Dicofen

Diclofenac sodium.

Each mL contains: Diclofenac sodium 25 mg.

Pharmacology: Inhibition of prostaglandin biosynthesis, which has been demonstrated experimentally, is considered fundamental to its mechanism of action. Prostaglandins play a major role in the causation of inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
In rheumatic diseases, the anti-inflammatory and analgesic properties of Diclofenac sodium elicit a clinical response characterized by marked relief from signs and symptoms e.g., pain at rest, pain on movement, morning stiffness and swelling of 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 diminishes inflammatory swelling and wound edema. When used concomitantly with opioids for the management of postoperative pain, Diclofenac sodium significantly reduces the need of opioids.
Pharmacokinetics: Approximately 20 min after IM injection 75 mg of Diclofenac, a mean peak plasma concentration of 2.5 mcg/mL (8 micromole/L) is attained. The plasma concentration is in linear relation to the size of the dose. The area under the concentration curve (AUC) is about twice as large as it is following oral or rectal administration of a dose of equal size, because about ½ the active substance is metabolized during its 1^st passage through the liver ("first-pass" effect) when administered via the oral or rectal route.
Diclofenac becomes bound to serum proteins at a rate 99.7%, chiefly to albumin (99.4%).
The total systemic clearance of Diclofenac in plasma is 263 ± 56 mL/min (min value ± SD). The terminal half-life in plasma is 1-2 hrs.
Pharmacokinetic behavior remains unchanged following repeated administration. No accumulation occurs provided the dosage intervals are observed. Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hrs after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hrs. Two hours after reaching the 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 hrs.
The biotransformation of Diclofenac involves partly glucuronidation of the intact molecule but mainly single and multiple hydroxylation resulting in several phenolic metabolites (3'-hydroxy, 4'-hydroxy, 5-hydroxy-, 4'5-dihydroxy-, 3'-hydroxy-4'-methoxy-diclofenac). The latter is largely converted to glucuronide conjugates.
About 60% of the administered dose is excreted in the urine in the form of metabolites from one of these 2 processes; <1% is excreted as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the feces.
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 <10 mL/min, the theoretical steady-state plasma levels of metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, nondecompensated cirrhosis), the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

Diclofenac, a phenylacetic derivative, is an NSAID. It is used mainly as the sodium salt for the relief of pain and inflammation in various conditions: musculoskeletal and joint disorders such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis; peri-articular disorders, such as sprains and strains; and other painful conditions such as renal colic, acute gout, dysmenorrheal, migraine and following some surgical procedures. It has also been used in some countries for the management of actinic keratoses and fever.

Diclofenac sodium may be given by deep intramuscular injection into the gluteal muscle in a dose of 75 mg once daily or, if required in severe conditions, 75 mg twice daily. Diclofenac sodium may also be given as a continuous or intermittent intravenous infusion in glucose (5%) or sodium chloride (0.9%) (both previously buffered with sodium bicarbonate) or as a bolus intravenous injection. For the treatment of postoperative pain a dose of 75 mg may be given over 30 to 120 minutes or as a bolus injection. The dose may be repeated once after 4 to 6 hours if necessary. To prevent postoperative pain, an initial dose of 25 to 50 mg diclofenac sodium may be given after surgery over 15 to 60 minutes followed by 5 mg/hour to a maximum of 150 mg daily. Alternatively, the initial dose may be given as a bolus injection over 5 to 60 seconds followed by additional injections up to the maximum daily dosage; this may be repeated after 4 to 6 hours if necessary although the total dose should not exceed the maximum daily dose of 150 mg. The maximum period recommended for parenteral use is 2 days. Diclofenac sodium is also used intramuscularly in renal colic in a dose of 75 mg repeated once after 30 minutes if necessary.
Children: Diclofenac solution for injection is not suitable for children.

Management of acute poisoning with non-steroidal anti-inflammatory agents consists essentially of supportive and symptomatic measures. There is no typical clinical picture resulting from an overdosage of Diclofenac.
The therapeutic measures to be taken in cases of overdosage are as follows: Absorption should be prevented as soon as possible after overdosage with Diclofenac sodium tablet by means of gastric lavage and activated charcoal.
Supportive and symptomatic treatment should be given for complications eg, hypotension, renal failure, convulsions, gastrointestinal irritation and respiratory depression.
Specific therapies e.g., forced diuresis, dialysis or hemoperfusion are unlikely to be helpful in accelerating the elimination NSAIDs, because of their high protein-binding rate and extensive metabolism.

Like other non-steroidal anti-inflammatory agents, Diclofenac sodium is also contraindicated in patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or by other drugs with prostaglandin synthetase-inhibiting activity. It should also not be given to patients with gastric or intestinal ulcer and with known hypersensitivity to Diclofenac Sodium and other excipients.
Absolute contraindications: Not to be given to those patients who have history of: Stroke: cerebrovascular accident (CVA); Heart attack: Myocardial infarction (MI); Coronary arteries bypass graft (CABG); Uncontrolled hypertension; Congestive heart failure (CHF) NYHA II - IV.

Close medical surveillance is imperative in patients with symptoms indicative of GI disorders, or a history of gastric or intestinal ulceration, in patients with ulcerative colitis or Crohn's disease, and in patients suffering from impaired hepatic function.
As with NSAIDs, values of one or more liver enzymes may increase. During prolonged treatment with Diclofenac sodium, monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function is indicated or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (eg, eosinophilia, rash, etc) Diclofenac sodium should be discontinued. Hepatitis may occur without prodromal symptoms. Caution is called for when using Diclofenac sodium in patients with hepatic porphyria, since it triggers 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 in those with extracellular volume depletion from any cause eg, before or after a major surgical operation. Monitoring of renal function is recommended as a precautionary measure when using Diclofenac sodium in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
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. During prolonged treatment with Diclofenac sodium, as with other NSAIDs monitoring of the blood count is recommended. Like other NSAIDs, Diclofenac sodium may temporarily inhibit platelet aggregation. Patients with defective of hemostasis should be carefully monitored.
Insufficient data are available as yet on the use of Diclofenac sodium ampoules during pregnancy and lactation. For this reason, their use is not recommended during pregnancy and lactation.
Effects on the Ability to Drive or Operate Machinery: Patients experiencing dizziness or other central nervous disturbances including visual disturbances should refrain from including a vehicle or operating machines.

Insufficient data are available as yet on the use of Diclofenac sodium ampoules during pregnancy and lactation. For this reason, their use is not recommended during pregnancy and lactation.

Gastrointestinal Tract: Occasional: Epigastric [pain, nausea, vomiting, diarrhea, abdominal cramps, dyspepsia, flatulence, anorexia. Rare: Gastrointestinal bleeding (hematemesis, melema, bloody diarrhea), gastric or intestinal ulcer with or without bleeding or perforation. Isolated Cases: Aphthous stomatitis, glossitis, esophageal lesions, diaphragm-like intestinal strictures, lower gut disorders e.g., nonspecific hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease; constipation, pancreatitis.
Central Nervous System: Occasional: Headache, dizziness, vertigo. Rare: Drowsiness.
Isolated Cases: Sensory disturbances, including paresthesias, memory disturbances, disorientation, insomia 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.
Skin: Occasional: Rashes. Rare: Urticaria. Isolated Cases: Bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reaction, purpura, including allergic purpura.
Kidney: Rare: Edema: Isolated Cases: Acute renal failure, urinary abnormalities, eg hematuria and proteinuria, interstitial nephritis nephrotic syndrome, papillary necrosis.
Liver: Occasional: Elevation of serum aminotransferase enzymes. Rare: Hepatitis with or without jaundice. Isolated Cases: Fluminant hepatitis.
Blood: Isolated Cases: Thrombocytopenia, leucopenia, hemolytic anemia, aplastic anemia, agranulocytosis.
Hypersensitivity: Rare: Hypersensitivity reactions eg, asthma, systemic anaphylactic/ anaphylactoid reactions including hypotension. Isolated Cases: Vasculitis, pneumonitis.
Cardiovascular System: Isolated Cases: Palpitation, chest pain, hypertension, congestive failure.
Other Organ System: Rare: Edema, injection site disorders in cases of injection administration (eg, local pain and induration; In Isolated Cases: Abscesses and local necrosis). Isolated Cases: Impotence (associated with Diclofenac sodium intake is doubtful), palpitation, chest pain, hypertension.

Lithium, Digoxin: Diclofenac sodium may raise their plasma concentrations.
Diuretics: 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 may increase the frequency of undesirable side 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 hemorrhage in patients receiving Diclofenac sodium and anticoagulants 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 effects.
However, isolated cases have been reported of both hypoglycemic and hyperglycemic effects necessitating changes in the dosage of hypoglycemic agents during treatment with Diclofenac sodium.
Methotrexate: Caution is called for when NSAIDs are administered <24 hrs before or after treatment with methotrexate since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.
Cyclosporin: May increase nephrotoxicity of cyclosporine.
Quinolone Antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

Ampoule: As a rule, Diclofenac sodium ampoules for IM uses are not mixed with other injection solutions. Infusion solution of sodium chloride (0.09%) or glucose (5%) without sodium bicarbonate as an additive, presents a risk of supersaturating, possibly leading to formation of crystals or precipitates. Infusion solutions other than those recommended should not be used.

Store at temperature not exceeding 30°C. Protect from light and heat.

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.

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