- Name of the medicinal product
Diclofenac Sodium Injection 75mg/1ml Taj Pharma
Diclofenac Sodium Injection 75mg/3ml Taj Pharma
- Qualitative and quantitative composition
a) Diclofenac Sodium Injection 75mg/1ml
Each ml Contains:
Diclofenac Sodium 75mg
Benzyl alcohol 4% v/v
Water for injection q.s
b) Diclofenac Sodium Injection 75mg/3ml
Each ml Contains:
Diclofenac Sodium 25mg
Benzyl alcohol 4% v/v
Water for injection q.s
For a full list of excipients, see section 6.1.
- Pharmaceutical form
Solution for injection
Clear to slightly amber coloured transparent solution
- Clinical particulars
4.1 Therapeutic indications
By intramuscular and subcutaneous injection: Diclofenac Sodium 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 (see section 4.3 and 4.4).
By intravenous bolus injection: for treatment or prevention of post-operative pain in the hospital settings (see section 4.3 and 4.4).
AKIS is indicated in adults. Use in children and adolescents is not recommended.
4.2 Posology and method of administration
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use).
Diclofenac Sodium for Injection can be administered either by intramuscular, subcutaneous or. intravenous bolus injection. AKIS is for short-term treatment only and should not be given for more than two days.
For mild and moderate grades of pain a lower dose may be sufficient. A dose of 75 mg may be needed for severe pain such as renal colic. Exceptionally and in severe cases a second dose of 75 mg can be administered after 6 hours. A dose of 150 mg must not be exceeded within any 24 hour period.
If more than one daily injection of AKIS is required, (up to a maximum, daily dose of 150 mg) it is advisable to change the injection area for subsequent injections. If necessary, one injection of AKIS can be used with other dosage forms of diclofenac up to the maximum daily dosage of 150mg.
The elderly are at increased risk of serious adverse reactions (see section 4.4 and 5.2). 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 Diclofenac Sodium for Injection is 150 mg.
Patients with renal impairment
Hydroxypropyl-β-cyclodextrin (HPβCD), an excipient in Diclofenac Sodium for Injection, is mainly eliminated through glomerular filtration. Therefore, patients with severe renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with Diclofenac Sodium for Injection. (See section 4.4 and 5.2). In patients with renal impairment the lowest effective dose should be used.
Patients with severe hepatic or cardiac failure
Diclofenac Sodium for Injection is contraindicated in patients with severe hepatic or cardiac impairment (see section 4.3). Caution is advised when administering Diclofenac Sodium for Injection to patients with mild to moderate hepatic impairment as well as to patients with a history of hypertension and/or mild to moderate congestive heart failure (see section 4.4). Also, patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration (see section 4.4).
The safety and efficacy of Diclofenac Sodium for Injection in children aged 0-18 years has not been established.
Method of administration
Diclofenac Sodium for Injection should only be administered by a healthcare professional. It can be administered intramuscularly or subcutaneously, into clean healthy tissue, or by intravenous bolus injection.
A single ampoule must be used rather than two ampoules to make up a known dose e.g. a single 75 mg injection rather than a 25mg and a 50 mg injection or a 50mg injection rather than two 25 mg injections.
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. A deep intragluteal injection into the upper outer quadrant of the buttock must be administered. If two injections daily are required, it is advised that the alternative buttock be used for the second injection. The product should be injected slowly to minimise local tissue damage.
The injection must be administered into the subcutaneous tissue, preferably in the upper part of the gluteus or in the upper part of the thigh. If two injections daily are required, it is advisable to rotate the injection area between the gluteus and the thigh. The needle must be fully introduced into the thickness of the skin fold which forms between the thumb and the index finger. Care should be taken to ensure that a blood vessel has not been entered. The product should be injected slowly and at a steady rate. Keep the skin folded between the fingers during injection.
By intravenous use
Diclofenac Sodium for Injection can be administered by intravenous bolus injection. Two alternative regimens are recommended:
- For the treatmentof 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 preventionof 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 dose of 150 mg. If necessary, treatment may be repeated after 4 to 6 hours, not exceeding 150 mg within any period of 24 hours.
AKIS must not be given by intravenous (i.v.) infusion.
Please refer to section 6.6 for instructions for use and handling.
- Known hypersensitivity to the active substance or to any of the excipients.
- Active gastric or intestinal ulcer, bleeding or perforation
- History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
- Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
- Last trimester of pregnancy (see section 4.6)
- Severe hepatic renal or cardiac failure (see section 4.4).
- Like other non-steroidal anti-inflammatory drugs (NSAIDs), Diclofenac is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.
- Haemostasis disorders or current anticoagulant treatment (for intramuscular route of administration only).
- Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Specifically for i.v. use:
- Concomitant NSAID or anticoagulant use (including low dose heparin).
- History of haemorragic 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.
4.4 Special warnings and precautions for use
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 concomitant use of Diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.
Caution is indicated in the elderly on the basis of medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to diclofenac.
Like other NSAIDs, Diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
The instructions for intramuscular injection should be strictly followed in order to avoid adverse events at the injection site, which may result in muscle weakness, muscle paralysis, hypoaesthesia and injection site necrosis.
Gastrointestinal bleeding, ulceration and perforation, which can be fatal, has been reported with all NSAIDs, including diclofenac, and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving Diclofenac, the medicinal product should be withdrawn.
As with all NSAIDs, including Diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing Diclofenac in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.
Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA)/aspirin or other medicinal products likely to increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see section 4.5). Close medical surveillance and caution should be exercised in patients with ulcerative colitis or Crohn’s disease, as their condition may be exacerbated (see section 4.8).
NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.
Close medical surveillance is required when prescribing Diclofenac to patients with impaired hepatic function, as their condition may be exacerbated. As with other NSAIDs including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with Diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), Diclofenac should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is called for when using Diclofenac in patients with hepatic porphyria, since it may trigger an attack.
As fluid retention and oedema have been reported in association with NSAID therapy, including Diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3). Monitoring of renal function is recommended as a precautionary measure when using Diclofenac in such cases.
Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
The excipient HPβCD is predominantly eliminated through the kidney by glomerular filtration. Therefore, patients with severe renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with AKIS injectable solution. In patients with renal impairment, the lowest effective dose should be used.
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 (see section 4.8). Patients appear to be at higher 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. AKIS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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 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).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration.
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically.
During prolonged treatment with Diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, Diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.
Anaemia may occur as a result of water retention or effects on erythropoiesis.
Consequently it is advisable to monitor the levels of haemoglobin and haematocrit if symptoms of anaemia are detected. Hyperpotassemia may occur in diabetic patients or those who are also taking potassium-sparing drugs (see section 4.5).
In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesics-asthma), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.
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 (see section section 4.8).
Injections must be carried out following strict rules of asepsis and antisepsis.
Duration of treatment
AKIS must not be administered for longer than 2 days. After 2 days, the need for an alternative NSAID should be reviewed and if long-term treatment with an NSAID is required, patients should be monitored for evidence of renal and hepatic dysfunction and blood count abnormalities. This is particularly important in the elderly.
4.5 Interaction with other medicinal products and other forms of interaction
The following interactions include those observed with Diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.
Lithium: NSAIDs have been reported to increase blood lithium levels via decreased renal excretion of lithium. If this combination is considered necessary, lithium plasma concentrations should be monitored carefully during the initiation, adjustment and withdrawal of diclofenac treatment.
Digoxin: If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Diuretics, ACE inhibitors and Angiotensin-II Antagonists: NSAIDs may reduce the antihypertensive effect of diuretics and other antihypertensive drugs (such as beta-blockers, angiotensin converting enzyme (ACE) inhibitors). 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 antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. 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 (see also section 4.4). Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4).
Other NSAIDs, corticosteroids and acetylsalicylic acid: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids or acetylsalicylic acid may increase the frequency of gastrointestinal undesirable effects (see section 4.4) and is not recommended.
Anticoagulants and heparin (administered in the elderly or at curative doses): Caution is recommended since concomitant administration with NSAIDs could increase the risk of bleeding via inhibition of platelet function and damage to the gastroduodenal mucosa (see section 4.4). NSAIDs may enhance the effects of anti-coagulants such as warfarin and heparin. Heparin is not recommended for administration to elderly patients or at curative doses. Careful monitoring of the international normalized ratio (INR) is required if co-administration cannot be avoided. Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Thrombolytics and anti-platelet agents: Caution is recommended since concomitant administration with NSAIDs could cause increased risk of bleeding via inhibition of platelet function and damage to the gastroduodenal mucosa.
Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4).
Antidiabetics: 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 both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.
Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased. Weekly blood count monitoring during the first few weeks of the combination is recommended. Monitoring should be increased in patients with impaired kidney function or in elderly subjects.
Pemetrexed in patients with normal renal function, CLcr > 80 ml/min: Increased risk of pemetrexed toxicity due to decrease in pemetrexed clearance. Biological monitoring of renal function is recommended.
Calcineurin inhibitors (e.g. Ciclosporin, tacrolimus): Nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combined treatment, monitoring of renal function is recommended, especially in the elderly
Deferasirox: The concomitant administration of NSAIDs and deferasirox may increase the risk of gastrointestinal toxicity. Close clinical monitoring should be performed when these drugs are combined.
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/ cholestyramine.
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 concentration and exposure to diclofenac due to inhibition of diclofenac metabolism.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Tacrolimus: 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.
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.
Despite being extensively bound to proteins, AKIS does not interfere with the protein binding of: salicylates, tolbutamide, and prednisolone.
4.6 Fertility, pregnancy and lactation
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %.
The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality.
In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
– cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
– renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;the mother and the neonate, at the end of pregnancy, to:
– possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
– inhibition of uterine contractions resulting in delayed or prolonged labour.
Consequently, diclofenac is contraindicated during the third trimester of pregnancy
Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.
As with other NSAIDs, the use of diclofenac 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 should be considered.
4.7 Effects on ability to drive and use machines
Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking Diclofenac, should refrain from driving or using machines.
4.8 Undesirable effects
The most common undesirable effects observed during clinical trials with AKIS are gastrointestinal in nature or injection site reactions which are generally mild and transitory.
Clinical trial data suggest that the intramuscular and subcutaneous use of diclofenac injectable solution is associated with injection site reactions, such as pain and haematoma, which frequency was significantly lower at the 25 and 50 mg dose than at the 75 mg dose. Following intravenous bolus injection of the 75 mg dose at injection rates of 5 to 30 seconds, a discomfort sensation in the area around the site of injection was reported. After administering diclofenac the following have also been reported: nausea, vomiting, diarrhoea and constipation.
The known adverse reactions with AKIS when used intramuscularly and subcutaneously, were injection site reactions, often related to an administration procedure, including pain at the injection site, erythema and rash. In some cases, hypersensitivity reactions also with generalized symptoms have been reported after treatment.
The undesirable effects are presented below according to MedDRA System Organ Class classification (SOC) and frequency of observation, in accordance with the following convention: very common (≥1/10); common (≥1/100 – <1/10); uncommon (≥1/1000 – <1/100); rare (≥1/10000 – <1/1000); very rare (<1/10000), not known (cannot be estimated from the data available).
|Body system||Frequency||Adverse Drug Reaction|
|Infection and infestations||Not known||Injection site necrosis|
|Immune system disorder||Rare||Hypersensitivity reaction|
|Nervous system disorders||Uncommon||Dizziness, Headache|
Diarrhoea, Vomiting, Constipation
|Hepatobiliary disorders||Uncommon||Hepatic enzymes increase|
|Skin and subcutaneous tissue disorders||Uncommon||Pruritus|
|Musculoskeletal and connective tissue disorders||Common||Limb discomfort|
|General disorders and administration site conditions||Very common||Injection site reactions|
The most appropriate MedDRA term is listed to describe a certain reaction. Synonyms or related conditions are not listed, but should be taken into consideration as well.
Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); Not known: cannot be estimated from the available data.
The following undesirable effects include those reported with either short-term or long-term use.
|Blood and lymphatic system disorders|
|Very rare||Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), Agranulocytosis.|
|Immune system disorders|
|Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Angioneurotic oedema (including face oedema).
|Very rare||Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.|
|Nervous system disorders|
Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
|Very rare||Visual disturbance, vision blurred, diplopia.|
|Ear and labyrinth disorders|
Tinnitus, hearing impaired.
|Very rare||Palpitations, chest pain, cardiac failure, myocardial infarction.|
|Very rare||Hypertension, vasculitis.|
|Respiratory, thoracic and mediastinal disorders|
|Asthma (including dyspnoea).
|Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding or perforation).
Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, Stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatitis, jaundice, liver disorder.
Fulminant hepatitis, hepatic necrosis, hepatic failure.
|Skin and subcutaneous tissue disorders|
Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura , allergic purpura, pruritus.
|Renal and urinary disorders|
|Very rare||Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.|
|General disorders and administration site conditions|
|Injection site reaction, injection site pain, injection site induration
Injection site necrosis.
|Infections and infestations|
|Very rare||Injection site abscess.|
Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
There is no typical clinical picture resulting from diclofenac over dosage. Over dosage can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.
Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.
Special measures such as forced diuresis, dialysis or haemo-perfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein binding and extensive metabolism.
- Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic category: non-steroidal antinflammatory drugs (NSAIDs):
It is therapeutic subgroup classification: musculo-skeletal system/anti-inflammatory and antirheumatic products/ non-steroids/acetic acid derivatives and related substances
Mechanism of action:
Diclofenac Sodium for Injection 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, diclofenac sodium often reduces the need for opioids.
The analgesic efficacy of AKIS 25, 50 and 75 mg solution for injection was evaluated in two pivotal dental pain studies. Patients with moderate to severe pain following dental impaction surgery were included in these studies.
In one study the analgesic efficacy of AKIS 25, 50 and 75 mg/ml subcutaneously administered was compared to placebo. AKIS at all strengths produced a statistically significant higher pain relief (as measured on the VAS) compared to placebo (p<0.001). AKIS also produced significantly higher analgesia compared to placebo in the secondary efficacy measures, time to onset of analgesia, use of rescue medication over the 8 hours following drug administration and patients with a 30% reduction in pain intensity at 1.5 hours following drug administration (p<0.001 in all comparisons to placebo; no statistical difference was detected in the comparisons between the active drugs).
In the second dental pain study the analgesic efficacy of AKIS 75 mg/ml subcutaneosly administered was compared to that of Voltarol® 75 mg/3 ml intramuscularly administered. No significant difference between the two treatments was observed at any time point over the 8 hours following drug administration. At 1.5 hours following drug administration (primary endpoint of the study), the 95% CI of the difference between the two treatments was entirely above the pre-defined margin of non-inferiority (-15 mm). AKIS was therefore proved to be therapeutically equivalent to Voltarol. The mean differences and 95% CIs of the difference at any time point over the 8 hours following drug administration are shown in the table below.
|Assessment time point||Means difference (95% CI)||p-value|
|15 minutes||0.7 (-4.02 ; 5.41)||0.7708|
|30 minutes||1.6 (-4.26 ; 7.55)||0.5826|
|45 minutes||1.3 (-4.93 ; 7.48)||0.6857|
|1 hour||-2.1 (-8.63 ; 4.44)||0.5272|
|1.5 hours||-1.8 (-8.26 ; 4.61)||0.5764|
|2 hours||-2.9 (-8.81 ; 3.11)||0.3457|
|3 hours||-3.7 (-10.12 ; 2.72)||0.2559|
|4 hours||-5.6 (-12.48 ; 1.21)||0.1061|
|5 hours||-5.7 (-12.84 ; 1.50)||0.1205|
|6 hours||-5.5 (-13.73 ; 2.70)||0.1864|
|7 hours||-6.7 (-15.47 ; 1.98)||0.1284|
|8 hours||-5.4 (-14.08 ; 3.25)||0.2183|
5.2 Pharmacokinetic properties
After administration of AKIS 75 mg/ml Solution for Injection by the i.m. route, absorption is rapid and the mean peak plasma concentration of 2.603 ± 0.959 µg/ml (2.5 ug/ml equals approximately 8 µmol/L) is reached after 34 minutes. The area under the concentration curve AUCo-t is 250.07 ± 46.89 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol (75mg/3ml) is 2.242 ± 0.566 µg/ml which is reached after 27 minutes and the AUCo-t is 246.70± 39.74 µg/ml.min. The AUC after i.m. administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
After administration of AKIS 75 mg/ml Solution for Injection by the s.c. route, absorption is rapid and the mean peak plasma concentrations of 2.138 ± 0.646 µg/ml (2.5 µg/ml equals approximately 8 µmol/l) is reached in 40 minutes. The AUCo-t is 261.94 ± 53.29 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol is 2.242 ± 0.566 µg/ml at 27 minutes and the AUCo-t is 246.70 ± 39.74 µg/ml.min. A subcutaneous dose of 75 mg of AKIS was bioequivalent to an intramuscularly administered dose of Voltarol 75 mg/3 ml in terms of AUC and Cmax. The AUC after subcutaneous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
Dose linearity in terms of AUC has been demonstrated for diclofenac absorbed after subcutaneous administration. Cmax was found to be not proportional to dose, with mean Cmax values of 1090 ng/ml, 1648.9 ng/ml and 1851.1 ng/ml with the 25 mg, 50 mg and 75 mg dose of AKIS respectively.
Intravenous bolus injection
After administration of AKIS 75mg/mL Solution for Injection by intravenous bolus, absorption sets in immediately, and mean peak plasma concentration of about 16.505 ± 2.829 µg/mL are reached in 3 minutes. In comparative pharmacokinetic studies, were diclofenac was measured in plasma up to 8 hours post-dose, AKIS 75 mg/mL i.v. bolus was found to be bioequivalent to Voltarol® 75 mg/3mL ampoule administered as a 30-min i.v. infusion (100 mL) in terms of systemic exposure (AUC0-t: 5193.46 ± 1285 ng/mL.h and 4584.13 ± 1014.20 ng/mL.h, for AKIS and Voltarol®, respectively), but with a substantially higher rate of absorption (Cmax for Voltarol® 75 mg/3mL infusion was 6.117 ± 1.051 µg/mL). Also, diclofenac peak plasma concentration (Cmax) following AKIS i.v. bolus injection was found to be comparable to that reported in the literature for a similar diclofenac sodium and hydroxyl-propyl-ß-cyclodextrin-containing solution for injection (Dyloject® 75mg/2mL, Javelin Pharm. Ltd., UK) given by the same route (Cmax: 15.147 ± 2.829 µg/mL). The diclofenac AUC after bolus intravenous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
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.
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.
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.
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.
5.3 Preclinical safety data
No new preclinical safety studies have been performed on sodium diclofenac. The safety profile of the medicinal product is well-established.
The local tolerance study demonstrated that the formulation does not present any significant unexpected local toxicity by either the intramuscular or subcutaneous routes of administration.
- Pharmaceutical particulars
6.1 List of excipients
Water for injections.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
The medicinal product must be used immediately after opening any remaining solution must be discarded.
6.4 Special precautions for storage
Store below 25°C. Do not refrigerate or freeze.
Store in the original packaging in order to protect from light.
6.5 Nature and contents of container
Transparent type I glass ampoule.
Package of 1, 3 and 5 ampoules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
An additional overfill is included in each ampoule to ensure that 1.0 mL of solution can be extracted.
Ampoules:- No special requirements.
The product should not be used if crystals or precipitates are observed.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
Diclofenac Sodium Injection 75mg/1ml Taj Pharma
Diclofenac Sodium Injection 75mg/3ml Taj Pharma
Patient Information Leaflet
What you need to know about Diclofenac sodium injection
Your doctor has decided that you need this medicine to help treat your condition.
In this leaflet:
- What Diclofenac sodium injection are, and what they are used for
- Things to consider before you start to take Diclofenac sodium injection
- How to take Diclofenac sodium injection
- Possible side effects
- How to store Diclofenac sodium injection
- Further information
1. What Diclofenac sodium injectionare, and what they are used for
Diclofenac sodium, the active ingredient in Diclofenac sodium injection, is one of a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs reduce pain and inflammation.
The intramuscular injection is used to treat a number of painful conditions including:
- ‘Flare-ups’ of joint or back pain
- Attacks of gout
- Pain caused by kidney stones
- Pain caused by
Diclofenac sodium injectioncan either be given as an injection into the muscle, or as a slow infusion into a vein. The intravenous infusion is used in hospitals to prevent or treat pain following an operation.
Diclofenac sodium injectionare not suitable for children.
2. Things to consider before you start to take Diclofenac sodium injectionSome people MUST NOT have this injection. Talk to your doctor if:
- you think you may be allergic to diclofenac sodium, sodium metabisulphite, aspirin, ibuprofen or any other NSAID, or to any of the other ingredients of Diclofenac sodium injection. (These are listed at the end of the ) Signs of a hypersensitivity reaction include
- swelling of the face and mouth (angioedema), breathing problems, chest pain, runny nose, skin rash or any other allergic type reaction
- you have now, or have ever had, a stomach (gastric) or duodenal (peptic) ulcer, or bleeding in the digestive tract (this can include blood in vomit, bleeding when emptying bowels, fresh blood in faeces or black, tarry faeces)
- you have had stomach or bowel problems after you have taken other NSAIDs
- you have heart, kidney or liver failure
- if you have established heart disease and/or cerebrovascular disease e.g. if you have had a heart attack, stroke, mini-stroke (TIA) or blockages to blood vessels to the heart or brain or an operation to clear bypass blockages
- if you have or have had problems with your blood circulation (peripheral arterial disease)
- you are more than six months pregnant
You should also ask yourself these questions before having a Voltarol Injection or Infusion:
- Do you suffer from any bowel disorders including ulcerative colitis or Crohn’s disease?
- Do you have kidney or liver problems, or are you elderly?
- Do you suffer from any blood or bleeding disorder?
- Do you have a condition called porphyria?
- Have you ever had asthma?
- Are you breastfeeding?
- Do you have angina, blood clots, high blood pressure, abnormally high levels of fat in your blood (raised cholesterol or raised triglycerides)?
- Do you have heart problems, or have you had a stroke, or do you think you might be at risk of these conditions (for example, if you have high blood pressure, diabetes or high cholesterol or are a smoker)?
- Do you have diabetes?
- Do you smoke?
- Do you have Lupus (SLE) or any similar condition?
- Could you be suffering from dehydration?
- Have you suffered any heavy loss of blood recently?
If the answer to any of these questions is YES, discuss your treatment with your doctor or pharmacist because Diclofenac sodium injectionmight not be the right medicine for you.
Are you taking other medicines?
Some medicines can interfere with your treatment. Tell your doctor or pharmacist if you are taking any of the following:
- Medicines to treat diabetes
- Anticoagulants (blood thinning tablets like warfarin)
- Diuretics (water tablets)
- Lithium (used to treat some mental problems)
- Methotrexate (for some inflammatory diseases and some cancers)
- Ciclosporin and tacrolimus (used to treat some inflammatory diseases and after transplants)
- Trimethoprim (a medicine used to prevent or treat urinary tract infections)
- Quinolone antibiotics (for infections)
- Any other NSAID or COX-2 (cyclo-oxgenase-2) inhibitor, for example aspirin or ibuprofen
- Mifepristone (a medicine used to terminate pregnancy)
- Cardiac glycosides (for example digoxin), used to treat heart problems
- Medicines known as SSRIs used to treat depression
- Oral steroids (an anti-inflammatory drug)
- Medicines used to treat heart conditions or high blood pressure, for example beta-blockers or ACE
- Voriconazole (a medicine used to treat fungal infections).
- Phenytoin (a medicine used to treat seizures)
- Colestipol/cholestyramine (used to lower cholesterol)
Always tell your doctor or pharmacist about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor.
- Are you pregnant or planning to become pregnant? Although not common, abnormalities have been reported in babies whose mothers have taken NSAIDs during pregnancy. You should not have a Voltarol Injection during the last 3 months of pregnancy as it may affect the baby’s circulation.
- Are you trying for a baby? Having Voltarol Injections may make it more difficult to You should talk to your doctor if you are planning to become pregnant, or if you have problems getting pregnant.
Will there be any problems with driving or using machinery?
Very occasionally people have reported that Diclofenac sodium injectionhave made them feel dizzy, tired or sleepy. Problems with eyesight have also been reported. If you are affected in this way, you should not drive or operate machinery.
Other special warnings
- You should take the lowest dose of Diclofenac sodium injection for the shortest possible time, particularly if you are underweight or
- There is a small increased risk of heart attack or stroke when you are taking any medicine like Diclofenac sodium injection. The risk is higher if you are taking high doses for a long time. Always follow the doctor’s instructions on how much to take and how long to take it for.
- If at any time while taking Diclofenac sodium injection you experience any signs or symptoms of problems with your heart or blood vessels such as chest pain, shortness of breath, weakness, or slurring of speech, contact your doctor
- Whilst you are taking these medicines your doctor may want to give you a check-up from time to
- If you have a history of stomach problems when you are taking NSAIDs, particularly if you are elderly, you must tell your doctor straight away if you notice any unusual
- Because it is an anti-inflammatory medicine, Diclofenac sodium injection may reduce the symptoms of infection, for example, headache and high temperature. If you feel unwell and need to see a doctor, remember to tell him or her that you are taking Diclofenac sodium injection.
- Diclofenac sodium injectioncontain the preservative, sodium This can sometimes cause allergic reactions and breathing difficulties.
- Diclofenac sodium injectionshould not be used in
Tell your doctor if you recently had or you are going to have a surgery of the stomach
or intestinal tract before taking Diclofenac sodium injection, as Diclofenac sodium injectioncan sometimes worsen wound healing in your gut after surgery.
3. How to take Diclofenac sodium injection
Your doctor will decide when and how to treat you with Diclofenac sodium injection. You will either be given an intravenous infusion (a drip into a vein) or an intramuscular injection (an injection into a muscle). The intramuscular injection is usually injected into the buttocks
The usual dose is:
One or two ampoules (75 to 150 mg) each day for one or two days.
Your doctor may give you a dose that is lower than the usual adult dose if you are elderly.
Not suitable for children.
A doctor, nurse or pharmacist will prepare the injection for you.
If you have had an operation and are in hospital, the ampoule contents may be diluted and put into a drip bag before being given to you. A nurse or doctor will usually then give you the injection or infusion. You would not usually have to give the injection to yourself.
The doctor may also prescribe another drug to protect the stomach to be taken at the same time, particularly if you have had stomach problems before, or if you are elderly, or taking certain other drugs as well.
What if you have had too much Diclofenac sodium injection? (Overdose)
If you think you have been given too much Diclofenac sodium injection tell your doctor or nurse straight away.
4. Possible side effects
Diclofenac sodium injectionare suitable for most people, but, like all medicines, they can sometimes cause side effects. Side effects may be minimised by using the lowest effective dose for the shortest duration necessary.
Some side effects can be serious
Tell the doctor straight away if you notice:
- Sudden and crushing chest pain (signs of myocardial infarction or heart attack)
- Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of heart failure)
- Sudden weakness or numbness in the face, arm or leg especially on one side of the body; sudden loss or disturbance of vision; sudden difficulty in speaking or ability to understand speech; sudden migraine-like headaches which happen for the first time, with or without disturbed vision. These symptoms can be an early sign of a
- Stomach pain, indigestion, heartburn, wind, nausea (feeling sick) or vomiting (being sick)
- Any sign of bleeding in the stomach or intestine, for example, when emptying your bowels, blood in vomit or black, tarry faeces
- Allergic reactions which can include skin rash, itching, bruising, painful red areas, peeling or blistering
- Wheezing or shortness of breath (bronchospasm)
- Swollen, face, lips, hands or fingers
- Yellowing of your skin or the whites of your eyes
- Persistent sore throat or high temperature
- An unexpected change in the amount of urine produced and/or its
- Mild cramping and tenderness of the abdomen, starting shortly after the start of the treatment with Diclofenac sodium injectionand followed by rectal bleeding or bloody diarrhoea usually within 24 hours of the onset of abdominal
Chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome
If you notice that you are bruising more easily than usual or have frequent sore throats or infections, tell your doctor.
The side effects listed below have also been reported.
Common side effects (These may affect between 1 and 10 in every 100 patients): Stomach pain, heartburn, nausea, vomiting, diarrhoea, indigestion, wind, loss of appetite Headache, dizziness, vertigo
Skin rash or spots
Raised levels of liver enzymes in the blood
Injection site reactions, symptoms include redness, swelling, change in the skin colour, inflammation, pain, and hypersensitivity.
Uncommon side effects (These may affect between 1 and 10 in every 1000 patients):
Fast or irregular heart beat (palpitations), chest pain, heart disorders, including heart attack or breathlessness, difficulty breathing when lying down, or swelling of the feet or legs (signs of heart failure), especially if you have been taking a higher dose (150 mg per day) for a long period of time.
Rare side effects (These may affect between 1 in every 1000 to 1 in every 10,000 patients): Stomach ulcers or bleeding (there have been very rare reported cases resulting in death, particularly in the elderly)
Gastritis (inflammation, irritation or swelling of the stomach lining) Vomiting blood
Diarrhoea with blood in it or bleeding from the back passage Black, tarry faeces or stools
Skin rash and itching
Fluid retention, symptoms of which include swollen ankles Liver function disorders, including hepatitis and jaundice
Asthma (symptoms may include wheezing, breathlessness, coughing and a tightness across the chest)
Injection site necrosis (dead skin and tissue around the injection site).
Very rare side effects (These may affect less than 1 in every 10,000 patients):
Effects on the nervous system:
Inflammation of the lining of the brain (meningitis), tingling or numbness in the fingers, tremor, visual disturbances such as blurred or double vision, taste changes, hearing loss or impairment, tinnitus (ringing in the ears), sleeplessness, nightmares, mood changes, depression, anxiety, irritability, mental disorders, disorientation and loss of memory, fits, headaches together with a dislike of bright lights, fever and a stiff neck.
Effects on the stomach and digestive system:
Constipation, inflammation of the tongue, mouth ulcers, inflammation of the inside of the mouth or lips, lower gut disorders (including inflammation of the colon, or worsening of colitis or Crohn’s disease), inflammation of the pancreas.
Effects on the chest or blood:
Hypertension (high blood pressure), hypotension (low blood pressure, symptoms of which may include faintness, giddiness or light headedness), inflammation of blood vessels (vasculitis), inflammation of the lung (pneumonitis), blood disorders (including anaemia).
Effects on the liver or kidneys:
Kidney or severe liver disorders including liver failure, presence of blood or protein in the urine.
Effects on skin or hair:
Facial swelling, serious skin rashes including Stevens-Johnson syndrome Lyell’s syndrome and other skin rashes which may be made worse by exposure to sunlight.
Effects on the reproductive system:
Other side effects that have also been reported with unknown frequency include:
Injection site abscess, hroat disorders, confusion, hallucinations, malaise (general feeling of discomfort), inflammation of the nerves in the eye, disturbances of sensation, tissue damage at the injection site.
Do not be alarmed by this list – most people have an injection of Diclofenac sodium injection without any problems. Reporting of side effects
If you get any side effects, talk your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet.
5. How to store Diclofenac sodium injection
Store below 30°C. Protect from light and heat. Keep out of the reach and sight of children.
Do not use Diclofenac sodium injectionafter the expiry date which is printed on the outside of the pack.
6. Further information
The glass ampoules contain 75 mg of the active ingredient, diclofenac sodium, in solution.
The ampoules also contain mannitol, sodium metabisulphite, benzyl alcohol, propylene glycol, sodium hydroxide, water.
7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST