DOVOBET - PACKAGE LEAFLET - LEAFLETS

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Dovobet - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Calcipotriol, Betamethasone

DOVOBET® 50 micrograms / + 0.5 mg / g ointment

Dovobet package inserts are available for pack sizes:

DOVOBET® 50 micrograms / + 0.5 mg / g ointment
DOVOBET GEL 50 micrograms / g / 0.5 mg / g Gel

Indications Why is Dovobet used? What is it for?

Dovobet ointment is used on the skin to treat plaque psoriasis (psoriasis vulgaris) in adults. Psoriasis is a disease in which skin cells are produced too quickly. This causes redness, peeling and thickening of the skin.

Dovobet ointment contains calcipotriol and betamethasone. Calcipotriol normalizes skin cell growth and betamethasone works by reducing inflammation.

Contraindications When Dovobet should not be used

Do not use DOVOBET:

if you are allergic (hypersensitive) to calcipotriol, betamethasone or any of the other ingredients of Dovobet
if you have problems with the calcium levels in your body (ask your doctor);
if you have other types of psoriasis: such as erythroderma, exfoliative or pustular (ask your doctor).

Since Dovobet contains a strong steroid, DO NOT use it on skin affected by:

skin infections caused by viruses (e.g. cold sores or chickenpox)
skin infections caused by fungi (such as athlete's foot or ringworm)
skin infections caused by bacteria
skin infections caused by parasites (such as scabies)
tuberculosis (TB)
perioral dermatitis (red rash around the mouth)
thin skin, easily damaged veins, stretch marks
ichthyosis (dry skin with fish-like scales)
acne (boils)
rosacea (severe flushing or redness of the skin on the face)
open skin sores or ulcers

Precautions for use What you need to know before taking Dovobet

Before using the drug, tell your doctor, nurse or pharmacist if

are using other medicines that contain corticosteroids, as side effects may occur
have used this drug for a long time and decide to stop treatment (when steroid treatment is stopped suddenly there is a risk that psoriasis will worsen or flare up)
have diabetes mellitus (diabetes), as blood sugar / glucose levels may be affected by the steroid
skin lesions tend to become infected, treatment may need to be stopped
have a certain type of psoriasis called guttate psoriasis

Special precautions

avoid applying the product to more than 30% of the body or using more than 15 g of product per day
avoid using bandages or clothing which may increase the absorption of the steroid
avoid use on large areas of damaged skin or mucous membranes or skin folds (eg groin, armpits, under breasts) as it may increase steroid absorption.
avoid applying the drug to the skin of the face or genitals (sexual organs), which are very sensitive to steroids
avoid excessive sunbathing, excessive use of the solarium and other forms of light treatment.

Children

Dovobet is not recommended for use in children under 18 years of age.

Interactions Which drugs or foods can modify the effect of Dovobet

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Warnings It is important to know that:

Pregnancy and breastfeeding

Do not use Dovobet if you are pregnant (or may be pregnant) or if you are breast-feeding, without first talking to your doctor. If your doctor has determined that you can breastfeed, be sure not to apply Dovobet ointment to the breast area.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

This drug is not expected to affect the ability to drive or use machines.

Important information about some of the ingredients of DOVOBET

Dovobet ointment contains butylated hydroxytoluene (E321). It can cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes and mucous membranes.

Dose, Method and Time of Administration How to use Dovobet: Posology

Always take Dovobet exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.

How to use Dovobet: cutaneous use.

Instructions for correct use

Only use Dovobet on psoriasis; not to be used on skin not affected by psoriasis.
Remove the cap and check that the seal on the tube is not broken before you use the ointment for the first time.
To break the seal, use the back of the cap.
While squeezing the tube, squeeze the ointment onto a clean finger.
Gently rub until the psoriasis area is covered and most of the ointment has been absorbed into the skin.
Do not bandage, bundle tightly or hide treated areas of skin.
Wash your hands thoroughly after using Dovobet (unless you have used the ointment to treat your hands). This will prevent accidental contact of the ointment with other parts of the body (especially the face, scalp, mouth and eyes).
Do not be alarmed if a small part of the ointment accidentally touches the healthy skin around the psoriatic plaque, but clean the skin if the drug spreads too far from the psoriatic area.
To achieve optimal effect, it is recommended not to bathe or shower immediately after the application of Dovobet ointment.
After applying the ointment, avoid contact with fabrics that could easily get stained with grease (for example: silk).

Duration of treatment

Use the ointment once a day. It may be more convenient to apply the ointment in the evening.
The initial treatment period is normally 4 weeks, but your doctor may decide on a different treatment period.
The doctor may decide to repeat the treatment.
Do not use more than 15 grams per day. If other calcipotriol-containing drugs are used, the total amount of calcipotriol-containing drugs should not exceed 15 grams per day and the treated area should not exceed 30% of the total body surface area.

What to expect with the use of DOVOBET

Most patients notice noticeable improvements after 2 weeks, although the psoriasis has not completely disappeared from the area.

Overdose What to do if you have taken an overdose of Dovobet

If you use more DOVOBET than you should

Contact your doctor if you have used more than 15g in one day.

Excessive use of Dovobet can cause problems with blood calcium levels, which usually normalize after stopping treatment.

Your doctor may find it necessary to have some blood tests to check if using too much ointment may have caused a problem with your blood calcium levels.

Overuse and prolonged use can also cause the adrenal glands to not function properly (the adrenal glands are located near the kidneys and produce hormones).

If you forget to use DOVOBET

Do not use a double dose to make up for a forgotten application.

If you stop taking DOVOBET

Use of Dovobet should be stopped as directed by your doctor. It may be necessary to stop using the drug gradually, especially after using it for a long time. If you have any further questions on the use of Dovobet, ask your doctor or pharmacist.

Side Effects What are the side effects of Dovobet

Like all medicines, Dovobet can cause side effects, although not everybody gets them.

Serious side effects:

Tell your doctor / nurse immediately or as soon as possible if you experience any of the following events. Treatment may need to be stopped

The following serious side effects have been reported with Dovobet:

Uncommon (may affect up to 1 in 100 people)

Worsening of psoriasis. Tell your doctor as soon as possible if your psoriasis gets worse.

Rare (may affect up to 1 in every 1,000 people)

Pustular psoriasis (red areas with yellowish pustules usually on the hands or feet) may occur. In this case, stop using Dovobet and tell your doctor as soon as possible.

Some serious side effects are known to be caused by betamethasone (a strong steroid), one of the components of Dovobet. Tell your doctor as soon as possible if you experience a serious side effect. These side effects occur more frequently after prolonged use, use in skin folds (eg groin, armpits or under the breasts), use with an occlusive bandage or use on a large skin surface.

Side effects include:

The adrenal glands can stop working properly. Symptoms are fatigue, depression and anxiety.
Cataracts (symptoms are blurred or blurred vision, difficulty seeing at night and sensitivity to light) or increased internal pressure in the eyes (symptoms are pain in the eye, red eyes, decreased vision or blurred vision).
Infections (because the immune system, which fights infections, can be suppressed or weakened).
Pustular psoriasis (a red area with yellowish pustules that usually appears on the hands or feet). If you notice this, stop using Dovobet and tell your doctor as soon as possible.
Interference with the metabolic control of diabetes mellitus (if you are diabetic you may experience fluctuations in blood sugar).

Serious side effects known to be caused by calcipotriol:

Allergic reactions with severe swelling of the face or other parts of the body such as the hands or feet. Swelling of the mouth / throat and difficulty in breathing may occur. If you have an allergic reaction, stop using Dovobet, tell your doctor immediately or go to the nearest hospital emergency room.
Treatment with this ointment can cause the calcium levels in your blood or urine to rise (usually when excessive amounts of the ointment are used). Symptoms of increased blood calcium levels are: excessive passing of urine, constipation, muscle weakness, confusion and coma. This can be serious and you should contact your doctor immediately. However, the levels will return to normal when treatment is stopped.

Less serious side effects

The following less serious side effects have been reported with Dovobet.

Common (may affect up to 1 in 10 people)

Itching
skin exfoliation

Uncommon (may affect up to 1 in 100 people)

Pain or skin irritation
Rash with inflammation of the skin (dermatitis)
Redness of the skin due to dilation of the capillaries (erythema)
Inflammation or swelling of the hair root (folliculitis)
Changes in skin color in the area where the ointment was applied
Rash
Burning sensation in the skin
Skin infection
Thinning of the skin
Appearance of red or purple discoloration on the skin (purpura or bruising)

Rare (may affect up to 1 in 1,000 people)

Infection of the hair follicles caused by fungi or bacteria (boils)
Allergic reactions
Hypercalcemia
Skin striae
Sensitization of the skin to the sun and consequent rash
Acne (pimples)
Dry skin
Rebound effect: a worsening of psoriasis symptoms after the end of treatment

Less serious side effects, due to the use of betamethasone, especially for a prolonged time, include those listed below, in case of any of these effects you should inform your doctor or nurse as soon as possible.

Thinning of the skin
Appearance of superficial veins or stretch marks
Hair growth changes
Red rashes around the mouth (perioral dermatitis)
Skin rash, with inflammation or swelling (allergic contact dermatitis)
Small gold-colored cysts (colloidal milio)
Skin discoloration (depigmentation)
Inflammation or swelling at the root of the hair (folliculitis)

Less serious side effects known to be caused by calcipotriol include the following:

Dry skin
Sensitivity of the skin to light, resulting in a rash
Eczema
Itching
Skin irritation
Sensation of burning and stinging
Redness of the skin due to dilation of the capillaries (erythema)
Rash
Rash with inflammation of the skin (dermatitis)
Worsening of psoriasis

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Italian Medicines Agency website: https: //www.aifa .gov.it / content / adverse-reaction-reports By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep out of the reach and sight of children.
Do not use Dovobet after the expiry date which is stated on the label after "EXP". The expiry date refers to the last day of the month.
Do not store above 25 ° C.
The tube should not be used 1 year after first opening. Write the date the tube was first opened in the space provided on the box.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What DOVOBET ointment contains

The active ingredients are:

calcipotriol and betamethasone

1 gram of ointment contains 50 micrograms of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate) The other ingredients are:

liquid paraffin
all-rac-α-tocopherol
polyoxypropylene-11-stearyl ether
soft white paraffin
butylated hydroxytoluene (E321)

Description of what DOVOBET looks like and contents of the pack

Dovobet ointment is an ivory to yellow ointment, supplied in aluminum / epoxyphenol tubes with a polyethylene screw cap.

Packaging: 15 g, 30 g, 60 g, 100 g and 120 g.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Dovobet can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

DOVOBET 50 MCG / 0.5 MG / G OIL

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One gram of ointment contains 50 mcg of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).

Excipients with known effects:

Butylated hydroxytoluene (E321) 50 mcg / g ointment.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Ointment.

White to yellow in color.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Topical treatment of stable plaque vulgaris psoriasis, traceable to topical therapy in adults.

04.2 Posology and method of administration

Dosage

Dovobet ointment should be applied to the affected areas once a day. The recommended treatment period is 4 weeks. Repeated courses of Dovobet for up to 52 weeks have been tested. If it is necessary to continue or resume treatment after 4 weeks, treatment should be continued after medical review and under regular medical supervision.

When using medicines containing calcipotriol, the maximum daily dose should not exceed 15 g. Body surface area treated with calcipotriol containing medicinal products should not exceed 30% (see section 4.4).

Special population

Impaired renal and hepatic function

The safety and efficacy of Dovobet ointment in patients with severe renal insufficiency or severe liver problems have not been established.

Pediatric population

The safety and efficacy of Dovobet ointment in children under 18 years of age have not been established. Currently available data in children aged 12 to 17 years are described in sections 4.8 and 5.1, but cannot be no recommendation on posology was given.

Method of administration

Dovobet ointment should be applied to the affected area.To achieve optimal effect, it is recommended not to bathe or shower immediately after the application of Dovobet ointment.

04.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Dovobet is contraindicated in erythrodermal, exfoliative and pustular forms of psoriasis.

Due to the presence of calcipotriol, Dovobet is contraindicated in patients with known disorders of calcium metabolism (see section 4.4).

Due to the presence of a corticosteroid, Dovobet is contraindicated in the following conditions: skin lesions of viral origin (for example, herpes or chicken pox), fungal or bacterial skin infections, parasitic infections, skin manifestations due to tuberculosis, perioral dermatitis, atrophy skin, atrophic striae, capillary fragility, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds (see section 4.4).

04.4 Special warnings and appropriate precautions for use

Effects on the endocrine system

Dovobet ointment contains a potent class III steroid, therefore concomitant treatment with other steroids should be avoided. Undesirable effects observed in relation to systemic corticosteroid treatment, such as adrenocortical suppression or interference with the metabolic control of diabetes mellitus, may also occur during topical corticosteroid treatment due to their systemic absorption. Application should be avoided. with occlusive dressings, as these increase the systemic absorption of corticosteroids. Application to large areas of damaged skin or to mucous membranes or skin folds should be avoided as this increases systemic absorption of corticosteroids (see section 4.8).

In a study conducted on patients with psoriasis on large areas of both the scalp and the body, following the use of high doses of Dovobet gel (applied to the scalp) in combination with high doses of Dovobet ointment (applied to the body) 5 of 32 patients experienced a decrease to limit of normal cortisol in response to ACTH stimulation after 4 weeks of treatment (see section 5.1).

Effects on calcium metabolism

Due to the presence of calcipotriol, hypercalcemia may occur if the maximum daily dose (15g) is exceeded. Serum calcium normalizes when treatment is stopped. The risk of hypercalcaemia is minimal when the recommendations on the use of calcipotriol are followed. Treatment involving more than 30% of body surface area should be avoided (see section 4.2).

Local adverse reactions

Dovobet ointment contains a potent class III steroid, therefore concomitant treatment with other steroids in the same treatment area should be avoided.

The skin of the face and genitals is very sensitive to corticosteroids. The medicine should not be used in these areas. The patient should be instructed on the correct use of the medicinal product in order to avoid accidental application or contact with the face, mouth and eyes. Hands should be washed after each application to avoid accidental contact with such areas.

Concomitant skin infections

If skin lesions become superinfected, they must be treated with antibacterial therapy.

However, if the infection worsens, corticosteroid treatment should be discontinued (see section 4.3).

Discontinuation of treatment

During the treatment of psoriasis with topical corticosteroids, when therapy is stopped, there is a risk of generalized pustular psoriasis and effects rebound. Medical supervision should therefore continue in the post-treatment period.

Prolonged use

With prolonged use there is an increased risk of both local and systemic undesirable effects related to the corticosteroid. Treatment should be discontinued in case of undesirable effects related to long-term use of the corticosteroid (see section 4.8.)

Use not analyzed

There is no experience with the use of Dovobet in guttate psoriasis.

Combined use and UV exposure

There is "limited experience" on the use of this medicine on the scalp. Dovobet ointment for psoriasis lesions on the body has been used in combination with Dovobet gel for psoriasis lesions on the scalp, but there is "limited" experience on the combined use of Dovobet with other topical anti-psoriasis administered on the same area. treated, and other anti-psoriatic medicines administered systemically or with phototherapy.

During treatment with Dovobet, physicians should advise patients to limit or avoid excessive exposure to both natural and artificial sunlight. Topical calcipotriol should only be administered concurrently with UV radiation exposure if physician and patients believe that the potential benefits outweigh the potential risks (see section 5.3).

Adverse reactions to excipients

Dovobet ointment contains butylated hydroxytoluene (E321) as an excipient which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

04.5 Interactions with other medicinal products and other forms of interaction

No interaction studies have been performed with Dovobet.

04.6 Pregnancy and lactation

Pregnancy

There are insufficient data regarding the use of Dovobet in pregnant women. Animal studies with glucocorticosteroids have shown reproductive toxicity (see section 5.3), however epidemiological investigations (less than 300 pregnancies evaluated) have not shown congenital abnormalities in newborns born to mothers treated with corticosteroids during pregnancy. The potential risk to humans is not defined. Therefore, during pregnancy Dovobet should only be used when the possible benefit justifies the potential risk.

Feeding time

Betamethasone is excreted in breast milk but, at the recommended therapeutic doses, the risk of developing side effects in the infant is considered unlikely. There are no data on the excretion of calcipotriol in breast milk. The physician should use caution when prescribing Dovobet to patients who are breastfeeding. The patient should be advised not to apply Dovobet to the breast during the lactation period.

Fertility

Studies conducted in rats with oral doses of calcipotriol and betamethasone dipropionate showed that there is no impairment of male and female fertility (see section 5.3).

04.7 Effects on ability to drive and use machines

Dovobet has no or negligible influence on the ability to drive and use machines.

04.8 Undesirable effects

The estimated frequency of adverse reactions is based on the pooled analysis of data from clinical trials, including post-authorization safety studies and spontaneous reporting.

The most frequently reported adverse reactions during treatment include various skin reactions such as itching and peeling of the skin.

Pustular psoriasis and hypercalcemia have been reported.

Adverse reactions are listed according to the MedDRA System Organ Class and individual adverse reactions are listed starting with the one with the greatest frequency. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Very common (≥1 / 10)

Common (≥1 / 100,

Uncommon (≥1 / 1000,

Rare (≥1 / 10,000,

Very rare (

Infections and infestations Uncommon ≥1/1000, skin infection *, folliculitis Rare ≥1 / 10,000, boil Disorders of the immune system Rare ≥1 / 10,000, Hypersensitivity Metabolism and nutrition disorders Rare ≥1 / 10,000, Hypercalcemia Skin and subcutaneous tissue disorders Common (≥1/100, skin exfoliation, itching Uncommon ≥1/1000, skin atrophy, psoriasis aggravated, dermatitis, erythema, rash **, purpura or ecchymosis, skin burning sensation, skin irritation Rare ≥1 / 10,000, pustular psoriasis, striae, photosensitization reactions, acne, dry skin General disorders and administration site conditions Uncommon ≥1/1000, application site pigmentation changes, application site pain *** Rare ≥1 / 10,000, rebound effect

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

** Various types of rash reactions have been reported such as exfolitative rash, common rash and pustular rash

*** Pain at the application site includes a burning sensation

Pediatric population

In an open, uncontrolled study, 33 adolescents aged 12-17 years with psoriasis vulgaris were treated with Dovobet ointment for 4 weeks up to a maximum of 56 g per week. No new adverse events were observed and no relevant data regarding the systemic effect of corticosteroids were identified. However, the size of the study does not allow firm conclusions to be drawn on the safety profile of Dovobet ointment in children and adolescents.

The following adverse reactions are believed to be related to the drug classes of calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse reactions include application site reactions, itching, skin irritation, burning or stinging sensation, dry skin, erythema, rash, dermatitis, eczema, worsening of psoriasis, photosensitivity and hypersensitivity reactions, including very rare cases of angioedema and facial edema.

Systemic effects such as hypercalcemia and hypercalciuria may appear very rarely following topical application (see section 4.4).

Betamethasone (as dipropionate)

Local reactions may occur after topical application, especially if prolonged, and include skin atrophy, telangiectasias, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, skin depigmentation and milio colloidal.

There may be a risk of developing generalized pustular psoriasis when treating psoriasis with topical corticosteroids.

Systemic reactions due to topical use of corticosteroids are rare in adults, however they can be severe. Adrenocortical suppression, cataracts, infections, interference with the metabolic control of diabetes mellitus and increased intraocular pressure may occur, particularly after prolonged treatment. systemic reactions occur more frequently if the application is performed in occlusive conditions (occlusive dressing, skin folds) if it is performed on large skin areas and in the case of prolonged treatments (see section 4.4).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions that occur after the authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk ratio of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency website : www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Use above the recommended dose may cause an increase in serum calcium which disappears after discontinuation of treatment. Symptoms of hypercalcaemia include polyuria, constipation, muscle weakness, confusion and coma.

Excessively prolonged use of topical corticosteroids can suppress the function of the pituitary-adrenal axis resulting in secondary adrenal insufficiency which is usually reversible. In these cases, symptomatic treatment is indicated.

In case of chronic toxicity, corticosteroid treatment should be withdrawn gradually.

Due to incorrect use, a patient with extensive erythrodermal psoriasis has been reported to be treated with a weekly dose of Dovobet ointment equal to 240 g (corresponding to a daily dose of approximately 34 g) for 5 months (maximum daily dose 15 g) developed Cushing's syndrome during treatment and subsequently pustular psoriasis after abrupt discontinuation of treatment.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antisporiasics; other topical antipsoriatic drugs, calcipotriol, combinations.

ATC code: D05AX52.

Calcipotriol is an analogue of vitamin D. The data obtained in vitro suggest that calcipotriol induces differentiation and inhibits keratinocyte proliferation. This is the underlying mechanism hypothesized to explain its efficacy in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppressive activity without however being able to resolve the underlying pathological condition. With occlusion, the effectiveness can be increased due to the greater penetration into the stratum corneum. In relation to this, the incidence of adverse effects will increase. In general, the mechanism by which the anti-inflammatory activity of topical corticosteroids occurs is not clear.

A safety study conducted in 634 patients with psoriasis investigated the administration of repeated courses of Dovobet ointment applied once daily, as required, either alone or alternating with Daivonex, for up to 52 weeks, compared with the use of Daivonex, from for only 48 weeks after an initial course of Dovobet ointment.

Adverse drug reactions were reported in 21.7% of patients in the Dovobet ointment group, 29.6% of the Dovobet ointment / Daivonex alternating group and 37.9% of the Daivonex group. Adverse reactions reported in more than 2% of patients in the Dovobet ointment group were pruritus (5.8%) and psoriasis (5.3%). Adverse events, possibly relevant to prolonged use of corticosteroids (eg skin atrophy, folliculitis, depigmentation, boils and purpura), were reported by 4.8% of patients in the Dovobet ointment group, since 2.8 % of patients in the group treated alternatively with Dovobet ointment / Daivonex and 2.9% in the Daivonex group.

Adrenal response to ACTH was assessed by measuring serum cortisol levels in patients with extensive psoriasis on both scalp and body, using up to 106 g per week of Dovobet gel in combination with Dovobet ointment. One observed one. decrease to limit of normal response to cortisol after 30 minutes of ACTH stimulation, in 5 of 32 patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) of those who continued treatment for 8 weeks. In all observed cases serum cortisol levels returned to normal 60 minutes after ACTH stimulation. No changes in calcium metabolism were observed in these patients. HPA, this study shows that very high doses of Dovobet gel and Dovobet ointment can have a slight effect on the HPA axis.

Pediatric population

Adrenal response to ACTH stimulation was measured in a 4-week uncontrolled study in 33 adolescents aged 12-17 years with body psoriasis, who used up to 56g per week of Dovobet ointment. No cases of HPA axis suppression have been reported. Hypercalcaemia has not been reported, but one patient experienced an increase in urine calcium possibly related to treatment.

05.2 Pharmacokinetic properties

Clinical studies carried out with radiolabelled ointment have shown that the systemic absorption of calcipotriol and betamethasone following the application of Dovobet ointment is less than 1% of the applied dose (2.5 g) on intact skin (625 cm2) for 12 hours. Application on psoriatic lesions and in occlusive bandaging conditions can increase the absorption of topical corticosteroids. Absorption through damaged skin is approximately 24%.

After systemic exposure, both active ingredients - calcipotriol and betamethasone dipropionate - are metabolised extensively and rapidly. The protein binding is approximately 64%. The plasma elimination half-life after intravenous administration is 5-6 hours. Due to the formation of a deposit in the skin, elimination after dermal application is on the order of days. Betamethasone is metabolised in particular in the liver, but also in the kidney, to glucuronide and sulphate esters. The main route of excretion of calcipotriol is fecal (rats and guinea pigs), while for betamethasone dipropionate the main route of excretion is urinary (rats and mice). In rats, tissue distribution studies with radiolabeled calcipotriol and betamethasone dipropionate showed that the highest levels of radioactivity were achieved in the kidney and liver, respectively.

In a study conducted on 34 patients with extensive psoriasis of the body and scalp, treated for a period of 4-8 weeks with concomitant applications of Dovobet gel and Dovobet ointment, the blood levels of calcipotriol and betamethasone dipropionate were maintained at below the quantifiable lower limits in all blood samples. In some patients it was possible to quantify a metabolite of calcipotriol and a metabolite of betamethasone dipropionate.

05.3 Preclinical safety data

Studies in animals have shown that corticosteroids can induce reproductive toxicity (cleft palate, skeletal malformations). In reproductive toxicity studies conducted in rats with long-term oral administration of corticosteroids, prolonged gestation time and prolonged and difficult labor were reported.In addition, a reduction in offspring survival, a reduction in body weight at birth and a greater difficulty in gaining weight later were observed. Impairment of fertility was not found. The relevance of these findings to humans is not. Note.

A dermal carcinogenicity study conducted with calcipotriol in mice and an oral carcinogenicity study with calcipotriol in rats revealed no special hazard for humans.

Photo (co) carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UV radiation to induce skin cancers.

A dermal carcinogenicity study conducted with betamethasone dipropionate in mice and an oral carcinogenicity study with betamethasone dipropionate in rats revealed no special hazard for humans. No photocarcinogenicity studies have been conducted with betamethasone dipropionate.