Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Dexcel-Pharma Ltd., 7 Sopwith Way, Drayton Fields, Daventry, Northamptonshire NN11 8PB, UK
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 (see section 4.5).
Caution is indicated in the elderly on basic 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 (see section 4.2).
As with other nonsteroidal anti-inflammatory drugsincluding diclofenac allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see section 4.8). 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.
This medicine contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Gastrointestinal bleeding (haematemesis, melaena), ulceration or 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 (GI) 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 If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be withdrawn.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 gastrointstinal disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac 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 (see section 4.2).
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. misoprostol or proton pump inhibitors) 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 (see below and section 4.5).
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 such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid (see section 4.5).
Close medical surveillance and caution should also 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 impairment of 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, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), diclofenac should be discontinued.
Hepatitis may occur with 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.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac sodium tablets should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).
Patients with congestive heart failure (NYHA-I) or 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.
Appropriate monitoring and advice are required for patients with a history of hypertension and congestive heart failure (NYHA-I) as fluid retention and oedema have been reported in association with NSAID therapy including diclofenac.
Clinical trial and epidemiological data consistently point towards 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.
Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Diclofenac may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
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.
Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.
The use of Diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Diclofenac should be considered (see section 4.6).
The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.
If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.
If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.
Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4).
Caution is recommended since concomitant administration could increase the risk of bleeding (see section 4.4). 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 (see section 4.4). Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in high dose can reversibly inhibit platelet aggregation.
Other NSAIDS including cyclo-oxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4).
Concomitant administration of SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4).
Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of hypoglycaemic and hyperglycaemic effects 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.
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 treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.
Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.
Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.
Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostaglandin effects of both NSAID and calcineurin inhibitor.
Convulsions may occur due an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.
When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
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.
Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentration and exposure to diclofenac due to inhibition of diclofenac metabolism.
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. 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:
The mother and the neonate, at the end of pregnancy, to:
Consequently, diclofenac sodium tablets are 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 (see section 5.2).
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 (see also section 4.4 regarding female fertility).
Patients who experience visual disturbances, dizziness, vertigo, somnolence central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operate machinery.
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:
| Blood and lymphatic system disorders | |
| Very rare | Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis. |
| Immune system disorders | |
| Rare | Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). |
| Very rare | Angioneurotic oedema (including face oedema). |
| Psychiatric disorders | |
| Very rare | Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder. |
| Nervous system disorders | |
| Common | Headache, dizziness. |
| Rare | Somnolence, tiredness. |
| Very rare | Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident. |
| Unknown | Confusion, hallucinations, disturbances of sensation, malaise. |
| Eye disorders | |
| Very rare | Visual disturbance, vision blurred, diplopia. |
| Unknown | Optic neuritis. |
| Ear and labyrinth disorders | |
| Common | Vertigo. |
| Very rare | Tinnitus, hearing impaired. |
| Cardiac disorders | |
| Uncommon* | Myocardial infarction, cardiac failure, palpitations, chest pain. |
| Unknown | Kounis syndrome |
| Vascular disorders | |
| Very rare | Hypertension, hypotension, vasculitis. |
| Respiratory, thoracic and mediastinal disorders | |
| Rare | Asthma (including dyspnoea). |
| Very rare | Pneumonitis. |
| Gastrointestinal disorders | |
| 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 (sometimes fatal particularly in the elderly). |
| 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. |
| Unknown | Ischaemic colitis |
| Hepatobiliary disorders | |
| Common | Transaminases increased. |
| Rare | Hepatitis, jaundice, liver disorder. |
| Very rare | Fulminant hepatitis, hepatic necrosis, hepatic failure. |
| Skin and subcutaneous tissue disorders | |
| 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. |
| Renal and urinary disorders | |
| Very rare | Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis. |
| Reproductive system and breast disorders | |
| Very rare | Impotence |
| General disorders and administration site conditions | |
| Rare | Oedema |
* The frequency reflects data from long-term treatment with a high dose (150mg/day).
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 (150 mg daily) and in long term treatment (see sections 4.3 and 4.4 ).
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.
Not applicable.
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