Ultraproct N

Fluocortolone pivalate, lignocaine hydrochloride.

Cream: 1 g cream contains 1 mg fluocortolone pivalate, 20 mg lignocaine hydrochloride.
Excipient/Inactive Ingredient: Polysorbate 60, Sorbitan stearate, Cetostearyl alcohol, Liquid paraffin, White soft paraffin, Disodium edetate, Sodium dihydrogen phosphate dihydrate, Disodium phosphate dodecahydrate, Benzyl alcohol, Purified water.
Suppository: 1 suppository contains 1 mg fluocortolone pivalate and 40 mg lignocaine hydrochloride.
Excipient/Inactive Ingredient: Hard fat.

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.

Symptomatic relief of pain and inflammation in adults for haemorrhoidal disease, non-infectious proctitis, and anal eczema (for rectal cream).

It is advisable to administer Ultraproct N after defaecation. The anal region should be cleaned thoroughly prior to use. The total duration of treatment should not exceed 2 weeks.
Paediatric population: Ultraproct N is not recommended for use in children under 18 years due to a lack of data on safety and efficacy.
Cream: Rectal cream should be applied twice a day, once in the morning and once in the evening (approximately up to 1 g cream per application). In the initial days of use, it can be applied three times daily. With improvement of symptoms, a single daily application is often sufficient.
A finger-tip unit of rectal cream is applied to the anal region with a finger, using the finger-tip to overcome the resistance of the sphincter. A finger-tip unit is the amount of rectal cream expressed from the tube and applied from the distal skin-crease to the tip of the index finger of an adult.
If the cream is to be applied intra-rectally, the applicator provided has to be screwed onto the tube and the tip inserted into the anus. A small quantity of cream can then be applied by exerting slight pressure on the tube.
Suppository: One suppository should be inserted deep into the anus twice a day, once in the morning and once in the evening. With improvement of symptoms, it is in many cases sufficient to insert one suppository per day or every second day.

Symptoms: The results of investigations of the acute toxic potential of the active substances in Ultraproct N show that there is no risk of acute toxic symptoms following accidental overdosage during a single rectal or perianal application of Ultraproct N to be expected. After accidental oral ingestion of the preparation (e.g. ingestion of several grams of cream), the main symptoms to be expected are likely to be systemic effects of lignocaine hydrochloride, which, depending on dose, may be manifested in the form of severe cardiovascular symptoms (depression of cardiac function or cardiac arrest in extreme cases) or symptoms related to the central nervous system (convulsions, dyspnoea or respiratory failure in extreme cases).
Management: The management of an overdose includes close monitoring of vital functions, supportive care including oxygen supply, and symptomatic treatment of central and cardiovascular symptoms (e g. including short acting barbiturates, beta-sympathomimetics, atropine). Dialysis is of negligible value.

Ultraproct N is contraindicated in case of topical infections in the affected area and if symptoms of the following disorders are present in the affected area: specific skin lesions (syphilis, tuberculosis), chickenpox, vaccination reactions, herpes genitalis.
Hypersensitivity to the active substances or to any of the excipients listed in Description.

Since Ultraproct N contains the active substance lignocaine and approximately 30 % of the dose applied is systemically available, this should be considered in patients taking medicines to treat irregular heartbeat (arrhythmia).
Effects on ability to drive and use machines: Ultraproct N has no or negligible influence on the ability to drive and use machines.
Cream: If Ultraproct N is applied to the genital or anal areas, the excipients paraffin and soft paraffin may reduce the strength of latex condoms used concomitantly, thus impairing the safety of the condoms. Care should be taken to ensure that Ultraproct N does not come into contact with the eyes. It is advisable to wash one's hands thoroughly after use.
The rectal use of the medicinal product Ultraproct N rectal cream utilizing the application nozzle provided may cause positive results during testing for doping.
Cetostearyl alcohol may cause local skin reactions (e.g. contact dermatitis).
Suppository: If suppositories have become softened owing to warm temperature: Put them in cold water without opening the aluminium foil strip prior to use.

Pregnancy: There are insufficient data on the use of Ultraproct N in pregnant women. Animal experimental studies with glucocorticosteroids have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
A number of epidemiological studies suggest that there could possibly be an increased risk of oral clefts among newborns of women who were treated with systemic glucocorticosteroids during the first trimester of pregnancy. Oral clefts are a rare disorder and if systemic glucocorticoseroids are teratogenic, these may account for an increase of only 1-2 cases per 1000 women treated while pregnant.
Data concerning topical glucocorticosteroid use during pregnancy are insufficient, however, a lower risk might be expected since systemic availability of topically applied glucocorticosteroids is very low. As a general rule, topical preparations containing glucocorticosteroids should not be applied during the first trimester of pregnancy.
Breastfeeding: The clinical indication for treatment with Ultraproct N must be carefully reviewed and the benefits weighed against the risks in pregnant and lactating women. In particular, prolonged use of Ultraproct N must be avoided.
Fertility: No investigation on the potential effects of fluocortolone or its esters has been performed. Studies in animals have shown no effects on fertility for lignocaine hydrochloride (see Pharmacology: Toxicology: Preclinical safety data under Actions).

After prolonged therapy with Ultraproct N (more than four weeks), there is a risk that the patient may develop local skin alterations, such as atrophy, striae or telangiectasias.
Cream: The incidence of the undesirable effects was calculated from pooled clinical trial data involving 661 patients.
Skin and subcutaneous tissue disorders: Uncommon (≥1/1,000 to <1/100): Allergic skin reactions to any of the excipients.
General disorders and administration site conditions: Common (≥1/100 to <1/10): Application site burning.
Uncommon (≥1/1,000 to <1/100): Application site irritation.
Suppository: The incidence of the undesirable effects was calculated from pooled clinical trial data involving 367 patients.
Skin and subcutaneous tissue disorders: Not known (frequency cannot be estimated from the available data): Allergic skin reactions to any of the excipients.
General disorders and administration site conditions: Common (≥1/100 to <1/10): Application site burning.
Uncommon (≥1/1,000 to <1/100): Application site irritation.

No interaction studies have been performed. Co-treatment with CYP3A inhibitors, including cobicistat-containing products, should be expected to increase the risk of systemic side effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects.

Incompatibilities: None known.

Anorectal Preparations

C05AA08 - fluocortolone ; Belongs to the class of products containing corticosteroids for topical use. Used in the treatment of hemorrhoids and anal fissures.

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