DICLOTEC
Technilab
Diclofenac Sodium
Anti-inflammatory – Analgesic
Action And Clinical Pharmacology: Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The mode of action is not fully known but it does not act through the pituitary-adrenal axis. Diclofenac sodium inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase. This inhibitory effect may partially explain its actions.
From a clinical efficacy standpoint, diclofenac sodium 75 mg has activity similar to 3.6 g of ASA.
Diclofenac sodium is similar in activity to equivalent dosages of indomethacin (75 to 150 mg daily) and causes fewer CNS side effects at these doses.
Although diclofenac sodium does not alter the course of the underlying disease, it has been found to relieve pain, reduce fever, swelling and tenderness, and increase mobility in patients with rheumatic disorders of the types listed.
Pharmacokinetics: Absorption: In humans, orally administered diclofenac sodium is rapidly and almost completely absorbed and distributed to blood, liver and kidneys. The plasma concentrations show a linear relationship to the amount of drug administered. No accumulation occurs provided the recommended dosage intervals are observed.
Enteric coating may delay the onset of absorption from 25 and 50 mg tablets. Absorption occurs more rapidly when the drug is administered on an empty stomach (Tmax 2.5 hours) than with meals (Tmax 6 hours). The bioavailability remains the same under both conditions. The mean peak plasma concentration of 1.5 g/mL (5 µmol/L) is attained, on average, 2 hours after ingestion of one 50 mg enteric-coated tablet.
Following administration of the slow-release (SR) diclofenac sodium, Cmax is reached at approximately 4 hours or later. Significant drug plasma concentrations persist when levels would have dropped almost to baseline values following enteric-coated tablet administration. Mean plasma concentrations of 13 ng/mL (40 nmol/L) were produced 24 hours after diclofenac SR 100 mg, or 16 hours after diclofenac SR 75 mg following administration of a single dose. Trough levels are approximately 22 to 25 ng/mL (70 to 80 nmol/L) during treatment with diclofenac SR 100 mg once daily, or 16 hours after diclofenac SR 75 mg administered twice daily. In pharmacokinetic studies, no accumulation of diclofenac sodium was found following repeated once daily administration of diclofenac SR 100 mg tablets or repeated twice daily administration of diclofenac SR 75 mg tablets.
Suppositories have a more rapid onset, but slower rate of absorption than oral enteric-coated tablets. Cmax is approximately 2/3 of that produced by an equivalent 50 mg enteric-coated tablet oral dose. Tmax occurs within 1 hour. The unchanged diclofenac plasma AUC values after rectal administration are within the range of values produced by equivalent oral enteric-coated tablet doses. Since about half the active substance is metabolized 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 as large as it is following a parenteral dose of equal size.
Distribution: Diclofenac sodium is extensively bound (99%) to serum albumin. The apparent volume of distribution is 0.12 to 0.17 L/kg. Single-dose (oral or i.m.) studies in rheumatoid patients with joint effusions have shown that diclofenac is distributed to the synovial fluid, where Tmax occurs 2 to 4 hours after plasma Tmax. Synovial fluid concentrations exceed plasma levels within 4 to 6 hours of administration. This elevation above plasma concentrations can be maintained for up to 12 hours. The synovial fluid elimination half-life is at least 3 times greater than that for plasma.
Biotransformation: Diclofenac undergoes single and multiple hydroxylation and methoxylation, producing 3′-, 4′-, 5-hydroxy, 4′-5-hydroxy and 3′-hydroxy-4′-methoxy derivatives of diclofenac. These phenolic metabolites are largely inactive and (along with the parent compound) are mostly converted to glucuronide conjugates.
Elimination: Plasma clearance of diclofenac is 263±56 mL/min. The mean terminal drug half-life in plasma is 1.8 hours after oral doses. In humans about 60% of the drug and its metabolites are eliminated in the urine and the balance through bile in the feces. More than 90% of an oral dose is accounted for in elimination products within 72 hours. About 1% of an oral dose is excreted unchanged in urine.
Special Populations: Renal Impairment: A single-dose pharmacokinetic study in patients with varying degrees of renal dysfunction (creatinine clearance rates ranging from 3 to 42 mL/min) suggests that moderate renal impairment does not affect the elimination rate of unchanged diclofenac from plasma but that it may reduce the elimination rate of the metabolites of the drug.
Hepatic Impairment: The kinetics and metabolism of diclofenac, as revealed in a study of 10 patients with impaired hepatic function (chronic hepatitis and nondecompensated cirrhosis) receiving a single oral dose of 100 mg, were the same as in patients without liver disease.
Geriatrics: The ability of elderly subjects to absorb, metabolize and excrete diclofenac sodium does not appear to differ significantly from those of young subjects.
Indications And Clinical Uses: The symptomatic treatment of rheumatoid arthritis and osteoarthritis, including degenerative joint disease of the hip.
Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.
Known or suspected hypersensitivity to the drug or other nonsteroidal anti-inflammatory drugs. The potential for cross-reactivity between different NSAIDs must be kept in mind.
Diclofenac sodium should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
Significant hepatic impairment or active liver disease.
Diclofenac sodium is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.
Suppositories are contraindicated in patients with any inflammatory lesions of the rectum or anus and in patients with a recent history of rectal or anal bleeding.
Manufacturers’ Warnings In Clinical States: Gastrointestinal (more pertinent to orally administered dosage forms): Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including diclofenac sodium.
Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with nonsteroidal anti-inflammatory drugs, even in the absence of previous gastrointestinal tract symptoms.
In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2 to 4% of patients treated for one year. The risk continues beyond 1 year and possibly increases.
The incidence of these complications increases with increasing dose.
Diclofenac sodium should be given under close medical supervision to patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn’s disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.
Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.
Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.
If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, diclofenac sodium should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.
No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.
Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.
Geriatrics: Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs): the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.
For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. See Precautions for further advice.
Cross-sensitivity: Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may also be sensitive to any of the other NSAIDs.
Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.
Pregnancy , Labor and Lactation: Diclofenac sodium readily crosses the placental barrier. The safety of diclofenac sodium in pregnancy and lactation has not been established, and its use is therefore not recommended. It should only be used during pregnancy for the most compelling reasons, and then only at the lowest effective dose. As with other prostaglandin inhibitors, this applies particularly to the last 3 months of pregnancy, because of the possibility of uterine inertia and/or premature closing of the ductus arteriosus.
The highest diclofenac level observed in the breast milk of 6 patients receiving oral diclofenac sodium doses of 3´50 mg day 1, followed by 2´50 mg day 2, was smaller than 5 ng/g. By extrapolation, an infant of 3 kg consuming 500 g/day (with a maximum concentration of 5 ng/g) of breast milk would receive less than 0.83 g/kg/day of diclofenac sodium. On the other hand, in 1 patient on long-term treatment with diclofenac sodium 150 mg daily, a level of 100 ng/mL (100 ng/g) was measured in breast milk; by extrapolation, an infant of 3 kg consuming 500 g/day of breast milk would receive less than 17 g/kg/day of diclofenac sodium.
Children: Diclofenac sodium is not recommended in children under 16 years of age. Safety and dosages for the pediatric age group have not been established.
Occupational Hazards: Headache, dizziness, lightheadedness and mental confusion have been reported following diclofenac sodium therapy. Patients experiencing these symptoms should be made aware that these side effects may occur and be cautioned against operating machinery or motor vehicles should they experience any of these symptoms.
Precautions: General: Diclofenac sodium should not be used concomitantly with diclofenac potassium since both exist in plasma as the same active organic ion.
Gastrointestinal: There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of diclofenac sodium therapy when and if these adverse reactions appear.
Renal Function: Long-term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug (NSAIDs) may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.
Diclofenac and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of diclofenac sodium should be considered and patients carefully monitored.
During long-term therapy, kidney function should be monitored periodically.
Genitourinary: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with diclofenac sodium must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.
Hepatic Function: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with nonsteroidal anti-inflammatory drugs.
Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.
Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with diclofenac sodium. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Diclofenac sodium should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with b-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.
Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when diclofenac sodium is administered.
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could occur with severe consequences.
Patients on long-term treatment with diclofenac sodium should have their hemopoietic system evaluated periodically. Bone marrow functional abnormalities, although rare, could have severe consequences. Periodic hematologic examinations (CBC and blood film examination) can detect anemias or blood dyscrasias secondary to possible gastrointestinal tract or bone marrow toxicity.
Infection: In common with other anti-inflammatory drugs, diclofenac sodium may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision has been reported with the use of diclofenac sodium and other nonsteroidal anti-inflammatory drugs. If such symptoms develop, the drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.
CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of diclofenac sodium. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.
Hypersensitivity Reactions: As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without prior exposure to drug. Careful questioning for patient history of asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs is important before starting therapy.
Drug Interactions: ASA or other NSAIDs: The use of diclofenac sodium in addition to any other NSAID, including those over the counter drugs (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects.
Serum levels of diclofenac may be reduced when the 2 drugs are taken simultaneously. The bioavailability of ASA is reduced by the presence of diclofenac. Although these pharmacokinetic interactions do not appear to be clinically relevant, there is no proven advantage in using these 2 medications together.
Digoxin: Diclofenac may increase the plasma concentration of digoxin. Dosage adjustment may be required.
Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding.
Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of diclofenac sodium with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.
Oral Hypoglycemics: Pharmacodynamic studies have shown no potentiation of effect with concurrent administration with diclofenac; however, there are isolated reports of both hypoglycemic and hyperglycemic effects in the presence of diclofenac, which necessitated changes in the dosage of hypoglycemic agents.
Diuretics: NSAIDs have been reported to decrease the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium, thus making it necessary to monitor levels.
Antihypertensives: Like other NSAIDs, diclofenac can reduce the antihypertensive effects of propranolol and other b-blockers, as well as other antihypertensive agents.
Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.
Methotrexate: Caution should be exercised when NSAIDs are administered less than 24 hours before or after treatment with methotrexate. Elevated blood concentrations of methotrexate may occur, increasing toxicity.
Lithium: Lithium plasma concentrations will increase when administered concomitantly with diclofenac (which affects lithium renal clearance). Dosage adjustment of lithium may be required.
Cyclosporine: Nephrotoxicity of cyclosporine may be increased because of the effect of NSAIDs on renal prostaglandins.
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Clinical Laboratory Tests: Diclofenac increases platelet aggregation time but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, and are unlikely to be clinically important.
Persistently abnormal or worsening renal, hepatic or hematological test values should be followed up carefully since they may be related to therapy.
Adverse Reactions: The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs (particularly orally administered formulations) are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred particularly in the elderly.
Adverse reactions reported in clinical trials and spontaneous reports are summarized below. Frequency estimate: frequent >10%, occasional >1 to 10%, rare >0.001 to 1%, isolated cases
Gastrointestinal (more pertinent to orally administered dosage forms): Occasional: epigastric, gastric, or abdominal pain, abdominal cramps, nausea, dyspepsia, anorexia, diarrhea, vomiting, flatulence. Rare: gastrointestinal bleeding (bloody diarrhea, melena, hematemesis) gastric and intestinal ulcerations with or without bleeding or perforation. Isolated: lower gut disorders (e.g., nonspecific hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), diaphragm-like intestinal strictures, hyperacidity, stomatitis, glossitis, coated tongue, esophageal lesions, constipation, pancreatitis.
Allergic: Rare: hypersensitivity reactions such as asthma in patients sensitive to ASA, e.g., bronchospasm; anaphylactic/anaphylactoid systemic reactions including hypotension. Isolated: vasculitis, pneumonitis.
CNS: Occasional: dizziness, headache, vertigo. Rare: drowsiness, malaise, impaired concentration, tiredness. Isolated: sensory disturbances including paresthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis.
Dermatologic: Occasional: rash, pruritus. Rare: urticaria. Isolated: bullous eruption, erythema, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.
Cardiovascular: Rare: palpitation, angina, arrhythmias. Isolated: exacerbation of cardiac failure, hypertension.
Special senses: Isolated: vision disturbances (blurred vision, diplopia), impaired hearing, tinnitus, taste alteration disorders.
Hematologic: Isolated: thrombocytopenia, leukopenia, agranulocytosis, hemolytic anemia, aplastic anemia, anemia secondary to gastrointestinal bleeding.
Renal: Rare: edema (facial, general, peripheral). Isolated: acute renal failure, nephrotic syndrome, urinary abnormalities (e.g., hematuria and proteinuria), interstitial nephritis, papillary necrosis.
Hepatic: Occasional: elevations (³3 times the upper normal limit) of serum aminotransferase enzymes (AST, ALT). Rare: liver function disorders including hepatitis with or without jaundice. Isolated: fulminant hepatitis.
Other: Administration of suppositories may occasionally give rise to local irritation, rarely local bleeding and exacerbation of hemorrhoids.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no specific antidote. In cases of overdosage with orally administered dosage forms, absorption should be prevented as soon as possible by the induction of vomiting, gastric lavage or treatment with activated charcoal. Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal irritation and respiratory depression. Measures to accelerate elimination (forced diuresis, hemoperfusion, dialysis) may be considered, but may be of limited use because of the high protein-binding and extensive metabolism.
Dosage And Administration: 50 or 100 mg suppositories may be given as substitute for the last of the 3 oral daily doses to a maximum of 150 mg/day.
Use whole suppositories. Do not split or use portions of suppositories.
Not recommended for use in patients under 16 years of age.
Availability And Storage: 50 mg: Each yellowish-white, torpedo-shaped suppository contains: diclofenac sodium 50 mg. Nonmedicinal ingredients: semisynthetic glycerides. Boxes of 30.
100 mg: Each yellowish-white, torpedo-shaped suppository contains: diclofenac sodium 100 mg. Nonmedicinal ingredients: semisynthetic glycerides. Boxes of 30.
Protect from light and elevated humidity. Keep away from excessive heat. Store between 15 to 30°C.
DICLOTEC Technilab Diclofenac Sodium Anti-inflammatory – Analgesic
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