Psotriol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PSOTRIOL® (PSOTRIOL)

Composition:

Active substances: calcipotriol, betamethasone;

1 g of gel contains 50 mcg of calcipotriol (as calcipotriol monohydrate) and 0.5 mg of betamethasone (as betamethasone dipropionate);

Excipients: hydrogenated castor oil, stearyl polyoxyl 10 ether (stabilized with butylhydroxytoluene), mineral oil.

Pharmaceutical form. Gel.

Main physicochemical characteristics: homogeneous, slightly opalescent, colorless gel, free from foreign particles.

Pharmacotherapeutic group.

Topical antipsoriatics. Other topical antipsoriatics. Calcipotriol combinations.

ATC code D05AX52.

Pharmacological properties.

Pharmacodynamics.

Calcipotriol is a vitamin D analogue. In vitro studies indicate that calcipotriol inhibits keratinocyte proliferation and promotes their differentiation. This is the likely mechanism of its action in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive, and immunosuppressive properties, but it does not treat the underlying disease. The use of occlusive dressings enhances the therapeutic effect by increasing penetration into the stratum corneum. As a result, the incidence of adverse reactions may increase. Overall, the mechanism of the anti-inflammatory activity of topical corticosteroids is not fully understood.

The adrenal response to adrenocorticotropic hormone (ACTH) was assessed by measuring serum cortisol levels in patients with extensive psoriasis of both the scalp and other body areas, using up to 106 g per week of a combination gel and ointment containing calcipotriol + betamethasone dipropionate. A borderline reduction in cortisol excretion in response to ACTH stimulation at 30 minutes was observed in 5 out of 32 patients (15.6%) after 4 weeks of treatment, and in 2 out of 11 patients (18.2%) who continued treatment for 8 weeks. In all cases, serum cortisol levels were within normal limits at 60 minutes after ACTH stimulation. There were no signs of altered calcium metabolism in these patients. Thus, regarding suppression of the hypothalamic-pituitary-adrenal (HPA) axis function, this study provided some evidence that very high doses of the gel and ointment containing calcipotriol + betamethasone dipropionate may have a weak effect on HPA axis function.

The efficacy of the gel containing calcipotriol + betamethasone dipropionate applied once daily was evaluated in two randomized, double-blind, 8-week clinical trials involving over 2900 patients with mild to moderate scalp psoriasis, as assessed by the Investigator's Global Assessment (IGA) of disease severity. Comparator treatments included betamethasone dipropionate in a gel vehicle, calcipotriol in a gel vehicle, and (in one of the studies) the gel vehicle alone; all were applied once daily. Results for the primary efficacy endpoint (absent or minimal disease severity according to IGA at 8 weeks) demonstrated that the gel containing calcipotriol + betamethasone dipropionate was statistically significantly more effective than the comparator treatments. Results on speed of onset, based on similar data at week 2, also showed that the gel containing calcipotriol + betamethasone dipropionate was statistically significantly more effective than the comparator treatments.

1Statistically significantly less effective than the gel containing calcipotriol + betamethasone dipropionate (P<0.001).

The efficacy of the gel containing calcipotriol + betamethasone dipropionate applied once daily was evaluated in a randomized, double-blind, 8-week clinical trial involving 296 patients with mild to moderate plaque psoriasis according to IGA.

Comparator treatments were betamethasone dipropionate in a gel vehicle, calcipotriol in a gel vehicle, and gel vehicle alone; all were applied once daily. Primary efficacy endpoints were disease control according to IGA at weeks 4 and 8. Disease control was defined as "clear skin" or "minimal disease" for patients with moderate disease severity at baseline, or as "clear skin" for patients with mild disease severity at baseline. Relative change in Psoriasis Area Severity Index (PASI) from baseline at weeks 4 and 8 were secondary efficacy endpoints.

1Statistically significantly less effective than the gel containing calcipotriol + betamethasone dipropionate (P<0.05).

1Statistically significantly less effective than the gel containing calcipotriol + betamethasone dipropionate (P<0.05).

In another randomized, investigator-blinded clinical trial involving 312 patients with at least moderate scalp psoriasis according to IGA, the efficacy of the gel containing calcipotriol + betamethasone dipropionate administered once daily was compared with that of the scalp solution containing calcipotriol + betamethasone dipropionate administered twice daily over a period of up to 8 weeks. Results for the primary efficacy endpoint (treatment response defined as absent or very mild disease severity according to IGA at week 8) demonstrated that the gel containing calcipotriol + betamethasone dipropionate was statistically significantly more effective than the scalp solution containing calcipotriol + betamethasone dipropionate.

1Statistically significantly less effective than the gel containing calcipotriol + betamethasone dipropionate (P<0.001).

In a randomized, double-blind, long-term clinical study involving 873 patients with at least moderate severity scalp psoriasis (according to IGA), the use of the gel containing calcipotriol + betamethasone dipropionate was compared with calcipotriol in a gel vehicle. Both medicinal products were applied once daily intermittently, as needed, for up to 52 weeks. Adverse reactions possibly associated with long-term corticosteroid use on the scalp were identified by an independent group of dermatologists working in a blinded manner. There was no difference in the percentage of patients who developed such adverse reactions between the treatment groups (2.6% in the group receiving the gel containing calcipotriol + betamethasone dipropionate and 3.0% in the group receiving calcipotriol; P = 0.73). Cases of skin atrophy were not reported.

Paediatric population

The effect on calcium metabolism was evaluated in two open, uncontrolled 8-week studies involving 109 adolescents aged 12–17 years with scalp psoriasis who used up to 69 g of gel containing calcipotriol + betamethasone dipropionate per week. No cases of hypercalcaemia or clinically significant changes in urinary calcium levels were recorded. The adrenal response to ACTH stimulation was assessed in 30 patients; one patient showed a reversible mild reduction in cortisol excretion in response to ACTH stimulation after 4 weeks of treatment, without clinical manifestations.

Pharmacokinetics.

Systemic exposure to calcipotriol and betamethasone dipropionate following topical application of the gel containing calcipotriol and betamethasone is comparable to that of the ointment containing calcipotriol and betamethasone in rats and minipigs. Results from clinical studies using radiolabelled ointment indicate that systemic absorption of calcipotriol and betamethasone is less than 1% of the applied dose (2.5 g) when applied to healthy skin (625 cm²) for 12 hours. Application to psoriatic plaques and under occlusive dressings may increase absorption of topically applied corticosteroids. Absorption through damaged skin is approximately 24%.

Following systemic exposure, both active ingredients—calcipotriol and betamethasone dipropionate—are rapidly and extensively metabolized. The medicinal product is approximately 64% protein-bound. The plasma half-life of the medicinal product after intravenous administration is 5–6 hours. Due to depot formation in the skin, elimination of the medicinal product from the skin after topical application occurs over several days.

Betamethasone is primarily metabolized in the liver, but also in the kidneys, forming glucuronides and sulfated esters. The main route of elimination of calcipotriol is via faeces (in rats and minipigs), and of betamethasone dipropionate via urine (in rats and mice). In rats, tissue distribution studies using radiolabelled calcipotriol and betamethasone dipropionate demonstrated that the kidneys and liver had the highest levels of radioactivity.

Levels of calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples from 34 patients treated for 4 or 8 weeks with either the gel or ointment containing calcipotriol + betamethasone dipropionate, in extensive psoriasis affecting both the body and the scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some patients.

Clinical characteristics.

Indications.

Topical treatment of scalp psoriasis. Topical treatment of mild to moderate plaque-type psoriasis, other than scalp psoriasis, in adults.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".

Use of the medicinal product Psotriol®, gel, is contraindicated in patients with psoriatic erythroderma, exfoliative or pustular psoriasis.

Due to the presence of calcipotriol, Psotriol®, gel, is contraindicated in patients with known disorders of calcium metabolism (see section "Special precautions for use").

Due to the presence of corticosteroid, Psotriol®, gel, is contraindicated in the following conditions: viral skin infections (e.g., herpes or varicella), fungal or bacterial skin infections, parasitic skin infections, cutaneous manifestations of tuberculosis, perioral dermatitis, skin atrophy, striae atrophicae, increased vascular fragility, ichthyosis, common acne, rosacea, rosacea acne, ulcers and wounds (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

No interaction studies with Psotriol®, gel, have been conducted.

Special precautions for use.

Effect on the endocrine system

Psoriel®, gel, contains a potent group III steroid. Concomitant treatment with other steroids should be avoided. Adverse reactions associated with systemic corticosteroid therapy, such as suppression of adrenal cortex function or effects on metabolic control in diabetes mellitus, may also occur during treatment with topically applied corticosteroids due to systemic absorption. Application of the medicinal product under occlusive dressings should be avoided, as this increases systemic absorption of corticosteroids.

Application to large areas of damaged skin, mucous membranes, or skin folds should be avoided, as this increases systemic absorption of corticosteroids (see section "Adverse reactions").

In a study of patients with extensive psoriasis of the scalp and/or extensive psoriasis of other body areas who received a combination of a gel containing calcipotriol + betamethasone dipropionate at high doses (application to the scalp) and an ointment containing calcipotriol + betamethasone dipropionate at high doses (application to other body areas), borderline reduction in cortisol excretion in response to ACTH stimulation was observed in 5 out of 32 patients after 4 weeks of treatment (see section "Pharmacodynamics").

Visual disturbances

Visual disturbances may occur with the use of systemic corticosteroids or topical corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, he or she should be referred to an ophthalmologist to determine possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSC), which has been reported after use of systemic and topical corticosteroids.

Effect on calcium metabolism

Due to the presence of calcipotriol, hypercalcemia may develop if the maximum daily dose (15 g) is exceeded. Serum calcium levels return to normal upon discontinuation of treatment. The risk of hypercalcemia is minimal when recommendations regarding calcipotriol are followed. The medicinal product should not be applied to skin areas exceeding 30% of body surface area (see section "Dosage and administration").

Local adverse reactions

Psoriel®, gel, contains a potent group III steroid. Concomitant treatment with other steroids on the same area should be avoided.

Facial skin and genital areas are highly sensitive to corticosteroids. The medicinal product should not be applied to these areas. Patients should be informed about proper use of the medicinal product to prevent application or accidental exposure to the face, oral cavity, or eyes. Hands should be washed after each application to prevent accidental transfer to these body areas.

Concomitant skin infections

If lesions become secondarily infected, antibacterial therapy should be initiated. However, if infection worsens, corticosteroid treatment should be discontinued (see section "Contraindications").

Withdrawal of therapy

When treating psoriasis with topical corticosteroids, there is a risk of generalized pustular psoriasis or rebound phenomena upon discontinuation of the medicinal product. Therefore, continued medical monitoring after stopping the medicinal product is necessary.

Long-term use of the medicinal product

Long-term use of corticosteroids increases the risk of local or systemic adverse reactions. Treatment should be discontinued if adverse reactions associated with prolonged corticosteroid use occur (see section "Adverse reactions").

Uses not evaluated

There is no experience with the use of Psoriel®, gel, in patients with guttate psoriasis.

Concomitant therapy and UV irradiation

An ointment containing calcipotriol + betamethasone dipropionate for treatment of psoriatic lesions on the body has been used in combination with a gel containing calcipotriol + betamethasone dipropionate for treatment of psoriatic lesions on the scalp. However, experience with combining the medicinal product containing calcipotriol + betamethasone dipropionate with other topical antipsoriatic agents applied to the same area, with systemic antipsoriatic agents, or with phototherapy is limited.

Patients using Psoriel®, gel, should be advised to limit or avoid excessive exposure to natural or artificial light. Topical calcipotriol should not be used in combination with UV irradiation unless the physician and patient consider that the expected benefit outweighs the potential risk.

Adverse reactions to excipients

Psoriel®, gel, contains butylhydroxytoluene as an excipient, which may cause local skin reactions (e.g., contact dermatitis) or irritation of the eyes and mucous membranes.

Use during pregnancy or breastfeeding.

Pregnancy

There are currently insufficient data on the use of Psoriel®, gel, in pregnant women. Animal studies with glucocorticosteroids have shown reproductive toxicity. However, epidemiological studies (fewer than 300 pregnancy outcomes) have not shown congenital anomalies in infants whose mothers used corticosteroids during pregnancy. The potential risk to humans has not yet been established. Therefore, Psoriel®, gel, should be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding period

Betamethasone passes into breast milk, but adverse reactions in the infant are unlikely when the medicinal product is used at therapeutic doses. There are no clinical data on the excretion of calcipotriol in breast milk. Psoriel®, gel, should be used with caution in breastfeeding women. Patients should not apply Psoriel®, gel, to the breasts during breastfeeding.

Fertility

Studies in rats with oral administration of calcipotriol or betamethasone dipropionate showed no reduction in fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

Psoriel®, gel, has no effect or has negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.

Dosage

Psotriol®, gel, should be applied to affected skin areas once daily.

The recommended treatment duration is 4 weeks for the scalp and 8 weeks for other body areas. If continued or renewed use of the medicinal product is required after 4 weeks, it should be done only after consultation with a physician and under regular medical supervision.

When using medicinal products containing calcipotriol, the maximum daily dose should not exceed 15 g. The area of application of medicinal products containing calcipotriol should not exceed 30% of the body surface (see section "Special instructions for use").

Application to the scalp

Psotriol®, gel, can be applied to all affected areas of the scalp. Usually, a quantity of 1 to 4 g per day (4 g corresponds to one teaspoon) is sufficient for treatment of the scalp.

Method of administration

Psotriol®, gel, should not be applied directly to the face or eyes. To achieve optimal effect, it is not recommended to take a shower, bath, or wash hair immediately after applying the gel to the scalp. Psotriol®, gel, should remain on the skin overnight or during the day.

Before use, shake the bottle well and apply Psotriol®, gel, to the affected area. After applying the gel, hands should be washed.

Special patient groups

Patients with renal or hepatic impairment

The safety and efficacy of Psotriol®, gel, in patients with severe renal insufficiency or severe liver disease have not been established.

Children

Paediatric population

The safety and efficacy of Psotriol®, gel, in children under 18 years of age have not been established. Available data on use in patients aged 12 to 17 years are described in sections "Pharmacodynamics" and "Adverse reactions", but no dosage recommendations can be provided.

Overdose.

Administration of the medicinal product in doses exceeding the recommended dose may lead to elevated serum calcium levels, which resolves upon discontinuation of treatment. Symptoms of hypercalcemia include polyuria, constipation, muscle weakness, confusion, and coma.

Prolonged excessive use of topical corticosteroids may suppress the hypothalamic-pituitary-adrenal function, leading to secondary adrenal insufficiency, which is usually reversible. In such cases, symptomatic treatment is indicated.

In cases of chronic toxicity, a gradual withdrawal of corticosteroids should be performed.

There have been reports of improper use of the medicinal product in a patient with generalized erythrodermic psoriasis who received treatment with 240 g per week of ointment containing calcipotriol + betamethasone dipropionate (corresponding to a daily dose of approximately 34 g) for 5 months (the maximum recommended daily dose is 15 g). This resulted in Cushing's syndrome during treatment and subsequent pustular psoriasis after abrupt discontinuation of therapy.

Adverse reactions.

The assessment of the frequency of adverse reactions is based on a pooled analysis of data from clinical studies, including post-marketing safety studies and spontaneous reports.

The most frequently reported adverse reaction during treatment is pruritus.

Adverse reactions are listed by MedDRA system organ class (SOC) and by frequency of occurrence. Within each frequency group, adverse reactions are presented in order of decreasing severity.

* Skin infections have been reported, including bacterial, fungal, and viral skin infections.

** Various types of rashes have been reported, such as exfoliative rash, papular rash, and pustular rash.

*** Temporary discoloration of hair at the site of application on the scalp to a yellowish hue has been reported in patients with light or grey hair.

**** Burning sensation at the application site is included under pain at the application site.

*****See section "Special precautions for use"

The adverse reactions listed below are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively.

Calcipotriol

Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensations, dry skin, erythema, rash, dermatitis, eczema, exacerbation of psoriasis, photosensitization, and hypersensitivity reactions, which in very rare cases may include angioneurotic edema and facial swelling.

Very rarely, systemic reactions may occur following topical application, leading to hypercalcaemia or hypercalciuria (see section "Special precautions for use").

Betamethasone (as dipropionate)

Following topical use, application site reactions may develop, especially during prolonged treatment, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation, and cutis rhomboidalis.

When treating psoriasis with topical corticosteroids, there may be a risk of developing generalized pustular psoriasis.

Systemic reactions related to topical corticosteroid use in adults are rare but can be severe. They may include adrenal suppression, cataract, infections, effects on metabolic control in diabetes mellitus, and increased intraocular pressure, particularly after prolonged use of the medicinal product. Systemic reactions occur more frequently when occlusive dressings (plastic, skin folds) are used, when the medicinal product is applied over large areas, or during long-term treatment (see section "Special precautions for use").

Paediatric population

In a study of 109 adolescents aged 12–17 years treated for scalp psoriasis with the medicinal product containing calcipotriol + betamethasone dipropionate for 8 weeks, no new adverse events or new adverse reactions were identified. However, the size of this study does not allow definitive conclusions regarding the safety profile of the gel containing calcipotriol + betamethasone dipropionate in adolescents compared to adult patients (see section "Pharmacodynamics").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 36 months. After first opening – 6 months.

Storage conditions.

Store at temperatures not exceeding 30°C. Keep out of reach and sight of children.

Packaging.

30 g in a bottle with dropper dispenser and screw cap; 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address and place of business.

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.