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Pharmacotherapeutic group: Vasoprotective agents, agents for treatment of haemorrhoids and anal fissures for topical use. ATC code: CO5AA08.
Pharmacology: Pharmacodynamics: Ultraproct N cannot remove the causes of development of haemorrhoidal disease, proctitis and anal eczema. A post-marketing study of Ultraproct N rectal cream (active substances as per Ultraproct N suppositories) in comparison to vehicle and fluocortolone pivalate monotherapy was performed in 241 patients with rectal bleeding due to haemorrhoid disease. Since efficacy results could not be evaluated properly, superiority of the fixed combination of active substances as present in Ultraproct N rectal cream compared to fluocortolone pivalate monotherapy has not been established yet.
If haemorrhoidal disease is accompanied by inflammation and eczematous skin symptoms, combined use of Ultraproct N suppositories and Ultraproct N rectal cream can be recommended.
Fluocortolone pivalate: Fluocortolone pivalate inhibits inflammatory and allergic skin reactions, and alleviates subjective symptoms, such as pruritus, smarting, and pain. The substance reduces dilatation of the capillaries, oedema of the interstitial cells and infiltration of the tissues. Capillary multiplication is inhibited.
Lignocaine hydrochloride: Lignocaine hydrochloride is a standard local anaesthetic which has been in use for many years. As it has analgesic and antipruritic properties, it has been found to be effective when used in suppositories and creams designed for the treatment of haemorrhoidal disease. The suppression of pain and pruritus is the result of the inhibition of afferent nerve pathways by the substance.
Pharmacokinetics: After rectal application of the cream in healthy male volunteers, a maximum of 15% of the dose of fluocortolone pivalate and 30% of the dose of lignocaine hydrochloride was systemically absorbed (radiolabelled active substances).
After rectal application of one single suppository to male healthy volunteers the systemic availability of fluocortolone pivalate was assessed to be about 5% and that of lignocaine to be about 24%.
Toxicology: Preclinical safety data: Acute toxicity: Based on the results of conventional studies into the acute toxicity, no specific risk to humans is to be expected after the therapeutic use.
Subchronic/chronic toxicity: In order to assess the systemic tolerance following repeated application of the active substances toxicity studies using dermal and rectal routes of application were carried out. The most prominent effects were the typical signs of overdose of the glucocorticosteroid or the local anaesthetic. Data obtained concerning the resorption and bioavailability of the two active substances indicate, however, that no pharmacodynamically effective systemic burden is to be expected if Ultraproct N is used according to prescription.
Reproductive toxicity: Based on embryotoxicity studies with fluocortolone / fluocortolone hexanoate and lignocaine hydrochloride, embryotoxic / teratogenic effects in humans are not expected to occur with the use of Ultraproct N.
There are hints from animal experiments that administration of systemic glucocorticoids during pregnancy might contribute to postnatal effects such as cardiovascular and/or metabolic diseases, and to permanent changes in density of glucocorticoid receptors, in neurotransmitter turnover and in behaviour in the offspring.
In general, glucocorticosteroids lead to embryotoxic and teratogenic effects (e.g oral clefts, skeletal malformations, intrauterine growth retardations, embryolethality) in the appropriate test systems. In view of these findings, particular care should be taken when prescribing Ultraproct N during pregnancy. The results of epidemiological studies are summarized in Use in Pregnancy & Lactation.
Fertility: The potential impact of Ultraproct N on fertility has not been investigated. Lignocaine hydrochloride was administered subcutaneously to rats at a dose level of 10 mg/kg bodyweight for a period of 8 months. During this time, the animals were mated three times and no effect on fertility was reported. No studies of the potential effect of fluocortolone or its esters on fertility have been performed in animals.
Genotoxicity and carcinogenicity: In-vitro and in-vivo studies gave no relevant indication on a genotoxic potential of fluocortolone. Specific tumorigenicity studies with fluocortolone/ fluocortolone pivalate have not been carried out. On the basis of the pharmacodynamic mode of action, the lack of evidence of a genotoxic potential, the chemical structure and the results of chronic toxicity studies, there is no suspicion of a tumorigenic potential for fluocortolone pivalate. There is at present no suggestion that lignocaine might be mutagenic. However, there are signs that a metabolite of lignocaine, 2,6-xylidine, that occurs in the rat and possibly also in humans, might have a mutagenic effect. These signs are based on in-vitro tests in which this metabolite was used at very high, almost toxic concentrations.
In a carcinogenicity study in rats with transplacental exposure and 2 years postpartum treatment with high doses of 2,6-xylidine both, malignant and benign tumors, especially in the nasal cavity (ethmoturbinal) were observed in a highly sensitive test system. It does not appear absolutely improbable that this may be relevant to humans. For this reason lignocaine should not be administered at high doses for prolonged periods.
Local tolerance: Investigations into the local tolerance on the skin and the mucosa did not reveal any changes beyond those topical side-effects known for glucocorticoids.
Experimental investigations for detection of possible sensitizing effects have not been carried out with the active substances of Ultraproct N. Data in the literature suggests that the active substances as well as the components of the formulation base could be responsible for the allergenic skin reactions observed only sporadically following use of Ultraproct N. However, Ultraproct N is only expected to provoke contact allergies in rare cases.
