PHAROFEN SUPPOSITORY

Description

Warning
* Cardiovascular Risk
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 of risk factors for cardiovascular disease may be at greater risk. NSAIDs is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
*Gastrointestinal Risk
NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, 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.

Pharmaceutical form:
Suppositories

Clinical particulars:
Therapeutic indications
Treatment of:
– Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and spondylarthritis, painful syndromes of the vertebral solumn, non-articular rheumatism.
– Acute attacks of gout.
– Post-traumatic and post-operative pain, inflammation, and swelling, e.g. following dental or orthopaedic surgery.
– Painful and/or inflammatory conditions in gynaecology, e.g. primary dysmenorrhea or adnexitis.
– Migraine attacks.
– 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.

Posology and method of administration:
The recommended initial daily dosage is 100-150 mg. in milder cases, as well as for long-term therapy, 75-100 mg daily is usually sufficient. The total daily dosage should be divided into 2-3 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 maximum daily dose of 150 mg). in primary dysmenorrhoea the daily usage should be individually adjusted and is generally 50-150 mg. initially a dose of 50-100 mg should be given and, if necessary, raised in the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started upon appearance of the first symptoms and, depending on the symptomatology, continued for a few days. Treatment of migraine attacks with Pharofen 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 dosage should be limited to 150 mg in divided doses.

Contraindications:
Gastric or intestinal ulcer. Known hypersensitivity to the active substance. Like other non-steroidal anti-inflammatory drugs (NSAIDs), Pharofen is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other drugs with prostaglandin-synthetase inhibiting activity. Proctitis.
Special warnings and special precautions for use:
Warnings
Gastrointestinal bleeding or ulceration/perforation can occur at any time during treatment, with or without warning symptoms or previous history. They generally have more serious consequences in the elderly. In the rare cases where gastrointestinal bleeding or ulceration occurs in patients receiving Pharofen, the drug should be withdrawn. As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases without earlier exposure to the drug. Like other NSAIDs, Pharofen may mask the signs and symptoms of infections due to its phamacodynamic properties.
Precautions
Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders or a history suggestive of gastric or intestinal ulceration, in patients with ulcerative colitis or Crohn’s disease, and in patients suffering from impaired hepatic function. As with other NSAIDs, value of one or more liver enzymes may increase. During prolonged treatment with Pharofen, 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, etc.) Pharofen should be discontinued. Hepatitis may occur without prodromal symptoms. Caution is called for when using Pharofen in patients with hepatic prophyria, since it may trigger an attack. Owing to the importance of prostaglandins in maintaining renal blood flow, particular caution is called for in patients with impaired cardiac or renal function, the elderly, patients being treated with diuretics, and 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 Pharofen in such cases. Discontinuation of therapy is usually followed by recovery to the pretreatment state. During prolonged treatment with Pharofen, as with other NSAIDs, monitoring of blood count is recommended. Like other NSAIDs, Pharofen may temporarily inhibit platelet aggregation. Patients with defects with haemostasis should be carefully monitored. Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight.

Interactions with other medicaments and other forms of interactions:
(Including interactions observed with other pharmaceutical forms of diclofenac sodium).
Lithium, digoxin: diclofenac sodium may raise plasma concentrations of lithium and digoxin.
Diuretics: like other NSAIDs, diclofenac sodium may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.
NSAIDs: concomitant administration of systemic NSAIDs may increase the frequency of undesirable effects.
Anticoagulants: although clinical investigations do not appear to indicate that diclofenac sodium affects the action of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac sodium and anti-coagulants concomitantly. Close monitoring of such patients is therefore recommended.
Antidiabetics: clinical studies have shown that diclofenac sodium can be given together with oral antidiabetic agents without influencing their clinical effect. However, isolated cases have been reported of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of hypoglycaemic agents during treatment with diclofenac sodium.
Methotrexate: caution is called for when NSAIDs 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.
Cyclosporin: the effects of NSAIDs on renal prostaglandins may increase the nephrotoxicity of cyclosporin.
Quinolone antibacterials: there have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

Pregnancy and lactation:
During pregnancy, Pharofen should be employed only for compelling reasons and only in the lowest effective doses. As in the case of other prostaglandin-synthetase inhibitors, this applies particularly to the last 3 months of pregnancy (owing to the possibility of uterine and/or premature closure of the ductus arteriosus). Following oral doses of 50 mg administered every 8 hours, the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.

Effects on ability to drive and use machines:
Patients experiencing dizziness or other central nervous system disturbances, including visual disturbances, should not drive or operate machinery.

Undesirable effects:
Frequency estimate: frequent more than 10%, occasional more than 1%-10%, rare more than 0.001%-1%, isolated cases less than 0.001%. The following undesirable effects include those reported with other pharmaceutical forms of diclofenac sodium either in short-term or long-term use.
Gastrointestinal tract
Occasional: epigastric pain, nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia, local irritation.
Rare: gastrointestinal bleeding (haematemesis, melaena, bloody diarrhea), gastric or intestinal ulcer with or without bleeding or perforation.
Isolated cases: aphthous stomatitis, glossitis, oesophageal lesions, diaphragm-like intestinal strictures, lower gut disorders such as non-specific haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease; constipation, pancreatitis, exacerbation of haemorrhoids.
Central nervous system
Occasional: headache, dizziness, vertigo.
Rare: drowsiness.
Isolated cases: sensory disturbances, including paraesthesias, memory disturbances, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis.
Special senses
Isolated cases: disturbances of vision (blurred vision, diplopia), impaired hearing, tinnitus, taste disturbances disorders.
Skin
Occasional: rashes.
Rare: urticaria.
Isolated cases: bullous eruptions, eczema, erythema multiform, Stevens-Johnson syndrome, Lyell’s syndrome (acute toxic epidermolysis), erythroderma, (exfoliative dermatitis), loss of hair, photosensitivity reaction, purpura, including allergic purpura.
Kidney
Rare: oedema.
Isolated cases: acute renal failure, urinary abnormalities such as haematuria and proteinuria, interstitial nephritis, nephrotic syndrome, papillary necrosis.
Liver
Occasional: elevation of serum aminotransferase enzymes.
Rare: hepatitis with or without jaundice.
Isolated cases: fulminant hepatitis.
Blood
Isolated cases: thrombocytopenia, leucopenia, haemolytic anaemia, aplastic anaemia, agranulocytosis.
Hypersensitivity
Rare: hypersensitivity reactions such as asthma, systemic anaphylactic/anaphylactoid reactions including hypotension.
Isolated cases: vasculitis, pneumonitis.
Cardiovascular system
Isolated cases: palpitation, chest pain, hypertension, congestive heart failure.

Overdose:
Management of acute poisoning with NSAIDs consists essentially of supportive and symptomatic measures. There is no typical clinical picture associated with overdosage of diclofenac sodium. Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal irritation, and respiratory depression. Forced diuresis, dialysis, or haemoperfusion are unlikely to be helpful in accelerating the elimination of NSAIDs because of their high protein-binding rate and extensive metabolism.

Pharmacological properties:
Pharmacodynamic properties
Phamacotherpeutic group
Non-steroidal anti-inflammatory drug (NSAID).
Mechanism of action
Pharofen contains diclofenac sodium, a non-steroidal anti-inflammatory compound with pronounced antirheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain, and fever. Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
Pharmacodynamic effects
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac sodium 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 postoperative inflammatory conditions, diclofenac sodium rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema. In clinical trials diclofenac sodium 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 dysmenorrhea, diclofenac sodium is capable of relieving the pain and reducing the extent of bleeding. Diclofenac sodium also has beneficial effects on the symptoms of migraine attacks.
Pharmacokinetic properties
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 gastrointestinal resistant tablets. The amount absorbed is linearly related to the size of the dose. 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.
Distribution
99.7% of diclofenac is bound to serum proteins, mainly to albumin 99.4%. The apparent volume of distribution calculated is 0.12-0.17 L/kg. Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 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 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 smaller extent than diclofenac.
Elimination
Total systemic clearance of diclofenac from plasma is 26356 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. 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.

Characteristics in patients
No relevant age-dependent differences in the drug’s absorption, metabolism, or excretion have been observed. 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. In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in
patients without liver disease.

Incompatibilities:
None known.

Special precautions for storage:
Protect from heat store at a temperature not exceeding 30C, in dry place.
Medicines should be kept out of reach of children.

Instructions for use/handling:
Not to be taken by mouth. The suppositories should not be cut apart, as incorrect storage conditions may lead to uneven distribution of the active substance.

Pack:
A carton box containing 5 suppositories in one PVC- PE strip with a pamphlet.