Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: IBSA Farmaceutici Italia Srl, Via Martiri di Cefalonia 2, 26900, Lodi (Italy)
Specifically for i.v. 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.
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 If gastrointestinal bleeding or ulceration occurs in patients receiving Diclofenac, the medicinal product should be withdrawn.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).
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.
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.
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.
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.
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.
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:
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.
Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking Diclofenac, should refrain from driving or using machines.
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).
Not known: Injection site necrosis
Rare: Hypersensitivity reaction
Uncommon: Dizziness, Headache
Common: Nausea
Uncommon: Diarrhoea, Vomiting, Constipation Gastritis
Not known: Ischaemic colitis
Uncommon: Hepatic enzymes increase
Uncommon: Pruritus
Common: Limb discomfort
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.
Table 1:
Very rare: Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), Agranulocytosis.
Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare: Angioneurotic oedema (including face oedema).
Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Common: Headache, dizziness.
Rare: Somnolence.
Very rare: Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
Very rare: Visual disturbance, vision blurred, diplopia.
Common: Vertigo.
Very rare: Tinnitus, hearing impaired.
Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction.
Very rare: Hypertension, vasculitis.
Rare: Asthma (including dyspnoea).
Very rare: Pneumonitis.
Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare: Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding or perforation).
Very rare: 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.
Common: Transaminases increased.
Rare: Hepatitis, jaundice, liver disorder.
Very rare: Fulminant hepatitis, hepatic necrosis, hepatic failure.
Common: Rash.
Rare: Urticaria.
Very rare: 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.
Very rare: Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
Common: Injection site reaction, injection site pain, injection site induration
Rare: Oedema, Injection site necrosis.
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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