Short-term treatment in the following acute conditions:

• Post-traumatic pain, inflammation and swelling, e.g., due to sprains.
• Post-operative pain, inflammation and swelling, e.g., following dental or orthopedic surgery.
• Painful and/or inflammatory conditions in gynecology, e.g., primary dysmenorrhea or adnexitis.
• Migraine attacks.
• Painful syndromes of the vertebral column.
• Non-articular rheumatism.
• As an adjuvant in severe painful inflammatory infections of the ear, nose, or throat, e.g. pharyngotonsillitis, otitis. In keeping with general therapeutic principles, the underlying disease should be treated with basic therapy, as appropriate. Fever alone is not an indication.

Dosage regimen
As a general recommendation, the dose should be individually adjusted. Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see Special warnings and precautions for use).

General target population
Adults
The recommended initial daily dose is 100 to 150 mg. In milder cases, 50 to 100 mg daily are usually sufficient. The daily dose should generally be divided in up to 3 separate doses.

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 total maximum of 200mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.

In migraine, an initial dose of 50 mg should be taken at the first signs of an impending attack. In cases where pain relief within 2 hours after the first dose is not sufficient, a further dose of 50 mg may be taken. If needed, further doses of 50 mg may be taken at intervals of 4 to 6 hours, not exceeding a total dose of 200 mg per day.

Special populations
Renal impairment
Oflam 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 diclofenac potassium to patients with renal impairment (see Special warnings and precautions for use).

Hepatic impairment
Oflam 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 diclofenac potassium to patients with mild to moderate hepatic impairment (see Special warnings and precautions for use).

Pediatric patients (below 18 years)
Oflam is not recommended for use in children and adolescents below 14 years of age. For treatment in children and adolescents below 14 years of age, oral drops and suppositories of diclofenac 12.5 mg and 25 mg are available.

For adolescents aged 14 years and over, 50 to 100 mg daily are usually sufficient, given as 1 to 2 divided doses.

The maximum daily dose of 150 mg should not be exceeded.

The use of diclofenac potassium in migraine attacks has not been established in children and adolescents.

Geriatric patients (65 years of age or above)
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 Special warnings and precautions for use).

Established cardiovascular disease or significant cardiovascular risk factors
Treatment with Oflam 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 diclofenac potassium only after careful consideration and only at doses ≤100 mg daily when treatment continues for more than 4 weeks (see Special warnings and precautions for use).

Method of administration
The contents of the sachet should be dissolved with stirring in a glass of natural (non-carbonated) water. The solution may remain slightly opalescent, but this should not influence the efficacy of the preparation. The solution should be swallowed preferably before meals.

• Known hypersensitivity to the active substance or to any of the excipients. • Active gastric or intestinal ulcer, bleeding or perforation (see Special warnings and precautions for use and Interaction with other medicinal products). • Last trimester of pregnancy (see Fertility, pregnancy and lactation). • Hepatic failure. • Renal failure (GFR <15 mL/min/1.73m2). • Severe cardiac failure (see Special warnings and precautions for use). • Like other non-steroidal anti-inflammatory drugs (NSAIDs), Oflam is also contraindicated in patients in whom the use of acetylsalicylic acid or other NSAIDs can precipitate asthma, angioedema, urticaria, or acute rhinitis (i.e., NSAID-induced cross-reactivity reactions). (see sections Special warnings and precautions for use and Interaction with other medicinal products).

Gastrointestinal effects
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 inpatients receiving diclofenac potassium, the treatment should be discontinued.

As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercized when prescribing diclofenac potassium in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see Interaction with other medicinal products). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation and in the elderly.

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with hemorrhage 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 low-dose acetylsalicylic acid (ASA) or other drugs likely to increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see Interaction with other medicinal products).

Close medical surveillance and caution should also be exercized in patients with ulcerative colitis or Crohn’s disease, as their condition may be exacerbated (see Interaction with other medicinal products).

NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac potassium after gastro-intestinal surgery.

Cardiovascular 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 Oflam 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 potassium 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.

Hematologic effects
Use of Oflam is recommended only for short-term treatment. If, however, Oflam is used for a prolonged period, monitoring of the blood count is recommended, as with other NSAIDs.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of hemostasis should be carefully monitored.

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 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.

Hepatobiliary effects
Close medical surveillance is required when prescribing diclofenac potassium 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 potassium, 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), Oflam should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.

Caution is called for when using diclofenac potassium in patients with hepatic porphyria, since it may trigger an attack.

Skin reactions
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 potassium (see Interaction with other medicinal products). 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 potassium 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.

Renal effects
As fluid retention and edema 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 and after major surgery (see Contraindications).Monitoring of renal function is recommended as a precautionary measure when using diclofenac potassium in such cases. Discontinuation of therapy is normally followed by a recovery to the pre-treatment state.

Geriatric patients
Caution is indicated in the elderly on basic medical grounds, especially in frail elderly patients or those with a low body weight.

Interactions with other NSAIDs
The concomitant use of Oflam with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive undesirable effects (see Interaction with other medicinal products).

Oflam contains potassium, aspartame, sugar (sucrose) and sodium
Oflam contains potassium. Each sachet of Oflam 50 mg Granules for Oral Solution contains contains 14.556 mg potassium. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Oflam contains aspartame. Each sachet of Oflam 50 mg Granules for Oral Solution contains 10 mg aspartame.  Aspartame is hydrolysed in the gastrointestinal tract when orally ingested. One of the major hydrolysis products is phenylalanine. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Oflam contains sugar (sucrose). Each sachet of Oflam 50 mg Granules for Oral Solution contains 1763 mg sugar. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. If the product is used for a period of more than two weeks, it may be harmful to the teeth. This should be taken into account in patients with diabetes mellitus.

Oflam contains sodium. Each sachet of Oflam 50 mg Granules for Oral Solution contains 0.448 mg sodium. This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.

Masking signs of infections
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 potassium and/or other pharmaceutical forms of diclofenac.

Observed interactions to be considered

CYP2C9 inhibitors:
Caution is recommended when co-prescribing diclofenac with CYP2C9 inhibitors (such as voriconazole), which could result in asignificant increase in peak plasma concentrations and exposure to diclofenac.

Lithium:
If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.

Digoxin:
If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive agents:
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 Special warnings and precautions for use).

Ciclosporin and tacrolimus:
Diclofenac, like otherNSAIDs, may increase the nephrotoxicity of ciclosporin and tacrolimus due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used inpatients not receiving ciclosporin or tacrolimus.

Drugs known to cause hyperkalemia:
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 Special warnings and precautions for use).

Quinolone antibacterials:
There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs . Anticipated interactions to be considered

Other NSAIDs and corticosteroids:
Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see Special warnings and precautions for use).

Anticoagulants and anti-platelet agents:
Caution is recommended since concomitant administration could increase the risk of bleeding (see Special warnings and precautions for use). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, thereare reports of an increased risk of hemorrhage inpatients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.

Selective serotonin reuptake inhibitors (SSRIs):
Concomitant administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see Special warnings and precautions for use).

Antidiabetics:
Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose levelis 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-existingrenal impairment.

Phenytoin:
When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Methotrexate:
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.

CYP2C9 inducers:
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.

Female fertility
As with other NSAIDs, the use of diclofenac potassium 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 potassium should be considered.

Male fertility
There is no human data on the effect of diclofenac potassium on male fertility.

Diclofenac administered to male and female rats at 4mg/kg/day (approximately 0.16 times the MRHD based on BSA comparison) did not affect fertility.

Pregnancy
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 has been shown to cross the placental barrier in humans. Use of NSAIDs, including diclofenac, can cause uterine inertia, premature closure of the fetal ductus arteriosus and fetal renal impairment leading to oligohydramnios.

Because of these risks, diclofenac potassium should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus.

In addition, diclofenac potassium should not be used during the third trimester of pregnancy (see Contraindications).

In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.41, 0.41, and 0.81 times, respectively, the maximum recommended human dose (MRHD) of diclofenac potassium, despite the presence of maternal and fetal toxicity.

Clinical considerations
Fetal Adverse Drug Reactions
Premature Closure of Fetal Ductus Arteriosus
As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of premature closure of the fetal ductus arteriosus (see Contraindications).

Oligohydramnios/Fetal Renal Impairment
Risk of fetal renal impairment with subsequent oligohydramnios has been observed when NSAIDs (including diclofenac) were used from the 20^th week of pregnancy onwards.

If an NSAID is necessary from the 20^th week gestation to the end of the 2^nd trimester, limit the use to the lowest effective dose and shortest duration possible (see Posology and method of administration). If Oflam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Oflam and follow up according to clinical practice.

Labor or Delivery
There are no studies on the effects of diclofenac potassium during labor or delivery. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia (see Contraindications). In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data
Human Data
Premature Closure of Fetal Ductus Arteriosus
Published literature reports that the use of NSAIDs during the third trimester of pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Fetal Renal Impairment
Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal impairment leading to oligohydramnios. 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug.

Animal Data
Reproductive and developmental studies in animals demonstrated that diclofenac administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (0.41 times the maximum recommended human dose [MRHD] of diclofenac potassium, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (0.41 and 0.81 times, respectively, the MRHD based on BSA comparison).

In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.08 and 0.16 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal mortality (caused by gastrointestinal ulceration and peritonitis) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, intrauterine growth retardation, and decreased fetal survival.

Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat, and led to premature closure of the fetal ductus arteriosus.

Lactation
Risk Summary
Like other NSAIDs, diclofenac passes into the breastmilk in small amounts. Therefore, diclofenac potassium should not be administered during breast feeding in order to avoid undesirable effects in the infant.  

Human Data
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother treated orally with a diclofenac salt of 150 mg/day. The estimated dose ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day.

Effects on ability to drive and use machines Patients who experience dizziness, vertigo, somnolence o rother central nervous system disturbances while taking diclofenac potassium, including visual disturbances, should not drive or operate machines.

 

Tabulated summary of adverse drug reactions

Adverse drug reactions from clinical trials and/or spontaneous or literature reports (Table 7-1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. 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 to<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000).

The following undesirable effects include those reported with diclofenac potassium and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.

Table 7-1 Adverse drug reactions

Blood and lymphatic system disorders
Thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anaemia), agranulocytosis.	Very rare
Immune system disorders
Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).	Rare
Angioedema (including faceedema).	Very rare
Psychiatric disorders
Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.	Very rare
Nervous system disorders
Headache, dizziness.	Common
Somnolence.	Rare
Paresthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, dysgeusia ,cerebrovascular accident.	Very rare
Eye disorders
Visual impairment, blurred vision, diplopia.	Very rare
Ear and labyrinth disorders
Vertigo.	Common
Tinnitus, impaired hearing.	Very rare
Cardiac disorders
Myocardial infarction, cardiac failure, palpitations, chest pain.	Uncommon*
Kounis syndrome	Frequency not known
Vascular disorders
Hypertension , vasculitis.	Very rare
Respiratory, thoracic and mediastinal disorders
Asthma (including dyspnea).	Rare
Pneumonitis.	Very rare
Gastrointestinal disorders
Nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, decreased appetite.	Common
Gastritis, gastrointestinal hemorrhage, hematemesis, melena, hemorrhagic diarrhea, gastrointestinal ulcer (with or without bleeding, gastrointestinal stenosis, or perforation, which may lead to peritonitis).	Rare
Colitis (including hemorrhagic colitis, ischemic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, oesophageal disorder, intestinal diaphragm disease, pancreatitis.	Very rare
Hepatobiliary disorders
Transaminases increased.	Common
Hepatitis, jaundice, liver disorder.	Rare
Fulminant hepatitis, hepatic necrosis, hepatic failure.	Very rare
Skin and subcutaneous tissue disorders
Rash.	Common
Urticaria.	Rare
Bullous dermatitis, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, Henoch-Schoenlein purpura, pruritus.	Very rare
Renal and urinary disorders
Acute kidney injury (acute renal failure), hematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.	Very rare
General disorders and administration site conditions
Edema.	Rare

* The frequency reflects data from long-term treatment with a high dose (150 mg daily).

Description of selected adverse drug reactions
Arteriothrombotic events
Meta-analysis and pharmacoepidemiological datapoint 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 Special warnings and precautions for use).

Visual effects
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.

Reporting of suspected adverse reactions
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:

• Saudi Arabia

The National Pharmacovigilance Centre (NPC)
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa

• Other GCC States

Please contact the relevant competent authority.

Symptoms
There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal hemorrhage, diarrhea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures
Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or hemoperfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein-binding and extensive metabolism.

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.

Diclofenac potassium has been found to exert a pronounced analgesic effect in moderate and severe pain. In the presence of inflammation, e.g., due to trauma or following surgical interventions, it rapidly relieves both spontaneous pain and pain on movement and diminishes inflammatory swelling and wound edema. Clinical studies have also revealed that in primary dysmenorrhoea the active substance is capable of relieving the pain and reducing the extent of bleeding. In migraine attacks diclofenac potassium has been shown to be effective in relieving the headache and in improving the accompanying symptoms nausea and vomiting.

Absorption:
Diclofenac is rapidly and completely absorbed from diclofenac potassium. Mean peak plasma concentrations of 5.5 micromol/L are attained after 5to 20 minutes after ingestion of one sachet of 50 mg.

Ingestion together with food is expected to have no influence on the amount of diclofenac absorbed although onset and rate of absorption may be slightly delayed.

Since about half of diclofenac is metabolized during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) is about half as large following oral or rectal administration as it is following a parenteral dose of equal size.

Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.

Distribution:
99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 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 half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, 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/metabolism
Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

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. One metabolite, 3’-hydroxy-4’-methoxy-diclofenac, has a much longer plasma half-life. However, this metabolite is virtually inactive.

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 through the bile in the faeces.

Linearity/non-linearity
The amount absorbed is in linear proportion to the size of the dose.

Special Populations:
Geriatric patients
No relevant age-dependent differences in the drug’s absorption, metabolism or excretion have been observed.

Renal impairment
In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Hepatic impairment
In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

Clinical studies
Diclofenac potassium is a well-established product.

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.

For more information, see Fertility, pregnancy and lactation.

 

-    Potassium bicarbonate
-    Aspartame
-    Sugar (sucrose)
-    Mannitol
-    Sodium saccharin
-    Peppermint powder

None.

24 months.

Store below 30°C.

Store in the original package.

Aluminum paper/polyethylene foil sachets.

Pack sizes: 10 Sachets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.