Composition

Each suppository contains:

Diclofenac sodium ........................................................................................ 12.5 mg, 25 mg, 50 mg, or 100 mg

Inactive ingredients: 

Isopropyl myristate, suppocire AM (Hard Fat).

Therapeutic Indications

EPIFENAC 25 mg, 50 mg and 100 mg Suppositories:

Adults and Elderly:

Relief of all grades of pain and inflammation in a wide range of conditions, including:

Arthritic conditions: Osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, and acute gout.

Acute musculo-skeletal disorders: Periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, and bursitis.

Other painful conditions resulting from trauma including: fracture, low back pain, sprains, strains, dislocations, orthopaedic, dental and other minor surgery. 

EPIFENAC 50 mg and 100 mg Suppositories are not indicated for use in children.

EPIFENAC 12.5 mg and 25 mg Suppositories Only:

Children (aged 1-12 years):

Juvenile chronic arthritis.

Children (aged 6 years and above): 

As monotherapy or as adjunct therapy with morphine or other opiates (due to its opiate-sparing effect) for the relief of acute post-operative pain.

Dosage and Administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Not to be taken by mouth, as per rectal administration only.

The suppositories should be inserted well into the rectum. It is recommended to insert the suppositories after passing stools.

Adults: 

75-150 mg daily, in divided doses (EPIFENAC 25 mg, 50 mg and 100 mg Suppositories Only).

The recommended maximum daily dose of EPIFENAC is 150 mg. This may be administered using a combination of dosage forms, e.g. tablets and suppositories. (EPIFENAC 25 mg and 50 mg Suppositories Only).

EPIFENAC 100 mg Suppositories may also be given as a once daily treatment, usually at night.

Where necessary, therapy may be combined with EPIFENAC 25 mg or 50 mg Tablets or Suppositories, up to the maximum dose of 150 mg per day.

Special populations:

Elderly: 

Although the pharmacokinetics of EPIFENAC are not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular, it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

Renal impairment: 

EPIFENAC is contraindicated in patients with severe renal impairment. 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 EPIFENAC to patients with mild to moderate renal impairment.

Hepatic impairment: 

EPIFENAC is contraindicated in patients with severe hepatic impairment. 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 EPIFENAC to patients with mild to moderate hepatic impairment.

Pediatric population:

Children (aged 1-12 years) with Juvenile Chronic Arthritis: 

1-3 mg/kg per day divided into 2 or 3 doses (EPIFENAC 12.5 mg and 25 mg Suppositories Only).

Children (aged 6-12 years) with Acute Post-operative Pain:

1-2 mg/kg per day in divided doses.

Treatment of acute post-operative pain should be limited to 4 days treatment (EPIFENAC 12.5 mg and 25 mg Suppositories Only).

Contraindications

Hypersensitivity to the active substance or any of the excipients.

Active, gastric or intestinal ulcer, bleeding or perforation.

History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Last trimester of pregnancy.

Severe hepatic, renal or cardiac failure.

Like other nonsteroidal anti-inflammatory drugs (NSAIDs), Epifenac is also contraindicated in patients in whom attacks of asthma, angioedema, urticaria or acute rhinitis are precipitated by ibuprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Proctitis.

Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Warnings and Precautions

General:

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The concomitant use of EPIFENAC with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.

Caution is indicated in the elderly on 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.

As with other NSAIDs including EPIFENAC, allergic reactions, including anaphylactic/ anaphylactoid reactions, can also occur without earlier exposure to the drug.

Like other NSAIDs, EPIFENAC may mask the signs and symptoms of the infection due to its pharmacodynamic properties.

Gastrointestinal effects: Gastrointestinal bleeding (haematemesis, melaena) ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, EPIFENAC should be withdrawn.

As with all NSAIDs, including EPIFENAC, close medical surveillance is imperative and particular caution should be excised when prescribing EPIFENAC in patients with symptoms indicative of gastrointestinal disorders, or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

The elderly have increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal.

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA/aspirin) or medicinal products likely to increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid.

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn's disease, as these conditions may be exacerbated.

Hepatic effects: Close medical surveillance is required when prescribing EPIFENAC to patients with impairment of hepatic function, as their condition may be exacerbated.

As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with EPIFENAC, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), EPIFENAC should be discontinued.

Hepatitis may occur with diclofenac without prodromal symptoms.

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

Renal effects: As fluid retention and oedema have been reported in association with NSAIDs 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 those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery. Monitoring of renal function is recommended as a precautionary measure when using EPIFENAC in such cases. Discontinuation therapy is usually followed by recovery to the pre-treatment state.

Skin effects: 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. Patients appear to be at the 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. Epifenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

SLE and Mixed Connective Tissue Disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.

Cardiovascular and Cerebrovascular effects: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), 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, NSAIDs are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, so the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac.

Clinical trial and epidemiological data consistently point towards increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150 mg daily) and in long term treatment.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with EPIFENAC after careful consideration.

Haematological effects: During prolonged treatment with EPIFENAC, as with other NSAIDs, monitoring of the blood count is recommended.

EPIFENAC may reversibly inhibit platelet aggregation. Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

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 oedema or urticaria, are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, EPIFENAC and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

Female fertility: The use of EPIFENAC may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of EPIFENAC should be considered.

Drug Interactions

The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.

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

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

Diuretics and Antihypertensive agents: Like other NSAIDs, concomitant use of EPIFENAC with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored.

Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

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.

Anticoagulants and Anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulant concomitantly.

Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of EPIFENAC with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs.

Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant administration of SSRI's may increase the risk of gastrointestinal bleeding (see Warnings and Precautions).

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 hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including EPIFENAC, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Ciclosporin: EPIFENAC, 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.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Quinolone antibacterials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID. Phenytoin: When using phenytoin concomitantly with EPIFENAC, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Colestipol and Cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer Epifenac at least one hour before or 4-6 hours after administration of colestipol/cholestyramine.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing EPIFENAC with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to EPIFENAC due to inhibition of diclofenac metabolism.

Pregnancy and Lactation

Pregnancy: 

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and or cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1% up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has shown to result in increased pre-and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during organogenetic period. If EPIFENAC is used by a woman attempting to conceive, or during the 1st trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to:

Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension).

Renal dysfunction, which may progress to renal failure with oligo-hydroamniosis.

The mother and the neonate, at the end of the pregnancy, to:

Possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

Inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, EPIFENAC is contraindicated during the third trimester of pregnancy.

Lactation: 

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, EPIFENAC should not be administered during breastfeeding in order to avoid undesirable effects in the infant.

Female fertility: 

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of EPIFENAC should be considered.

Effects on ability to drive and to use machines

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operating machinery.

 

Undesirable Effects

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: Very common: (>1/10); Common (≥ 1/100, <1/10); Uncommon (≥ 1/1,000, <1/100); Rare (≥1/10,000, <1/1000); Very rare (<1/10,000); Not known: cannot be estimated from available data.

The following undesirable effects include those reported with other short-term or long-term use.

Blood and Lymphatic system disorders:

Very rare: Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.

Immune system disorders:

Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).

Very rare: Angioneurotic oedema (including face oedema).

Psychiatric disorders:

Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.

Nervous system disorders:

Common: Headache, dizziness.

Rare: Somnolence, tiredness.

Very rare: Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.

Unknown: Confusion, hallucinations, disturbances of sensation, malaise.

Eye disorders:

Very rare: Visual disturbance, blurred vision, diplopia.

Unknown: Optic neuritis.

Ear and Labyrinth disorders:

Common: Vertigo.

Very rare: Tinnitus, impaired hearing.

Cardiac disorders:

Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction.

Vascular disorders:

Very rare: Hypertension, hypotension, vasculitis.

Respiratory, Thoracic and Mediastinal disorders:

Rare: Asthma (including dyspnoea).

Very rare: Pneumonitis.

Gastrointestinal disorders:

Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.

Rare: Gastritis, gastrointestinal haemorrhage, haematemesis, haemorrhagic diarrhoea, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal, particularly in the elderly).

Very rare: Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.

Hepatobiliary disorders:

Common: Increased Transaminases.

Rare: Hepatitis, jaundice, liver disorder.

Very rare: Fulminant hepatitis, hepatic necrosis, hepatic failure.

Skin and Subcutaneous tissue disorders:

Common: Rash.

Rare: Urticaria.

Very rare: Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.

Renal and Urinary disorders:

Very rare: Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders and Administration site conditions:

Rare: Application site irritation, oedema.

Reproductive system and Breast disorders:

Very rare: Impotence.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high doses (150 mg daily) and in long-term treatment.

Overdose

Symptoms: 

There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting or convulsions.

In the case of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures: 

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered.

Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient’s clinical condition.

Pharmacological Properties

Pharmacodynamic properties:

In 15 clinical studies involving the use of rectal diclofenac in the treatment of postoperative pain in children with an overall mean age of 8 years, the use of rescue analgesia (particularly opiates) was reduced. (12.5 mg and 25 mg suppositories only).

Pharmacotherapeutic group: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

Mechanism of action:  Epifenac is a nonsteroidal agent with marked analgesic/anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).

Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

Pharmacokinetic properties:

There is limited kinetic data from 6 children aged 6-16 years with juvenile chronic arthritis who received a once daily dose of diclofenac for 2 weeks. When corrected for a body weight of 75 kg, kinetic parameters were similar to those in adults. (12.5 mg and 25 mg suppositories only). 

Absorption: Absorption is rapid; although the rate of absorption is slower than from enteric-coated 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 enteric-coated tablets (1.95 ± 0.8 μg/ml (1.9 μg/ml ≡ 5.9 μmol/l)).

Bioavailability: As with oral preparations, the AUC is approximately a half of the value obtained from a parenteral dose.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed.

The plasma concentrations attained in children given equivalent doses (mg/kg, b.w.) are similar to those obtained in adults. (12.5 mg and 25 mg suppositories only).

Distribution: The active substance is 99.7% protein bound, mainly to albumin (99.4%). Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.

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, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination: The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours. About 60% of the administered dose is excreted in the urine in the form of 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.

Characteristics in patients:

No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute IV infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with 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.

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

Storage

EPIFENAC 12.5 mg, 25 mg, 50 mg Suppositories: Store at a temperature 2°C - 8°C.

EPIFENAC 100 mg Suppositories: Store at a temperature not exceeding 25°C.

Packaging

EPIFENAC 12.5 mg, 25 mg, 50 mg, 100 mg Suppositories:  Box containing 1 strip of 5 suppositories.

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