Source: Medicines Authority (MT) Revision Year: 2019 Publisher: Novartis Ireland Limited, Vista Building, Elm Park, Merrion Road, Ballsbridge, Dublin 4, Ireland
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids acetic acid derivatives and related substances
ATC code: M01AB05
Catatfast contains the potassium salt of diclofenac, a non-steroidal compound with pronounced antirheumatic, analgesic, anti-inflammatory, and antipyretic properties. Catafast has a rapid onset of action, which makes it particularly suitable for the treatment of acute painful and inflammatory conditions. 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 potassium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.
Catafast has been found to exert a pronounced analgesic effect in moderate and severe pain. In the presence of inflammation, e.g. due to trauma or following surgical interventions, it rapidly relieves both spontaneous pain and pain on movement and diminishes inflammatory swelling and wound edema. Clinical studies have also revealed that in primary dysmenorrhoea the active substance is capable of relieving the pain and reducing the extent of bleeding. In migraine attacks Catafast has been shown to be effective in relieving the headache and in improving the accompanying symptoms nausea and vomiting.
Diclofenac is rapidly and completely absorbed from diclofenac potassium. Mean peak plasma concentrations of 5.5 micromol/L are attained after 5 to 20 minutes after ingestion of one sachet of 50 mg.
Ingestion together with food is expected to have 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.
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.
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 lesser 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 in linear proportion to the size of the dose.
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 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.
Catafast is a well established product.
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 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 Contraindications and 4.6, pregnancy and lactation).
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