Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: Novartis Ireland Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland <u>Marketing License Holder Representative in Cyprus:</u> Novartis Pharma Services Inc., Methonis Tower, 73 Arch. Makarios ...
Pharmacotherapeutic group: Nonsteroidal anti-inflammatory drug (NSAID)
ATC code: M01AB05
Cataflam tablets contain the potassium salt of diclofenac, a nonsteroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.
Diclofenac is a potent inhibitor of prostaglandin bio-synthesis and modulator of arachidonic acid release and uptake.
Cataflam tablets have a rapid onset of action and are therefore suitable for the treatment of acute episodes of pain and inflammation.
In migraine attacks Cataflam has been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.
Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.
Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption.
Peak plasma concentration after one 50 mg sugar-coated tablet was 3.9 µmol/l after 20-60 minutes. Ingestion together with food has no influence on the amount of diclofenac absorbed although onset and rate of absorption may be slightly delayed Since about half of diclofenac is metabolized during its first passage through the liver (“first pass” effect), the area under the concentration curve (AUC) is about half as large following oral or rectal administration as it is following a parenteral dose of equal size.
99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%) [8,68]. 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 16. 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 [16,68,71,72].
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 179.
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.
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.
The amount absorbed is in linear proportion to the size of the dose.
The age of the patient has no influence on the absorption, metabolism, or excretion of diclofenac.
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 four times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis) the kinetics and metabolism are the same as for 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 nimal 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 fetal 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 ductus arteriosus in the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as constriction of the ductus arteriosus in utero are pharmacologic consequences of this class of prostaglandin synthesis inhibitors (see sections 4.3 and 4.6).
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