Source: Health Products Regulatory Authority (ZA) Revision Year: 2025 Publisher: NOVARTIS SOUTH AFRICA (PTY) LTD, Magwa Crescent West, Waterfall City, Jukskei view, Johannesburg, 2090, +27113476600
A 3.1 Antirheumatics (anti-inflammatory agents)
Diclofenac is a non-steroidal compound with antirheumatic, anti-inflammatory, analgesic and antipyretic properties. In vitro its active substance strongly inhibits prostaglandin-synthetase and also has an inhibitory effect on platelet aggregation.
Inhibition of prostaglandin biosynthesis, which has been demonstrated experimentally, is regarded as having an important bearing on its mechanism of action. Prostaglandins play a major role in the pathophysiology of inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress the proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterized 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.
VOLTAREN 75 AMPOULES, have been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin, an effect which sets in within 15 to 30 minutes.
Diclofenac is absorbed after passage through the stomach.
Following ingestion of one tablet on an empty stomach, absorption occurs more rapidly than when the tablet is taken during or after a meal, but bioavailability remains the same.
The plasma concentrations show a linear relationship to the size of the dose. Peak levels are attained in 1 to 4 hours with the tablets and in the case of the suppositories in less than 1 hour.
The systematic availability of diclofenac from VOLTAREN 75 TABLETS and VOLTAREN SIMPLE REGIMEN 100 is on average 82% of that achieved with same dose of VOLTAREN administered in the form of gastro-resistant tablets (possibly due to release-rate dependent "first-pass" metabolism).
As a result of a slower release of the active substance from VOLTAREN 75 TABLETS and VOLTAREN SIMPLE REGIMEN 100, peak concentrations attained are lower than those observed following the administration of gastro-resistant tablet.
Mean peak plasma concentrations of 0,5 μg/mL or 0,4 μg/mL (1,6 μmol or 1,25 μmol/l) are reached on average 4 hours after ingestion of prolonged release tablet of 100 mg or 75 mg. Mean plasma concentrations of 13 ng/ml (40nmol/l) can be recorded at 24 hours (16 hours) after administration of Voltaren prolonged-release 100 mg (75 mg) tablets.
Since 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.
The peak plasma concentration, though comparable with that reached after a single coated tablet of 25 mg, is maintained over a longer period due to the larger quantity of diclofenac contained in VOLTAREN 75 TABLETS and VOLTAREN SIMPLE REGIMEN 100.
After administration of 75 mg diclofenac by intramuscular injection, absorption sets in immediately and mean peak plasma concentrations of about 2.5 μg/ml (or 8 μmol/l) are reached after about 20 minutes.
The amount absorbed is in linear proportion to the size of the dose.
When 75 mg diclofenac is administered as an intravenous infusion over 2 hours, mean peak plasma concentrations are about 1,9 μg/ml (5,9 μmol/l)
Shorter infusions result in higher peak plasma concentrations, while longer infusions give plateau concentration proportional to the infusion rate after 3 to 4 hours. In contrast, plasma concentrations decline rapidly once peak levels have been reached following intramuscular injection or administration of gastro- resistant tablets.
The area under the concentration curve (AUC) after intramuscular or intravenous administration is about twice as large as it is following oral or rectal administration, because about half of the active substance is metabolised during its first passage through the liver ("first pass" effect) when administered via the oral or rectal routes.
Diclofenac shows a rapid onset of absorption from suppositories, although the rate of absorption is slower than from gastro-resistant tablets administered orally. After administration of 50 mg suppositories, the 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 gastro resistant tablets.
Since 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.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those attained in adults.
For all formulations, the pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
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 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.
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The total terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the 2 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 glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% excreted as unchanged substance.
The rest of the dose is eliminated as metabolites through the bile in the faeces.
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 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.
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