Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Mibe Pharma UK Ltd, 4 Coleman Street, 6th Floor; London, United Kingdom, EC2R 5AR
Pharmacotherapeutic group: Other dermatologicals
ATC code: D11AX18
Diclofenac is a non-steroidal anti-inflammatory medicinal product.
The mechanism of action of diclofenac in actinic keratosis is not known but may be related to inhibition of the cyclo-oxygenase pathway leading to reduced prostaglandin E2 (PGE2) synthesis. The efficacy of the treatment has only been demonstrated in placebo-controlled studies. Comparative studies with externally applied 5-fluorouracil have not been conducted. The long-term effect of diclofenac-containing gel has not been established.
Diclofenac-containing gel has been shown to clear AK lesions with maximum therapeutic effect seen 30 days after cessation of medicinal product therapy.
Mean absorption of diclofenac through the skin ranges from <1% to 12% with large interindividual variability. Absorption depends on the topically applied dose and the site of application.
Diclofenac binds highly to serum albumin.
Biotransformation of diclofenac partly involves conjugation of the intact molecule, but mainly consists of single and multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac. Metabolism of diclofenac following percutaneous and oral administration is similar.
Diclofenac and its metabolites are excreted mainly in the urine. Following oral administration, the systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean ± standard deviation). Terminal plasma half-life is short (1-2 hours). The metabolites also have short terminal half-lives of 1-3 hours.
Following topical application, the absorption rates of diclofenac on normal and compromised epidermis are similar although there are large interindividual differences. The systemic absorption of diclofenac is approximately 12% of the administered dose for compromised skin and 9% for intact skin.
Published animal studies have shown that, when diclofenac is administered orally, adverse reactions affect mainly the gastrointestinal tract. Diclofenac inhibited ovulation in rabbits and impaired implantation as well as early embryonic development in rats. The embryotoxic/foetotoxic potential of diclofenac was evaluated in three animal species (rat, mouse, rabbit). Foetal death and growth retardation occurred at materno-toxic doses. However, based on the available data, diclofenac is not considered to be teratogenic. The gestational period and the duration of parturition were prolonged with diclofenac. Doses lower than materno-toxic doses did not affect postnatal development. Results from extensive genotoxicity and carcinogenicity testing suggest that it is unlikely that diclofenac poses a significant carcinogenic hazard to humans.
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