Dovobet gel: Indications, Dosage, Precautions, Adverse Effects
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Dovobet gel - Product Information

Manufacture: LEO Pharma
Country: Canada
Condition: Atopic Dermatitis, Dermatitis, Dermatological Disorders, Lichen Planus, Lichen Sclerosus, Plaque Psoriasis
Class: Topical steroids
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: monohydrate, betamethasone dipropionate, hydrogenated castor oil, paraffin liquid (contains α-tocopherol), and polyoxypropylene-11-stearyl ether (contains butylhydrox- ytoluene)

Summary product information

Route of
Administration
Dosage Form / Strength

Clinically Relevant Nonmedicinal
Ingredients
topicalGel; 50 mcg/g calcipotriol (as
monohydrate) and 0.5 mg/g
betamethasone (as dipropionate)
none
For a complete listing see Dosage
Forms, Composition and Packaging
section.

Indications and clinical use

DOVOBET gel (calcipotriol and betamethasone dipropionate gel) is indicated for the topical treatment of:

  • moderate to severe scalp psoriasis vulgaris in patients 18 years and older for up to 4 weeks.
  • mild to moderate plaque psoriasis vulgaris on the body in patients 18 years and older for up to 8 weeks

Contraindications

  • Known hypersensitivity to DOVOBET gel (calcipotriol and betamethasone dipropionate gel), to any ingredient in the formulation or to components of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • Ophthalmic use
  • Patients with known disorders of calcium metabolism.
  • Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers ,wounds, perianal and genital pruritus.
  • Guttate, erythrodermic, exfoliative and pustular psoriasis.
  • Patients with severe renal insufficiency or severe hepatic disorders.

Warnings and precautions

General

DOVOBET gel (calcipotriol and betamethasone dipropionate gel) should not be used on the face, axillae, flexures, groin, or genitals.

Hypercalcemia and hypercalciuria have been observed with the use of DOVOBET gel. Due to the content of calcipotriol, hypercalcemia may occur if the maximum daily dose (15 g) or maximum weekly dose (100 g) is exceeded. The body surface area treated should not exceed 30%. The effects of DOVOBET gel on calcium metabolism following treatment durations of more than 8 weeks have not been evaluated.

If hypercalemia or hypercalciuria develop, treatment should be discontinued until parameters of calcium metabolism have normalized. Serum calcium is quickly normalized when treatment is discontinued. The risk of hypercalcemia is minimal when the recommendations relevant to calcipotriol are followed (see Monitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION).

Carcinogenesis and Mutagenesis

Calcipotriol when used in combination with ultraviolet radiation (UVR) may enhance the known skin carcinogenic effect of UVR. This potential risk is based on the pre-clinical finding in mice of a reduced time to tumor formation from long term exposure of UVR and topically applied calcipotriol (see TOXICOLOGY, Carcinogenicity).

Patients who apply DOVOBET gel to exposed skin (e.g. a bald scalp) should avoid excessive exposure to both natural and artificial sunlight (e.g. phototherapy, tanning beds, sun lamps, etc.).

Endocrine and Metabolism

DOVOBET gel contains a potent World Health Organization (WHO) group III steroid and concurrent treatment with other corticosteroids must be avoided.

Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary- adrenal (HPA) axis suppression with the potential for clinical glucocorticoid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid.

In a study of 32 patients with both extensive scalp and extensive body psoriasis using a combination of high doses of DOVOBET gel (scalp application) and high doses of DOVOBET ointment1 (body application), 5 of 32 patients (15.6%) showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment. In another study of 43 patients with extensive scalp and body psoriasis treated with DOVOBET gel on the body and scalp, adrenal suppression was identified in 3 of 43 patients (7.0%) after 4 weeks of treatment and in 0 of 36 patients who provided data after 8 weeks of treatment (see ACTION AND CLINICAL PHARMACOLOGY and Part II: CLINICAL TRIALS, Special Studies).

Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent steroids, use over large surface areas, use over prolonged periods, use under occlusion, use on an altered skin barrier, and use in patients with liver failure. Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure. See also Special Populations, Pediatrics.

Application of topical corticosteroid products including DOVOBET on large areas of broken skin (i.e. open sores) or under occlusive dressings should therefore be avoided. The use of occlusion may increase penetration of the stratum corneum, increasing the risk of adverse events.Manifestations of Cushing's syndrome, effects on the metabolic control of diabetes mellitus (e.g. hyperglycaemia, glucosuria) and unmasking of latent diabetes mellitus can also be produced in some patients by systemic absorption of topical corticosteroids.

Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression (see Monitoring and Laboratory Tests).If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Ophthalmologic

DOVOBET gel is not for ophthalmic use. DOVOBET gel may cause eye irritation. Avoid contact with the eyes or conjunctiva (see Skin).

Skin

DOVOBET gel should not be used on the face, axillae, flexures, groin, or genitals. The patient must be instructed in the correct use of DOVOBET gel (e.g. washing their hands after each application) to avoid accidental transfer or application to these regions or to the mouth, mucous membranes or eyes (see DOSAGE AND ADMINISTRATON).

Facial skin is very sensitive to Vitamin D analogues and corticosteroids. Dermatitis has been observed with the use of DOVOBET gel. Uncommon local adverse reactions (such as eye irritation or irritation of facial skin), were observed when the drug was accidentally administered in the area of the face, or accidentally to the eyes or conjunctiva (see ADVERSE REACTIONS). Should facial dermatitis develop in spite of the precautions above, DOVOBET gel therapy should be discontinued.

Local adverse reactions may be more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse reactions may be irreversible. Treatment should be discontinued in the case of corticosteroid adverse effects related to the use of DOVOBET gel.

When treating psoriasis with topical corticosteroid containing products, including DOVOBET gel, it is recommended that treatment be interrupted periodically. There may be a risk of generalised pustular psoriasis or rebound psoriasis when discontinuing corticosteroids after prolonged periods of use. Medical supervision should therefore continue in the post-treatment period.

Concomitant skin infections should be treated with an appropriate antimicrobial agent. If the infection persists, DOVOBET gel should be discontinued until the infection has been adequately treated.

See also Carcinogenesis, Endocrine and Metabolism and, ADVERSE DRUG REACTIONS and Part II Clinical Pharmacology.

Special Populations

Pregnant Women

The safety of calcipotriol and/or topical corticosteroids for use during pregnancy has not been established. Pregnant women were excluded from the clinical studies conducted with DOVOBET gel. When given systemically, calcipotriol has been shown to be fetotoxic and betamethasone dipriopionate has been shown to be teratogenic in animals (see PART II, TOXICOLOGY, Reproduction and Mutagenicity). The use of DOVOBET gel is not recommended in pregnant women.

Nursing Women

The safety of calcipotriol and/or topical corticosteroids for use in nursing women has not been established. It is not known whether calcipotriol can be excreted in breast milk. Betamethasone passes into breast milk, but it is not known if topical application of corticosteroid containing products, including DOVOBET gel, can lead to sufficient systemic absorption to produce detectable quantities in breast milk. The use of DOVOBET gel is not recommended in nursing women.

Pediatrics (<18 years of age)

Since there is no clinical trial experience with the use of DOVOBET gel in children, use is not recommended. Children may demonstrate greater susceptibility to systemic corticosteroid related adverse effects due to a larger skin surface area to body weight ratio as compared to adults.

Geriatrics (≥ 65 years of age)

Of the 824 patients treated with DOVOBET gel for psoriasis on the body in controlled Phase II and III clinical studies, 124 were at least 65 years of age, and 36 were at least 75 years of age. Blood parathyroid hormone increased was reported more frequently in subjects 65 years and older. The clinical significance of this is not known. Of the 1,953 patients treated with DOVOBET gel for scalp psoriasis in the controlled clinical studies, 334 were 65 years or older, and 84 were 75 years or older. Overall the adverse event reporting rate for DOVOBET gel was comparable between subjects aged 65 years of age and over and those younger than 65.

Monitoring and Laboratory Tests

Treatment with DOVOBET gel in the recommended amounts (See DOSAGE AND ADMINISTRATION) does not generally result in changes in laboratory values. However, in patients at risk of hypercalcaemia it is recommended that baseline serum calcium levels be obtained before starting treatment with subsequent monitoring of serum calcium levels at suitable intervals. If serum calcium becomes elevated, DOVOBET gel administration should be discontinued and serum calcium levels should be measured once weekly until they return to normal.

An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, reduce the frequency of application, or substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA Axis function is generally prompt and complete upon discontinuation of topical corticosteroids (see Endocrine and Metabolism and, ACTION AND CLINICAL PHARMACOLOGY).

Adverse reactions

Overview

Studies on the Body

In a safety pool of randomized, multi-centre prospective vehicle- and/or active controlled clinical trials in subjects with plaque psoriasis on non-scalp areas, patients applied study product once daily for up to 8 weeks. A total of 824 patients were treated with DOVOBET gel (calcipotriol and betamethasone dipropionate gel) and the mean weekly dose was 29.0g (median 22.6g). Adverse drug reactions were adverse events that the investigators considered at least possibly related to study treatment. Approximately 6% of patients treated with DOVOBET gel experienced an adverse reaction. In this safety pool, the most common adverse reaction in the DOVOBET gel group was pruritus.

In the safety pool of controlled clinical trials, adverse reactions led to discontinuation of treatment with DOVOBET gel in 0.8% of patients. Patients discontinued treatment due to the following adverse reactions: application site pain, pain of skin, skin irritation, dermatitis contact, dry skin, pruritus and psoriasis.

Studies on the Scalp

The clinical trial programme for DOVOBET gel has included more than 1,900 patients with scalp psoriasis treated with DOVOBET gel. Approximately 8% of patients treated with DOVOBET gel experienced an adverse reaction. Based on data from clinical trials, the most common adverse reaction is pruritus.

Adverse reactions led to discontinuation of treatment with DOVOBET gel in 0.1-0.2% of patients. Patients discontinued treatment due to the following adverse reactions: pruritus, skin pain or irritation, dermatitis, eye irritation, rash, burning sensation, face oedema, folliculitis and dry skin.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Clinical Studies on the Body

One randomized, double-blind, vehicle-controlled, 8-week pivotal trial (n=1152) was conducted to evaluate the efficacy and safety of DOVOBET gel compared to betamethasone 0.5 mg/g (as dipropionate) in the gel vehicle, calcipotriol 50 mcg/g in the gel vehicle and the gel vehicle-alone administered once daily in subjects with mild to moderate psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs). Mild to moderate psoriasis vulgaris was determined by the Investigator‟s global assessment of disease severity (IGA).The mean baseline extent of psoriasis was similar among the four treatment groups (approximately 11-13% of body surface area). The mean amount of study medication used per week over the course of the study was similar among the DOVOBET gel, betamethasone gel and gel vehicle groups (approximately 28-32 g/week) and greatest in the calcipotriol group (approximately 37g/week).

Adverse drug reactions were adverse events that the investigators considered at least possibly related to study treatment. In the pivotal study, the incidence of withdrawal due to adverse reactions was highest in the calcipotriol gel group (5.2%) vs. 0.6% in the DOVOBET gel group, 0% in the betamethasone gel group and 0% in the vehicle group. Among patients treated with DOVOBET gel, the adverse drug reactions leading to withdrawal were: application site pain, psoriasis, and dermatitis contact. Signs of skin atrophy were assessed visually by the investigator. There were no reports in any treatment group that were related to skin atrophy, striae, telangiectasia, skin hypopigmentation or hypertrichosis.

Table 1 lists adverse drug reactions reported in at least 1% of subjects in any treatment group in the pivotal trial of DOVOBET gel on the body. Overall, adverse drug reactions were reported most frequently in the calcipotriol gel group (5.3%), followed by the DOVOBET gel group (5.0%), the vehicle group (4.2%) and the betamethasone gel group (3.1%).

Table 1. Adverse Drug Reactions Occurring in ≥ 1% of Patients for the Pivotal Body Study: safety analysis set
DOVOBET gel
(n=482)
Betamethasone gel
(n=479)
Calcipotriol gel
(n=96)
Gel
vehicle
(n=95)
Primary System Organ Class1
Preferred Term1
Number of
Patients
%Number of
Patients
%Number of
Patients
%Number of
Patients
%
Ear and labyrinth disorders
Vertigo00.000.000.011.1
General disorders and administration site disorders
Application site pain20.410.200.011.1
Infections and infestations
Candidiasis00.000.011.100.0
Investigations
Blood parathyroid hormone
increased
71.561.300.011.1
Skin and subcutaneous tissue disorders
Dermatitis contact10.200.011.100.0
Pruritus30.600.011.122.1
Psoriasis10.200.011.100.0
Rash papular10.200.000.011.1
Skin irritation00.010.211.100.0

Clinical Studies on the Scalp

Two pivotal and 4 supporting controlled clinical studies were conducted in scalp psoriasis. For the pivotal scalp studies, adverse drug reactions reported by at least 1% of patients in any treatment group are summarized in Table 2. Overall, the incidence of patients with at least one ADR was lowest in the DOVOBET gel group.

Table 2. Adverse Drug Reactions Occurring in ≥ 1% of Patients for the Pivotal Scalp Studies: safety analysis set
DOVOBET gel
(n=1093)
Betamethasone gel
(n=1104)
Calcipotriol gel
(n=548)
Gel
vehicle
(n=135)
Primary System Organ Class1
Preferred Term1
Number of
Patients
%Number of
Patients
%Number of
Patients
%Number of
Patients
%
Nervous system disorders
Headache60.5111.010.210.7
Burning sensation20.260.5101.800.0
Skin and subcutaneous tissue disorders
Pruritus252.3181.6458.275.2
Skin irritation50.550.5152.732.2
Alopecia40.460.530.521.5
Erythema40.440.4162.910.7
Dry skin10.130.361.100.0
General disorders and administration site conditions
Pain10.100.030.532.2

Less Common Clinical Trial Adverse Drug Reactions (<1%) for Studies on the Body

The following is a list of less common adverse reactions reported in the pivotal trial conducted in body psoriasis. Adverse reactions reported in <1% of patients treated with DOVOBET gel and not otherwise listed in Table 1 above, are included. Adverse reactions are listed by MedDRA SOC.


General Disorders and Administration Site Conditions: Application site pain, feeling of body temperature change.

Infections and Infestations: Cellulitis, folliculitis and sinusitis.

Investigations: Blood phosphorus decreased.

Nervous System Disorder: Dizziness

Skin and Subcutaneous Tissue Disorders: Dermatitis, guttate psoriasis, rash

Vascular Disorders: Flushing

Less Common Clinical Trial Adverse Drug Reactions (<1%) for Studies on the Scalp

From clinical trials conducted in scalp psoriasis, the uncommon adverse reactions are listed by MedDRA SOC from most to least frequent.


Eye Disorders: eye irritation.

Infections: otitis externa.

Investigations: elevated blood calcium.

Skin and Subcutaneous Tissue Disorders: burning sensation of the skin, skin pain or irritation, folliculitis, dermatitis, contact dermatitis, erythema, acne, dry skin, exacerbations of psoriasis, rash and pustular rash, and face oedema.


See also ACTION AND CLINICAL PHARMACOLOGY and Part II: CLINICAL TRIALS, Special Studies.

Other Adverse Drug Reactions

Adverse reactions observed for the individual drug substances calcipotriol and betamethasone dipropionate are described below.

Calcipotriol

Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, aggravated psoriasis, photosensitivity and hypersensitivity reactions. There have been infrequent reports of angioedema and facial oedema. Isolated cases of hypercalcaemia or hypercalciuria have been reported (see WARNINGS AND PRECAUTIONS).

Betamethasone dipropionate

Local reactions can occur after topical use especially during prolonged application including, skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis, there may be a risk of generalised pustular psoriasis.

Systemic effects due to topical use of corticosteroid containing products, including DOVOBET gel in adults occur infrequently but can be severe. Adrenocortical suppression, cataract, infections, impact on the metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur, especially after long-term treatment. Application of DOVOBET gel under occlusion or for prolonged treatment periods may result in an increased risk of systemic adverse events, and is therefore not recommended (see WARNINGS AND PRECAUTIONS).

Post-Market Adverse Drug Reactions

The following serious and unexpected adverse events not previously listed in the clinical trial adverse reactions section of the Product Monograph have been reported. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The list below includes reactions reported in patients using the gel and/or ointment formulations of DOVOBET.


Blood and lymphatic system disorders: lymphadenopathy

Ear and labyrinth disorders: auricular swelling

Eye disorders: glaucoma

General disorders and administration site conditions: drug ineffective, oedema peripheral

Infections and infestations: gastroenteritis, respiratory tract infection, staphylococcal infection, upper respiratory tract infection

Injury, poisoning and procedural complications: overdose

Nervous system disorders: migraine, tension headache

Psychiatric disorders: suicidal ideation

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: dyspnoea

Skin and subcutaneous tissue disorders: erythrodermic psoriasis, skin atrophy, skin exfoliation

Surgical and medical procedures: off label use

Vascular disorders: haematoma


Drug interactions

Drug-Drug Interactions

There is no experience of concomitant therapy with other antipsoriatic drugs. No drug interaction studies have been performed.

Drug-Lifestyle Interactions

Patients who apply DOVOBET gel to exposed skin (e.g. a bald scalp) should avoid excessive exposure to both natural and artificial sunlight (e.g. phototherapy, tanning beds, sun lamps, etc.). (See WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis).

Dosage and administration

Dosing Considerations

  • DOVOBET gel (calcipotriol and betamethasone dipropionate gel) is not recommended for use in children and adolescents below the age of 18 years.
  • DOVOBET gel is FOR TOPICAL USE ONLY and not for ophthalmic use.

Recommended Dose and Dosage Adjustment

DOVOBET gel should be applied to affected areas of the body once daily for up to 8 weeks and to affected areas of the scalp once daily for up to 4 weeks. After satisfactory improvement has occurred, the drug can be discontinued. If recurrence takes place after discontinuation, treatment may be reinstituted.

The maximum daily dose including other calcipotriol-containing products on the body should not exceed 15 g and the maximum weekly dose should not exceed 100 g. The total body surface area treated, including scalp and body should not exceed 30%.

When using the Applicator

After priming, each full actuation delivers 0.05 g of DOVOBET gel.

Missed Dose

If a dose is missed, the patient should apply DOVOBET gel when he/she remembers, but only once on a given day and then continue on as usual.

Administration

Application under occlusive dressings should be avoided since it increases systemic absorption of corticosteroids.

DOVOBET gel should not be applied directly to the face or eyes (see WARNINGS AND PRECAUTIONS, Ophthalmologic, Skin).

When using the Bottle

The bottle should be shaken before each use and DOVOBET gel applied to the affected area. The hands should be washed after use.

When using the Applicator

Prior to the first use of the applicator the cartridge and the applicator head must be assembled (see Part III, Consumer Information). After assembly, the applicator needs to be primed before initial use. DOVOBET gel is applied to the affected area by using the applicator. The hands should be washed after use if DOVOBET gel gets on the fingers.

In order to achieve optimal effect, it is not recommended to take a shower or bath, or to wash the hair in case of scalp application, immediately after application of DOVOBET gel. DOVOBET gel should remain on the skin during the night or during the day. Patients should be advised that DOVOBET gel should not be applied to the scalp 12 hours before or after colouring, perming or any chemical hair treatments.

Overdosage

Use of DOVOBET gel (calcipotriol and betamethasone dipropionate gel) above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued. In such cases, it is recommended to monitor serum calcium levels once weekly until they return to normal. Excessive prolonged use of topical corticosteroid containing products, including DOVOBET gel, may suppress the pituitary-adrenal functions, resulting in secondary adrenal insufficiency which is usually reversible. If this occurs, symptomatic treatment is indicated. In cases of chronic toxicity, treatment with DOVOBET gel must be discontinued gradually. It has been reported that due to misuse one patient treated with 240 g of DOVOBET ointment (50 mcg/g calcipotriol and 0.5 mg/g betamethasone, as dipropionate) weekly (corresponding to a daily dose of approximately 34 g) for 5 months(maximum recommended dose 15 g daily) developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

DOVOBET gel is a combination of the vitamin D analogue calcipotriol and the corticosteroid betamethasone dipropionate.

Calcipotriol is a non-steroidal antipsoriatic agent, derived from the naturally occurring vitamin D. Calcipotriol exhibits a vitamin D-like effect by competing for the 1,25(OH)2D3 receptor. Calcipotriol is as potent as 1,25(OH)2D3, the naturally occurring active form of vitamin D, in regulating cell proliferation and cell differentiation, but much less active than 1,25(OH)2D3 in its effect on calcium metabolism. Calcipotriol induces differentiation and suppresses proliferation of keratinocytes (without any evidence of a cytotoxic effect), thus reversing the abnormal keratinocyte changes in psoriasis. The therapeutic goal envisaged with calcipotriol is thus a normalization of epidermal growth.

Topical corticosteroids such as betamethasone dipropionate have anti-inflammatory, anti- pruritic, vasoconstrictive and immunosuppressive properties. In general, the mechanism of the anti-inflammatory activity of topical corticosteroids is unclear. Corticosteriods are thought to induce phospholipase A2 inhibitor proteins, preventing arachidonic acid release and the biosynthesis of potent mediators of inflammation.

Pharmacodynamics

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined DOVOBET gel (on the scalp) and DOVOBET ointment (on the body) (study A). A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients.

In addition, HPA axis suppression was evaluated in adult patients (n=43) with extensive psoriasis involving 15-30% of the body surface area (including the scalp) (study B). Treatment consisted of once daily application of DOVOBET gel on the body and the scalp for up to 8 weeks. Adrenal suppression, as indicated by a 30-minute post-stimulation cortisol level ≤ 18 mcg/dL, was observed in 3 of 43 patients (7%) after 4 weeks of treatment and in 0 of the 36 patients who provided data after 8 weeks treatment.

A study was conducted to evaluate the atrophogenic potential of betamethasone dipropionate in DOVOBET gel compared with marketed betamethasone dipropionate ointment and gel vehicle. The study was conducted as an intra-individual comparison of once daily application for 4 weeks in 48 healthy volunteers. Skin thickness was measured by sonography performed before treatment, weekly during the 4-week treatment period and 2 weeks after the end of treatment. DOVOBET gel induced reversible skin thinning, which was similar to that induced by betamethasone dipropionate ointment.

Pharmacokinetics

Absorption

The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied DOVOBET gel is comparable to DOVOBET ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone dipropionate from the DOVOBET ointment formulation is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm2) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids.

Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients with extensive psoriasis involving the scalp and body and treated for 4 or 8 weeks with DOVOBET gel on the scalp and DOVOBET ointment on the body. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients. While the biological activity of the calcipotriol metabolite is less than that of calcipotriol, the activity of the betamethasone dipropionate metabolite cannot be distinguished from the activity of the parent compound.

The serum levels of calcipotriol and betamethasone dipropionate and their major metabolites were measured after 4 weeks of once daily application of DOVOBET gel to 15-30% of the body surface area (body and scalp areas). Calcipotriol and its major metabolite were below the lower limit of quantification in all serum samples and betamethasone dipropionate was quantifiable in 1 of the samples in 5 of 43 (11.6%) patients. The primary metabolite of betamethasone dipropionate was quantifiable in 16 of 43 (37.2%) patients.

Metabolism

Calcipotriol metabolism following systemic uptake is rapid and occurs in the liver.Calcipotriol is metabolized to MC1046 (the α,β-unsaturated ketone analog of calcipotriol), which is metabolized further to MC1080 (a saturated ketone analog). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.

Betamethasone dipropionate is metabolized to betamethasone 17-propionate and betamethasone, including the 6β-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17- propionate (B17P) is the primary metabolite.

Storage and stability

Store at 15oC - 30oC. Do not refrigerate. Keep out of reach of children and pets.

Bottle: Shake before use. Protect from light, keep the bottle in the outer carton. Use within 6 months of first opening the bottle.

Applicator: Prime applicator before first use. Use within 6 months of assembly and before the expiry date.

Dosage forms, composition and packaging

Dosage Form

Gel: almost clear, colourless to slightly off-white lipophilic gel.

Composition

Applicator: The applicator dispenses 2.5 mcg calcipotriol (as monohydrate) and 0.025 mg betamethasone (as diproprionate) in 0.05 g of DOVOBET gel per full actuation after priming.

Non-medicinal ingredients: Hydrogenated castor oil, liquid paraffin (contains α-tocopherol) and polyoxypropylene-11-stearyl ether (contains butylhydroxytoluene).

Packaging

Bottle: Available in 60 g, and 2 x 60 g polyethylene bottles.

Applicator: Available in 60 g (equivalent to 68 mL) polypropylene cartridges (with a high- density polyethylene plunger and screw cap). The carton contains a cartridge, applicator head and cover. The cartridge, applicator head and cover are assembled prior to use.