Source: Υπουργείο Υγείας (CY) Revision Year: 2014 Publisher: HEXAL AG, Industriestraße 25, D-83607 Holzkirchen, Telephone: +49 (0) 80 24 / 908-0, Telefax: +49 (0) 80 24 / 908-1290, e-mail: service@hexal.de <u>Distributor in Cyprus:</u> P.T.Hadjigeorgiou Co Ltd, ...
ATC code: M01AB05
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, acetic acid derivatives and related substances
Diclac 50ID HEXAL contains diclofenac sodium, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered to be 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.
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac 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 post-operative inflammatory conditions, diclofenac rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
In clinical trials diclofenac 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 dysmenorrhoea, diclofenac is capable of relieving the pain and reducing the extent of bleeding.
Diclofenac is completely absorbed from the gastro-resistant tablets after their passage through the stomach. Although absorption is rapid, its onset may be delayed due to the gastro-resistant coating of the tablet.
Mean peak plasma concentrations of 1.5 micrograms/mL (5 micromol/L) are attained on average 2 hours after ingestion of one tablet of 50 mg.
The passage of a tablet through the stomach is slower when ingested with or after a meal than when it is taken before a meal, but the amount of diclofenac absorbed remains the same.
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.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
99.7% of diclofenacbinds 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.
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.
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.
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the two 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 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.
The amount absorbed is linearly related to the size of the dose.
No relevant age-dependent differences in the drug’s absorption, metabolism or excretion have been observed.However, in a few elderly patients a 15-minute intravenous infusion resulted in 50% higher plasma concentrations than expected from the data on young healthy subjects.
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.
Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses. In standard preclinical animal studies, there was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. Except for minimal foetal effects at maternally toxic doses the prenatal, perinatal and postnatal development of the offspring was not affected.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat, and led to premature closure of the ductusarteriosus in the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased foetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as constriction of the ductusarteriosusin utero are pharmacologic consequences of this class of prostaglandin synthesis inhibitors (see sections 4.3 Contraindication and 4.6 Pregnancy and lactation).
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