, aspirin or other nonsteroidal anti inflammatory drugs.
Specifically for intravenous 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 risk of haemorrhage.
- A history of asthma.
- Hypovolaemia or dehydration from any cause.
- Severe heartfailure ,hepatic failure and renal failure.
- During the last trimester of pregnancy.
- History of gastrointestinal bleeding or perforation , related to previous NSAIDs therapy.
6- Dosage and administration:
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 alternate buttock.be used for the second injection.
It should not be given for more than 2 day ,if necessary , treatment can be continued with tablets or suppositories.
Combination with other dosage forms of diclofenac (tablets or suppositories) can be used up to the maximum daily usage of 150mg.
Renal colic :one 75mg ampoule intramusculary. A further ampoule may be administered after30 minutes if necessary. The recommended maximum dialy dose of 150 mg in any combination of the three formulation of Diclofenac should not be exceeded.
Diclofenac Injection can also be given by an intravenous infusion , never as a bolus)
Prior to infusion it must be diluted with 100-500ml of either sodium chloride solution 0.9% or glucose solution 5%, both solutions should be buffered with sodium bicarbonate solution(0.5ml 8.4% or 1ml 4.2%).
For the treatment of moderate to severe post-operative pain ,75mg should be infused over a period of 30 minutes to 2 hours. This can be repeated after 4-6 hours , without exceeding 150mg within any 24 hour period.
For the prevention of post-operative pain , a loading dose of 25mg -50mg should be infused after surgery over 15 minutes to an hour, followed by a continuous infusion of around 5mg per hour up to a maximum of 150mg daily.
The elderly are at increased risk of the adverse reaction .
If an NSAID is considered necessary , the lowest dose should be used and the patient should be monitored for GI bleeding during NSAID theraby.
To be taken preferably with or after food.
Children (Aged 1-12 years):
Diclofenac injection 75mg/3ml is not suitable for children.
Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
Like other NSAIDs , Diclofenac may mask the signs and symptoms of infection due to its pharmacodynamics properties.
Concomitant use of NSAIDs with intravenous diclofenac is contraindication.
Cardiovascular ,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 diuretic and the elderly .Renal function should be monitored in these patients.
Gastro-intestinal: Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastrointestinal ulceration ,with ulcerative colitis ,crohn´s disease ,or haematological abnormalities.
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 serious GI events.
The risk of GI bleeding ,ulceration or perforation is higher with increasing NSAID dose ,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 thereby 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.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids , selective serotonin –reuptake inhibitors and anti-platelet agent.
When GI bleeding or ulceration occurs in patients receiving diclofenac ,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 these condition may be exacerbated.
Hepatic: close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.
SLE and mixed connective tissue disease: in patient with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.
Dermatological 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.
Patients appear to be at high risk for these reaction early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac injection should be discontinued at the first appearance of skin rash ,mucosal lesions, or any other sign of hypersensitivity.
As with other nonsteroidal anti-inflammatory drugs , allergic reaction, including anaphylactic / anaphylactoid reaction, can also occur without earlier exposure to the drug.
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.
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 event (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
- 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 usedand renal function monitored.
Use of intravenous diclofenac is contraindicated in patients with a history of asthma.
if abnormal liver function test persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), diclofenac injection should be discontinued ,hepatitis may occur without prodromal symptoms. Use of Diclofenac injection in patients with hepatic porphyria may trigger an attack.
Diclofenac injection may reversibly inhibit platelet aggregation.
patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
Caution is required in patients with a history of heart failure or hypertension since oedema has been reported in association with NSAIDs. The elderly have an increased frequency of adverse reaction to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
All patients who are receiving non-steroidal 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.
Impaired Female Fertility:
The use of Diclofenac 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 Diclofenac injection should be considered.
9- DRUG INTERACTIONS:
Anti-hypertensive: reduced antihypertensive effect.
Diuretics: Diclofenac reduce diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: Diclofenac decrease elimination of lithium.
Methotrexate: Diclofenac Decrease elimination of methotrexate.
Ciclosporil1with Diclofenac: Increase risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Other analgesics: Concomitant use of NSAIDs with intravenous diclofenac is contraindicated
Corticosteroids.: Increased risk of gastrointestinal ulceration or bleeding
Anticoagulants: NSAIDs may enhance the effects of anti-coagulants such as warfarin. Concomitant use of anticoagulants with intravenous diclofenac is contraindicated
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.
Quinolone antibiotics: Patients taking NSAIDs and quinolones may have an
increased risk of developing convulsions.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine.
Pregnancy And Lactation:
Pregnancy: NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus. use in the last trimester of pregnancy is contraindicated.
Lactation: NSAIDs can appear in breast milk in very low concentrations NSAIDs should, if possible, be avoided when breast feeding.
Effects an ability To Drive and use machines:
Dizziness, drowsiness, visual disturbances or headaches are possible undesirable effects after taking NSAIDs, if affected, patients should not drive or operate machinery.
10- Side effects:
If serious side-effects occur, Diclofenac should be withdrawn.
Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur .nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease and have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Hypersensitivity: 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 .
c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and less commonly, bullous dermatoses (including epidermal necrolysis, erythema multiform and exfoliative dermatitis).
Cardiovascular: oedma has been reported in association with NSAID treatment.
* Other adverse events reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.
Hepatic: Abnormal liver function, hepatitis and jaundice.
Neurological & special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto immune disorders, such as systemic lupus erythematosus, mixed connective tissue
disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or
disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Dermatological: bullous reactions including stevens johnson syndrome and toxic epidermal necrolysis (very rare) photosensitivity.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (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).
Symptoms of overdose include headache, nausea, vomiting, epigastric pain,
gastrointestinal bleeding, rarely diarrhea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
b) Therapeutic measure:
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 a potentially life-threatening overdose.
Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with Intravenous diazepam. Other measures may be indicated by the patient's clinical condition.
Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, gastro-intestinal irritation, and respiratory depression; specific therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.
Dic1ofenac ampoules for intramuscular or intravenous use should not be mixed with other solutions for injections, other than those for diluting as directed in Instruction for use and handling:
When used intravenously, Diclofenac Injection should be given as an intravenous infusion, never as bolus. Prior to infusion it must be diluted with l00-500ml of either sodium chloride solution(0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5ml-.8.4% or l ml 4.2%).Intravenous infusions should be freshly made up and immediately.
Only clear solution should be used.
DICLOFENAC-ELSAAD : A Pack of 5 ampoules of 3ml.
Store at room temperature below 25°C, protect from light and freezing.