Voltaren/Voltaren SR

The active substance is sodium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (= diclofenac sodium).
Voltaren EC tablet: One gastro-resistant tablet contains 25 mg or 50 mg of diclofenac sodium.
Excipients/Inactive Ingredients: Core for 25 mg and 50 mg: colloidal anhydrous silica, lactose, maize starch, sodium starch glycollate, povidone, microcrystalline cellulose, magnesium stearate.
Coating for 25 mg: hypromellose, yellow iron oxide (E 172), purified talc, titanium dioxide (E 171), methacrylic acid copolymer, polyethylene glycol 8000, simeticone, polyoxyethylene 40 hydrogenated castor oil.
Coating for 50 mg: hypromellose, yellow iron oxide (E 172), purified talc, titanium dioxide (E 171), methacrylic acid copolymer, polyethylene glycol 8000, simeticone, red iron oxide (E 172), polyoxyethylene 40 hydrogenated castor oil.
Voltaren SR-FC tablet: Prolonged-release coated tablets containing 75 mg or 100 mg of diclofenac sodium (phenylacetic acid derivative).
Excipients/Inactive Ingredients: Tableting excipients.
Voltaren suppository: One suppository contains 12.5 mg, 25 mg, 50 mg, or 100 mg of diclofenac sodium.
Excipients/Inactive Ingredients: Hard fat.

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic product, non-steroid, acetic acid derivative and related substance. ATC code: M01AB05.
Pharmacology: Pharmacodynamics: Mechanism of action: Voltaren contains the sodium salt of diclofenac, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis has been demonstrated experimentally and is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain, and fever.
In vitro, diclofenac sodium does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
Pharmacokinetics: Distribution: Diclofenac is 99.7% bound to serum proteins, mainly albumin (99.4%). The apparent volume of distribution has been calculated at 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been reached. The apparent elimination half-life from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma values, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.
Biotransformation: Biotransformation of diclofenac is partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation. This results in several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are subsequently converted to glucuronide conjugates. Two of these phenolic metabolites are pharmacologically active, but to a much lesser extent than diclofenac itself.
Elimination: Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. The virtually inactive metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer plasma half-life.
About 60% of the administered dose is excreted in the urine as 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 via the bile in the faeces.
Linearity/non-linearity: The amount absorbed is in linear proportion to the size of the dose.
Pharmacokinetics in special populations: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed.
Renal impairment: In patients with renal impairment, the drug's single-dose pharmacokinetics do not suggest any accumulation of unchanged active substance with the usual dosage schedule. In patients with a creatinine clearance of <10 mL/min, theoretical steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared via the bile.
Hepatic impairment: In patients with hepatic impairment (chronic hepatitis or non-decompensated cirrhosis), the pharmacokinetics and metabolism of diclofenac are the same as in patients without liver disease.
Toxicology: Preclinical safety data: Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity, and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses.
Voltaren EC tablet: Pharmacology: Pharmacodynamics: Pharmacodynamic effects: In rheumatic diseases, the anti-inflammatory and analgesic properties of Voltaren elicit a clinical response characterised by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In post-traumatic and post-operative inflammatory conditions, Voltaren rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
In clinical trials Voltaren has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. Clinical studies have also revealed that, in primary dysmenorrhoea, Voltaren is capable of relieving the pain and reducing the extent of bleeding.
Pharmacokinetics: Absorption: Diclofenac is completely absorbed from the gastro-resistant tablets after their passage through the stomach. Although absorption is rapid, its onset may be delayed due to the gastro-resistant coating of the tablet.
Mean peak plasma concentrations of 1.5 micrograms/mL (5 micromol/L) are attained on average 2 hours after ingestion of one tablet of 50 mg.
The passage of a tablet through the stomach is slower when ingested with or after a meal than when it is taken before a meal, but the amount of diclofenac absorbed remains the same.
Since about half of diclofenac is metabolised during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Toxicology: Preclinical safety data: There was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. The prenatal, perinatal and postnatal development of the offspring was not affected.
Voltaren SR-FC tablet: Pharmacology: Pharmacodynamics: Clinical efficacy: In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterised by improved function and marked relief of signs and symptoms such as pain at rest, pain on movement, morning stiffness and swelling of the joints. In post-traumatic and post-operative inflammatory conditions, Voltaren rapidly relieves both spontaneous pain and pain on movement, and reduces inflammatory swelling and wound oedema.
In clinical trials, the product has also been shown to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. It can relieve the pain, and also reduce bleeding, in primary dysmenorrhoea.
Pharmacokinetics: Absorption: Judged on the basis of the urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from Voltaren prolonged-release coated tablets as from the gastro-resistant coated tablets. However, on average the systemic bioavailability of diclofenac from Voltaren prolonged-release coated tablet is approximately 82% of that attained with the same dose of Voltaren administered in the form of gastro-resistant coated tablets (possibly due to release-rate-dependent first-pass metabolism). Owing to the slower release of the active substance from Voltaren prolonged-release coated tablets, peak plasma concentrations are lower than with the gastro-resistant coated tablets.
Mean peak plasma concentrations of 0.5 μg/ml and 0.4 μg/ml are attained on average 4 hours after administration, respectively, of 100 mg or 75 mg prolonged-release coated tablets. Ingestion with food has no notable effect on the absorption and systemic bioavailability of Voltaren prolonged-release coated tablets.
On the other hand, mean plasma concentrations of 13 ng/ml are recorded 24 hours (16 hours) after ingestion of 100 mg (75 mg).
Ingestion of 100 mg once daily or 75 mg twice daily produces trough plasma levels of approximately 22 ng/ml and 25 ng/ml, respectively.
Distribution: A low concentration of diclofenac (100 ng/ml) was detected in the breast milk of one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Toxicology: Preclinical safety data: The increased incidence of lymphomas (thymus) in mice, and subcutaneous fibromas, fibroadenomas (mammary gland) or C-cell adenomas (thyroid gland) in rats were all within the historical control range of the laboratory for the animal strain used, and are considered to have occurred by chance.
In all toxicity studies carried out in rats, hypertrophy of mesenteric lymph nodes or lymphadenitis with reactive hyperplasia were observed. These changes were accompanied by neutrophilia that was also observed in studies in monkeys. These are presumably secondary reactions to the ulcers observed in the gastrointestinal tract. In a two-year study, a dose-dependent increase in thrombotic vascular occlusions in the heart was observed in rats treated with diclofenac.
Reproductive toxicity: Additional studies indicate that, with repeated oral doses in rats (>1 mg/kg body weight), diclofenac causes effects that influence fertility (lower testosterone level, and decreased epididymal and testicular weight in association with histopathological changes). Similar effects were also observed in the F1 generation following doses of ≥1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of 2 mg/kg diclofenac sodium led to an increased spermatid count. Further studies describe a decreased mating frequency in female rats following a repeated dose of ≥0.5 mg/kg diclofenac. For this reason, an influence on both male and female fertility cannot be ruled out.
Diclofenac crosses the placental barrier in rodents. Administration of NSAIDs (including diclofenac) inhibited ovulation in rabbits and implantation and placentation in rats, and led to premature closure of the ductus arteriosus in pregnant rats. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as closure of the ductus arteriosus in utero are pharmacological effects of this class of prostaglandin synthetase inhibitors (see Contraindications and Use in Pregnancy & Lactation).
In a study in mice, teratogenicity (cleft palate) was observed at the maternally toxic dose of 4 mg/kg. In rats and rabbits, doses up to the maternally toxic level did not lead to teratogenic effects. Delayed ossification and reduced fetal weight in a study in rabbits were the only changes observed in these investigations.
At maternally toxic doses, the perinatal and post-natal development of the offspring were impaired (fertility, see as previously mentioned, also birth weight and delayed post-natal growth).
Voltaren suppository: Pharmacology: Pharmacodynamics: Pharmacodynamic effects: In rheumatic diseases, the anti-inflammatory and analgesic properties of Voltaren elicit a clinical response characterised by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In post-traumatic and post-operative inflammatory conditions, Voltaren rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
In clinical trials Voltaren has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. Clinical studies have also revealed that, in primary dysmenorrhoea, Voltaren is capable of relieving the pain and reducing the extent of bleeding.
Voltaren also has beneficial effects on the symptoms of migraine attacks.
Pharmacokinetics: Absorption: Diclofenac shows a rapid onset of absorption from suppositories, although the rate of absorption is slower than from gastro-resistant tablets administered orally. After the administration of 50 mg suppositories, peak plasma concentrations are attained on average within 1 hour, but maximum concentrations per dose unit are about two thirds of those reached after administration of gastro-resistant tablets.
Since about half of diclofenac is metabolised during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Toxicology: Preclinical safety data: There was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. The prenatal, perinatal and postnatal development of the offspring was not affected.

In keeping with standard therapeutic principles, the underlying disease should be treated with specific therapy, as appropriate. Fever alone is not an indication.
Voltaren EC tablet/SR-FC tablet/suppository: Treatment of inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondylarthritis, painful syndromes of the vertebral column, non-articular rheumatism.
Treatment of post-traumatic and post-operative pain, inflammation, and swelling, e.g. following dental or orthopaedic surgery.
Treatment of painful and/or inflammatory gynaecological conditions, e.g. primary dysmenorrhoea or adnexitis.
Voltaren EC tablet/suppository: Treatment of inflammatory and degenerative forms of rheumatism: juvenile rheumatoid arthritis.
Treatment of acute attacks of gout.
As an adjuvant in severe painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis.
Voltaren suppository: Treatment of migraine attacks.

As a general recommendation, the dose should be individually adjusted and the lowest effective dose given for the shortest possible duration.
Voltaren EC tablet/suppository: Adults: The recommended initial daily dose is 100 to 150 mg. In milder cases, as well as for long-term therapy, 75 to 100 mg daily is usually sufficient.
The total daily dose should generally be divided into 2 to 3 doses. To suppress nocturnal pain and morning stiffness, treatment with tablets during the day can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).
In primary dysmenorrhoea, the daily dose should be individually adjusted and is generally 50 to 150 mg. A dose of 50 to 100 mg should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
Children and adolescents: Children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily in 2 to 3 divided doses, depending on the severity of the disorder.
For treatment of juvenile rheumatoid arthritis, the dose can be raised up to a maximum of 3 mg/kg daily, given in divided doses.
The maximum daily dose of 150 mg should not be exceeded.
Voltaren EC tablet: The tablets should be swallowed whole with liquid, preferably before meals, and must not be divided or chewed.
Children and adolescents: Because of their dosage strength, Voltaren 50 mg gastro-resistant tablets are not recommended for use in children and adolescents below 14 years of age. Voltaren 25 mg gastro-resistant tablets could be used in these patients.
Voltaren SR-FC tablet: Usual dosage: Adults: The usual daily dose of Voltaren is 100 mg, i.e. one 100 mg prolonged-release coated tablet. In milder cases and for long-term therapy, one 75 mg or 100 mg prolonged-release coated tablet per day is normally sufficient. If symptoms are most pronounced at night or in the morning, Voltaren should preferably be taken in the evening.
The maximum recommended daily dose is 100 mg.
The prolonged-release coated tablets should be swallowed whole with liquid, preferably with meals.
Special dosage instructions: Established cardiovascular disease or significant cardiovascular risk factors: Treatment with Voltaren is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension or significant risk factors for cardiovascular disease should be treated with Voltaren only after careful consideration, and only at doses of up to 100 mg daily if treated for more than 4 weeks (see Precautions).
Diclofenac, particularly at higher doses (150 mg per day), is associated with an increased risk of serious cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events which can be fatal) that is comparable to COX-2 inhibitors. Evidence suggests that the risk may increase with the dose and duration of use. Treatment with diclofenac is not recommended in patients with pre-existing cardiovascular disease or cerebrovascular disease, or presenting risk factors for cardiovascular disease. For these patients, treatment options other than NSAIDs, particularly COX-2 inhibitors and diclofenac, should be considered first.
Patients with hepatic impairment: Voltaren is contraindicated in patients with hepatic failure (see Contraindications).
No specific studies have been carried out in patients with hepatic impairment; therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Voltaren to patients with mild to moderate hepatic impairment (see Precautions).
Patients with renal impairment: Voltaren is contraindicated in patients with renal failure (GFR <15 ml/min/1.73 m²) (see Contraindications).
No specific studies have been carried out in patients with renal impairment; therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Voltaren to patients with renal impairment (see Precautions).
Elderly patients: No adjustment of the starting dose is generally required for elderly patients. However, caution is indicated on basic medical grounds, especially for frail elderly patients or those with a low body weight (see Precautions).
Children and adolescents: Voltaren must not be given to children under 1 year of age.
Voltaren 75 mg and 100 mg prolonged-release coated tablets are not suitable for children and adolescents.
Voltaren suppository: The suppositories should be inserted well into the rectum. It is recommended to take the suppositories after passing stools.
Not to be taken by mouth, as per rectal use only.
Adults: Treatment of migraine attacks with Voltaren suppositories should be started with a dose of 100 mg at the first signs of an impending attack. Additional suppositories up to 100 mg may be taken on the same day if required. Should the patient require further therapy on the following days, the maximum daily dose should be limited to 150 mg in divided doses.
Children and adolescents: Voltaren 12.5 mg or 25 mg suppositories are recommended for use in children and adolescents below 14 years of age. Because of their dosage strength, Voltaren 50 mg suppositories are not recommended for children and adolescents below 14 years of age.
Voltaren 100 mg suppositories are not suitable for children and adolescents.

Signs and symptoms: There is no typical clinical picture following diclofenac overdose. Overdose can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of severe intoxication, acute renal failure and liver damage are possible.
Therapeutic measures: Treatment of acute intoxication 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 disorders, and respiratory depression.
Special measures such as forced diuresis, dialysis or haemoperfusion are unlikely to be helpful in eliminating NSAIDs, including diclofenac, due to their high protein binding and extensive metabolism.
Voltaren EC tablet/SR-FC tablet: Therapeutic measures: Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life-threatening overdose.

Known hypersensitivity to the active substance or to any of the excipients.
Active gastric and/or duodenal ulcers, gastrointestinal bleeding or perforation.
Severe hepatic failure (Child-Pugh class C) (cirrhosis of the liver and ascites).
Severe renal failure (GFR <15 ml/min/1.73 m²).
Severe cardiac failure (NYHA III-IV).
Third trimester of pregnancy (see Use in Pregnancy & Lactation).
Voltaren EC tablet/suppository: Like other non-steroidal anti-inflammatory drugs (NSAIDs), Voltaren is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.
Voltaren SR-FC tablet: History of bronchospasm, angioedema, urticaria, acute rhinitis, nasal polyps or allergy-like symptoms after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs.
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Active, or history of recurrent peptic ulcer/haemorrhage.
Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis).
Treatment of post-operative pain after coronary bypass surgery (or use of a heart-lung machine).
Voltaren suppository: Proctitis.

Voltaren EC tablet/suppository: 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 occur in patients receiving Voltaren, the medicinal product should be withdrawn.
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 Voltaren (see Adverse Reactions). 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. Voltaren 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.
Like other NSAIDs, Voltaren may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Voltaren SR-FC tablet: General warning for the use of systemic non-steroidal anti-inflammatory drugs: Gastrointestinal ulceration, bleeding or perforation may occur at any time during treatment with non-steroidal anti-inflammatory drugs (NSAIDs), whether COX-2 selective or not, even in the absence of warning symptoms or a predisposing history. To minimise this risk, the lowest effective dose should be given for the shortest possible duration of treatment.
Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain COX-2 selective inhibitors. It is not yet known whether this risk correlates directly with the COX-1/COX-2 selectivity of individual NSAIDs. As no comparable clinical study data are available at present for long-term treatment with the maximum dosage of diclofenac, the possibility of a similarly elevated risk cannot be ruled out. Until such data becomes available, a careful risk-benefit assessment must be carried out prior to using diclofenac in patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial occlusive disease or considerable risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Due to this risk, too, the lowest effective dose should be given for the shortest possible duration of treatment.
The renal effects of NSAIDs include fluid retention with oedema and/or arterial hypertension. For this reason, diclofenac should be used with caution in patients with cardiac impairment and other conditions that predispose to fluid retention. Caution is also indicated in patients who take concomitant diuretics or ACE inhibitors, or who are at increased risk of hypovolaemia.
The consequences are generally more serious in the elderly. If gastrointestinal bleeding or ulceration occurs in patients undergoing treatment with Voltaren, the medicinal product should be withdrawn.
Cutaneous reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and drug rash with eosinophilia and systemic symptoms (DRESS), have been reported very rarely in association with the use of NSAIDs, including Voltaren (see Adverse Reactions). Patients appear to be at highest risk at the start of treatment, with the onset of the reaction usually occurring within the first month of treatment. Voltaren should be discontinued at the first sign of rash, mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions - including anaphylactic/anaphylactoid reactions - may occur in rare cases, even without prior exposure to diclofenac.
Masking signs of infection: Its pharmacodynamic properties mean that, like other NSAIDs, diclofenac may mask the signs and symptoms of infection.

General: The concomitant use of Voltaren 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 Interactions).
Caution is required 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.
Respiratory effects (pre-existing asthma): 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 to NSAIDs such as asthma exacerbations (analgesic intolerance or analgesic-induced 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 (e.g. rash, pruritus or urticaria) to other substances.
Gastrointestinal effects: As with all NSAIDs, including diclofenac, close medical surveillance is required and particular caution should be exercised when prescribing Voltaren in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see Adverse Reactions). The risk of GI bleeding is greater with higher NSAID doses and in patients with a history of ulcers (particularly if complicated with bleeding or perforation) and in the elderly.
Treatment should be initiated and maintained at the lowest effective dose to reduce the risk of GI toxicity in patients with a history of ulcers (particularly if complicated with bleeding or perforation) and in the elderly.
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 required in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, antiplatelet agents or selective serotonin reuptake inhibitors (see Interactions).
Hepatic effects: Close medical surveillance is required when prescribing Voltaren to patients with impaired hepatic function, as their condition may be exacerbated (see Adverse Reactions).
As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with Voltaren (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), Voltaren should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is required when using Voltaren in patients with hepatic porphyria, since it may trigger an attack.
Renal effects: As fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac, particular caution is required in patients with impaired cardiac or renal function, in patients with a history of hypertension, in the elderly, in patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see Contraindications). Monitoring of renal function is recommended as a precautionary measure when using Voltaren in such cases. Patients usually recover to their pre-treatment state following discontinuation of therapy.
Haematological effects: As with other NSAIDs, complete blood counts are recommended during long-term treatment with Voltaren.
Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with coagulation disorders should be carefully monitored.
Effects on ability to drive and use machines: Patients experiencing visual disturbances, light-headedness, dizziness, drowsiness, vertigo, somnolence, or other central nervous system disturbances while taking Voltaren should refrain from driving or using machines.
Voltaren EC tablet: General: Voltaren gastro-resistant tablets contain lactose and therefore are not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Gastrointestinal effects: 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 Adverse Reactions).
Voltaren SR-FC tablet: General: Voltaren prolonged-release coated tablets contain sucrose and are therefore not recommended in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.
This medicine contains less than 1 mmol (23 mg) of sodium per dosage unit (coated tablet and prolonged-release coated tablet), making it practically "sodium-free".
Gastrointestinal effects: NSAIDs, including diclofenac, can be associated with an increased risk of a gastrointestinal anastomosis leak. Caution is required with the use of Voltaren after gastrointestinal surgery and close medical monitoring is recommended.
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
Hepatic effects: As with all NSAIDs, including diclofenac, levels of one or more liver enzymes may rise during treatment with Voltaren. This has been observed very frequently with diclofenac in clinical studies (in approximately 15% of patients), but is very rarely accompanied by clinical symptoms. Most of these cases involve borderline increases. Frequently (in 2.5% of cases) the increases observed were moderate (≥3 to <8 times the upper limit of normal), while the incidence of marked increases (≥8 times the upper limit of normal) remained around 1%. Elevated liver enzyme levels were accompanied by clinically manifest liver damage in 0.5% of cases in the previously mentioned clinical studies. Elevated enzyme levels were generally reversible after discontinuation of the drug.
In addition to elevated liver enzymes, there have been rare reports of severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis and hepatic failure which, in isolated cases, had a fatal outcome.
In rare cases, diclofenac has been associated with serious liver injury.
Renal effects: Owing to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of NSAIDs, including diclofenac, frequently (1-10%) results in oedema and hypertension.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease: No information is available from controlled clinical studies regarding the use of Voltaren in patients with advanced renal disease. Therefore, treatment with Voltaren is not recommended in these patients with advanced renal disease. If therapy must be initiated, close monitoring of the patient's renal function is advisable.
Cardiovascular effects: Treatment with NSAIDs including diclofenac, particularly at high doses and for prolonged periods, may be associated with a slightly increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
Treatment with Voltaren is generally not recommended in patients with established cardiovascular disease (heart failure, established ischaemic 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, hyperlipidaemia, diabetes mellitus and smoking) should be treated with Voltaren only after careful consideration and only at doses of up to 100 mg daily if treated 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 arterial thromboembolic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warning. Patients should be instructed to see a physician immediately in case of such an event.
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Use in Pregnancy: Voltaren is contraindicated for use during the third trimester of pregnancy because of risks of premature closure of the ductus arteriosus and the potential to prolong parturition. Caution is recommended in prescribing Voltaren during the first and second trimesters of pregnancy, particularly from the middle to end of the second trimester of pregnancy (onset at approximately 20 weeks) due to possible fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment or failure.
Voltaren should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus.
Published studies and post-marketing reports describe maternal Non-Steroidal Anti-Inflammatory Drug (NSAID) use at approximately 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment or failure. NSAIDs were shown to cause significant reduction in fetal urine production prior to reduction of amniotic fluid volume. There have also been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction and renal impairment without oligohydramnios, some of which were irreversible, even after treatment discontinuation.
These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
Complications of prolonged oligohydramnios may for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If after careful consideration of the benefit-risk, NSAID treatment is considered necessary to be administered anywhere from the middle (onset at approximately 20 weeks) to the end of the second trimester of pregnancy, the use should be limited to the lowest effective dose and shortest duration possible. It is also recommended that ultrasound monitoring of amniotic fluid be considered if Voltaren treatment extends beyond 48 hours and that NSAIDs treatment be discontinued if oligohydramnios occurs, followed by appropriate medical follow up.
Voltaren suppository: Gastrointestinal effects: 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 Adverse Reactions).

Voltaren EC tablet/suppository: Pregnancy: The use of diclofenac in pregnant women has not been studied. Therefore, Voltaren should not be used during the first two trimesters of pregnancy unless the potential benefit to the mother outweighs 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 Contraindications). Animal studies have not shown any directly or indirectly harmful effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Lactation: Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Voltaren should not be administered during breast-feeding in order to avoid undesirable effects in the infant.
Fertility: As with other NSAIDs, the use of Voltaren 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 Voltaren should be considered.
Voltaren SR-FC tablet: Pregnancy: Inhibition of prostaglandin synthesis may have a negative impact on pregnancy and/or embryofetal development. Data from epidemiological studies suggest an elevated risk of miscarriage and of cardiac malformation and gastroschisis following administration of a prostaglandin synthetase inhibitor during early pregnancy. The risk is assumed to rise with the dose and the duration of therapy.
In animals, administration of a prostaglandin synthetase inhibitor has been shown to result in increased pre-implantation and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis (see Pharmacology: Toxicology: Preclinical safety data under Actions).
First/second trimester: During the first and second trimesters of pregnancy, diclofenac should not be given unless absolutely necessary. If diclofenac is used by a woman attempting to conceive, or during the first or second trimesters of pregnancy, the dose should be kept as low - and the duration of treatment as short - as possible.
Oligohydramnios/neonatal renal impairment: Use of NSAIDs in the 20^th week of pregnancy or later may lead to fetal renal impairment, which may cause oligohydramnios and, in some cases, neonatal renal impairment. These adverse effects occur, on average, after days to weeks of treatment, although in rare cases oligohydramnios has been reported as early as 48 hours after initiation of NSAID treatment. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of neonatal renal impairment invasive procedures such as exchange transfusion or dialysis were required. Consider ultrasound monitoring of the amniotic fluid if Voltaren treatment lasts longer than 48 hours. Discontinue Voltaren if oligohydramnios occurs and follow up according to clinical practice.
Third trimester: Diclofenac is contraindicated during the third trimester of pregnancy.
All prostaglandin synthetase inhibitors may expose the fetus to the following risks: cardiopulmonary toxicity (with premature closure of the ductus arteriosus, and pulmonary hypertension, also see Pharmacology: Toxicology: Preclinical safety data under Actions); renal dysfunction, which may progress to renal failure with oligohydramnios.
All prostaglandin synthetase inhibitors may expose the mother and child to the following risks: possible prolongation of bleeding time, an effect of inhibition of platelet aggregation even at very low doses; inhibition of uterine contractions, resulting in delayed or prolonged labour.
Breast-feeding: As with other NSAIDs, small amounts of diclofenac pass into the breast milk. As a precaution, diclofenac should therefore not be used by women who are breast-feeding. If treatment is essential, the infant should be switched to bottle feeding.
Fertility: Diclofenac may impair female fertility and is therefore not recommended in women attempting to conceive. Consideration should be given to stopping diclofenac in women who are having difficulty conceiving, or in those being tested for infertility.
In animals, based on relevant data, impairment of male fertility cannot be ruled out (see Pharmacology: Toxicology: Preclinical safety data under Actions). The relevance of this finding for humans is unclear.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports.
The following undesirable effects include those reported with Voltaren and/or other pharmaceutical forms of diclofenac during 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: Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare: Angioedema (including facial oedema).
Psychiatric disorders: Very rare: Disorientation, depression, insomnia, nightmares, irritability, psychotic disorder.
Nervous system disorders: Common: Headache, dizziness/light-headedness.
Rare: Somnolence.
Very rare: Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances/dysgeusia, cerebrovascular accident.
Eye disorders: Very rare: Visual disturbances, vision blurred/visual impairment, diplopia.
Ear and labyrinth disorders: Common: Vertigo.
Very rare: Tinnitus, hearing impaired.
Respiratory, thoracic and mediastinal disorders: Rare: Asthma (including dyspnoea).
Very rare: Pneumonitis.
Gastrointestinal disorders: Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia/decreased appetite.
Rare: Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding, gastrointestinal stenosis or perforation, which may lead to peritonitis).
Very rare: Colitis (including haemorrhagic colitis, ischaemic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatobiliary disorders: Common: Transaminases increased.
Rare: Hepatitis, jaundice, liver disorder/hepatic dysfunction.
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/alopecia, photosensitivity reaction, purpura, allergic purpura/Henoch-Schönlein purpura, pruritus.
Renal and urinary disorders: Very rare: Acute kidney injury (acute renal failure), haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions: Rare: Oedema.
Voltaren EC tablet/suppository: Cardiac disorders: Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders: Very rare: Hypertension, vasculitis.
Voltaren SR-FC tablet: Cardiac disorders: Uncommon*: Myocardial infarction, heart failure, palpitations, chest pain.
Not known: Kounis syndrome.
Vascular disorders: Common: Hypertension.
Very rare: Vasculitis.
Gastrointestinal disorders: Voltaren prolonged-release coated tablets may provoke chronic inflammatory conditions with pseudomembranes and strictures in the lower intestines (small and large intestines).
Skin and subcutaneous tissue disorders: Not known: Drug rash with eosinophilia and systemic symptoms (DRESS).
Renal and urinary disorders: Common: Fluid retention, oedema.
* The frequency reflects data from long-term treatment with a high dose (150 mg/day).
Meta-analyses of controlled clinical studies and pharmacoepidemiological data point towards an increased risk of arterial thromboembolic events (for example, myocardial infarction or stroke) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (see Warnings and Precautions).
Description of selected adverse effects: Visual effects: Visual disturbances such as visual impairment, blurred vision and 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.
Reporting of suspected adverse effects: Reporting suspected adverse effects after authorisation of the medicinal product is very important. It allows continued monitoring of the risk-benefit ratio of the medicinal product. Healthcare professionals are asked to report any suspected new or serious adverse effects.
Voltaren suppository: Gastrointestinal disorders: Rare: Proctitis.
Very rare: Haemorrhoids aggravated.
General disorders and administration site conditions: Common: Application site irritation.

The following interactions were observed with Voltaren and/or other pharmaceutical forms of diclofenac.
Lithium: Diclofenac may increase plasma concentrations of co-administered lithium. Monitoring of serum lithium levels is recommended.
Digoxin: Diclofenac may increase plasma concentrations of co-administered digoxin. Monitoring of serum digoxin levels is recommended.
Diuretics and antihypertensive agents: As with other NSAIDs, co-administration of diclofenac may reduce the antihypertensive effects of diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin-converting-enzyme [ACE] inhibitors). Therefore, the combination should be administered with caution, and patients, especially the elderly, should have their blood pressure monitored regularly. Patients should be adequately hydrated, and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly with diuretics and ACE inhibitors due to the increased risk of nephrotoxicity (see Warnings and Precautions).
Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects (see Precautions).
Anticoagulants and antiplatelet agents: Caution is required since co-administration could increase the risk of bleeding (see Precautions). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there have been reports of an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Selective serotonin reuptake inhibitors (SSRIs): Co-administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see Precautions).
Antidiabetic agents: 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 reactions following administration of diclofenac, requiring adjustment of the dosage of the antidiabetic agent. For this reason, monitoring of blood glucose levels is recommended as a precautionary measure during combination therapy.
Methotrexate: Caution is required when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate because blood levels of methotrexate may rise, and methotrexate toxicity may increase.
Ciclosporin: 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.
Quinolone antibiotics: There have been isolated reports of convulsions that may have been due to concomitant use of quinolones and NSAIDs.
Phenytoin: If phenytoin is used concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Voltaren EC tablet/suppository: Drugs known to cause hyperkalaemia: Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, which should therefore be monitored frequently.
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 concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
Voltaren SR-FC tablet: CYP2C9 inducers: Caution is required when co-administering diclofenac with CYP2C9 inducers (such as rifampicin). This could result in a significant decrease in plasma concentration and exposure to diclofenac.
CYP2C9 inhibitors: Caution is required when co-administering diclofenac with CYP2C9 inhibitors (such as voriconazole). This could result in a significant increase in peak plasma concentrations and exposure to diclofenac.
Tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of tacrolimus 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 tacrolimus.
Drugs known to cause hyperkalaemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased plasma potassium levels, which should therefore be monitored frequently.
Antidiabetic agents: There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with metformin, especially in patients with pre-existing renal impairment.

Voltaren EC tablet: Instructions for use and handling: No special requirements.
Incompatibilities: Not applicable.
Voltaren suppository: Instructions for use and handling: The suppositories should not be cut apart, as incorrect storage conditions may lead to uneven distribution of the active substance.
Incompatibilities: Not applicable.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AB05 - diclofenac ; Belongs to the class of acetic acid derivatives and related substances of non-steroidal antiinflammatory and antirheumatic products.

P₁S₁S₃