Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: P.T.Hadjigeorgiou Co Ltd, P.O.Box 53158-3301, Limassol, Cyprus, Tel: 25372425, Fax: 25376400, e-mail: info.pth@cytanet.com.cy
Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known.
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have 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 treatment should be discontinued.
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 and in the elderly.
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) 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-reuptakeinhibitors (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 Undesirable effects).
Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
Treatment with diclofenac is generally not recommended in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) should be treated with diclofenac only after careful consideration and only at doses ≤100 mg daily when treatment continues for more than 4 weeks.
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks.
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. Like other NSAIDs diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis 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 edema or urticaria are more frequent than in other patients. Therefore, special caution 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.
Special caution is recommended when diclofenac is used parenterally in patients with bronchial asthma because symptoms may be exacerbated.
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 (e.g. in the form of tablets or suppositories) 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.
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 Undesirable effects). Patients appear to be at highest risk of 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 should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug.
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 of 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.
Injection site reactions have been reported after the administration of diclofenac intramuscularly, including injection site necrosis and embolia cutis medicamentosa, also known as Nicolau Syndrome (particularly after inadvertent subcutaneous administration). Appropriate needle selection and injection technique should be followed during i.m. administration of diclofenac (see section 6.6 – Special precautions for disposal).
Caution is indicated in the elderly on basic medical grounds, especially in frail elderly patients or those with a low body weight.
The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to undesirable effects (see section 4.5).
Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
The following interactions include those observed with diclofenac solution for injection and/or other pharmaceutical forms of diclofenac.
Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to 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. 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(see section 4.4)..
Diclofenac, like otherNSAIDs, 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 or tacrolimus.
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).
There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (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 isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Concomitant administration of systemic NSAIDs, including diclofenac, and 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 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.
There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with metformin, especially in patients with pre-existing renal impairment
When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
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.
Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac
There are no data to suggest any recommendations for women of child-bearing potential.
There are insufficient data on the use of diclofenac in pregnant women. Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Diclofenac should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risk to the foetus. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia and/or premature closure of the ductus arteriosus (see section 4.3 and 5.3).
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.
Not applicable.
Adverse drug reactions from clinical trials and/or spontaneous or literature cases(Table 1)are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactionsare ranked by frequency, with the most frequent reactionsfirst. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).
The following undesirable effects include those reported with diclofenac solution for injection and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.
Table 1. Adverse drug reactions:
| Infections and infestations | |
| Very rare: | Injection site abscess |
| Blood and lymphatic system disorders | |
| Very rare: | Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis |
| Immune system disorders | |
| Rare: | Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock) |
| Very rare: | Angioedema (including face oedema) |
| IPsychiatric disorders | |
| Very rare: | Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder |
| INervous system disorders | |
| Common: | Headache, dizziness |
| Rare: | Somnolence |
| Very rare: | Paraesthesia, memory impairment, convulsion, anxiety, tremor, meningitis aseptic, dysgeusia, cerebrovascular accident |
| Eye disorders | |
| Very rare: | Visual impairment, vision blurred, diplopia |
| Ear and labyrinth disorders | |
| Common: | Vertigo |
| Very rare: | Tinnitus, hearing impaired |
| Cardiac disorders | |
| Uncommon*: | Myocardial infarction, cardiac failure, palpitations, chest pain |
| Not known: | Kounis syndrome |
| Vascular disorders | |
| Very rare: | Hypertension, vasculitis |
| Respiratory, thoracic and mediastinal disorders | |
| Rare: | Asthma (including dyspnoea) |
| Very rare: | Pneumonitis |
| Gastrointestinal disorders | |
| Common: | Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, decreased appetite |
| 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, glossitis, oesophageal disorder, intestinal diaphragm disease, pancreatitis |
| 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: | Dermatitis bullous, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dermatitis exfoliative, alopecia, photosensitivity reaction, purpura, Henoch-Schonleinpurpura, pruritus |
| Renal and urinary disorders | |
| Very rare: | Acute renal failure, haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis |
| General disorders and administration site conditions | |
| Common: | Injection site reaction, injection site pain, injection site induration |
| Rare: | Oedema, Injection site necrosis |
* The frequency reflects data from long-term treatment with a high dose (150 mg/day).
Adverse drug reactions from post-marketing experience (frequency not known)
The following adverse drug reaction has been derived from post-marketing experience with diclofenac. Because this reaction was reported voluntarily from a population of uncertain size, it is not possible to reliably estimate its frequency which is therefore categorized as not known.
Table 2. Adverse drug reaction derived from post-marketing experience (frequency not known):
| Injection site reactions |
| Embolia cutis medicamentosa (Nicolau syndrome) |
Meta-analysis and pharmacoepidemiological data point towards a small increased risk of arteriothrombotic events (for example myocardial infarction) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (see section 4.4).
Visual disturbances such as visual impairment, blurred vision or diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.
As a rule, diclofenac solution for injection should not be mixed with other injection solutions.
Infusion solutions of sodium chloride 0.9% or glucose 5% without sodium bicarbonate as an additive present a risk of supersaturation, possibly leading to formation of crystals or precipitates. Infusion solutions other than those recommended should not be used.
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