Dovobet Oint: Indications, Dosage, Precautions, Adverse Effects
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Dovobet Oint - 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: calcipotriol, betamethasone dipropionate, white soft paraffin, liquid paraffin, polyoxypropylene-11-stearyl ether (contains butylhydroxytoluene), alpha-tocopherol.

calcipotriol and betamethasone dipropionate

Summary Product Information

Route of
Administration
Dosage Form / Strength Clinically Relevant Nonmedicinal
Ingredients
topical Ointment,
50 mcg/g calcipotriol 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 (calcipotriol and betamethasone dipropionate) ointment is indicated for the topical treatment of psoriasis vulgaris for up to 4 weeks.

DOVOBET should not be used on the face.

Contraindications

  • Patients who are hypersensitive to DOVOBET (calcipotriol and betamethasone dipropionate), to any ingredient in the formulation or to components of the tube. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • Ophthalmic use.
  • Treatment of viral, fungal or bacterial skin infections, tuberculosis of the skin, syphilitic skin infections, chicken pox, eruptions following vaccinations, and in viral diseases such as herpes simplex, varicella and vaccinia.

Warnings and Precautions

General

If DOVOBET (calcipotriol and betamethasone dipropionate) is used in excess of the maximum recommended weekly amount of 100 g, it is important to monitor the serum calcium levels at regular intervals due to the risk of hypercalcemia secondary to excessive absorption of calcipotriol. If the serum calcium level becomes elevated, therapy should be discontinued and the serum calcium level monitored until it returns to normal.

Carcinogenesis

Calcipotriol when used in combination with ultraviolet radiation (UVR) may enhance the known skin carcinogenic effect of UVR (see TOXICOLOGY, Carcinogenicity).

Endocrine and Metabolism

Application on large areas of damaged skin, under occlusive dressings, or in skin folds should be avoided since it increases systemic absorption of corticosteroids and the risk of adverse effects such as adrenal suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing‟s syndrome, hyperglycaemia and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids. Occlusive dressings should not be applied if body temperature is elevated.

All of the adverse effects associated with systemic use of corticosteroids, including adrenal suppression, may also occur following topical administration of corticosteroid containing products such as DOVOBET, especially in children.

Skin

DOVOBET should not be used on the face since this may give rise to itching and erythema of the facial skin. Patients should be instructed to wash their hands after each application of DOVOBET in order to avoid inadvertent transfer to the face. Should facial dermatitis develop in spite of these precautions, DOVOBET therapy should be discontinued.

Prolonged use of corticosteroid-containing preparations may produce striae or atrophy of the skin or subcutaneous tissues. Therefore, it is recommended that corticosteroid treatment be interrupted periodically, and that one area of the body be treated at a time. Topical corticosteroids should be used with caution on lesions of the face, groin and axillae as these areas are more prone to atrophic changes than other areas of the body. If skin atrophy occurs, discontinue treatment. There may be a risk of rebound psoriasis when discontinuing corticosteroids after prolonged periods of use (see ADVERSE REACTIONS).

Special Populations

Pregnant Women

The safety of calcipotriol and/or topical corticosteroids for use during pregnancy has not been established. Although studies in experimental animals have not shown teratogenic effects with calcipotriol, studies with corticosteroids have shown teratogenic effects. The use of DOVOBET 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 or if topical application of corticosteroids can lead to sufficient systemic absorption to produce detectable quantities in breast milk. The use of DOVOBET is not recommended in nursing women.

Pediatrics (<18 years of age)

There is no clinical trial experience with the use of DOVOBET in children. Children may demonstrate greater susceptibility to systemic steroid related adverse effects due to a larger skin surface area to body weight ratio as compared to adults.

Monitoring and Laboratory Tests

Treatment with DOVOBET in the recommended amounts (See DOSAGE AND ADMINISTRATION) does not generally result in changes in laboratory values. However, in patients at risk for 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 administration should be discontinued and serum calcium levels should be measured once weekly until they return to normal. Patients with marginally elevated serum calcium may be treated with DOVOBET, provided that serum calcium is monitored at suitable intervals.

Adverse Reactions

In clinical trials, the most common adverse reaction associated with DOVOBET (calcipotriol and betamethasone dipropionate) was pruritus. Pruritus was usually mild and no patients were withdrawn from treatment.

Calcipotriol is associated with local reactions such as transient lesional and perilesional irritation. Rare cases of hypersensitivity reaction have been reported. Hypercalcemia can develop but is usually related to excessive administration (i.e. greater than the recommended weekly amount of 100 g ointment or 5 mg calcipotriol - See DOSAGE AND ADMINISTRATION).

Topical corticosteroids can cause the same spectrum of adverse effects associated with systemic steroid administration, including adrenal suppression. Adverse effects associated with topical corticosteroids are generally local and include dryness, itching, burning, local irritation, striae, atrophy of the skin or subcutaneous tissues, telangiectasia, hypertrichosis, folliculitis, skin hypopigmentation, allergic contact dermatitis, maceration of the skin, miliaria, or secondary infection. If applied to the face, acne rosacea or perioral dermatitis can occur. In addition, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical corticosteroid products.

In a randomized, double-blind, parallel group, safety study of psoriasis patients with at least moderate disease severity, DOVOBET ointment was used intermittently on an 'as needed' basis under medical supervision (N=207). Patients were followed for up to 52 weeks. The median amount of study drug used was 15.4 g/week. The effects of DOVOBET ointment on calcium metabolism were not studied and the effects on adrenal suppression were not adequately studied. The following adverse drug reactions were reported in 1% or more of patients: pruritus (5.8%), psoriasis (5.3%), skin atrophy (based on a dermatologist‟s visual assessment) (1.9%), folliculitis (1.9%), burning sensation (1.4%), skin depigmentation (1.4%), and erythema (1.0%). One case of serious flare-up of psoriasis was reported.

Drug Interactions

There is no experience of concomitant therapy with other antipsoriatic drugs.

Dosage and Administration

Dosing Considerations

  • DOVOBET (calcipotriol and betamethasone dipropionate) is FOR TOPICAL USE ONLY and not for ophthalmic use.
  • There is no clinical trial experience with the use of DOVOBET in children.

Recommended Dose and Dosage Adjustment

DOVOBET should be applied topically to the affected areas 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 recommended adult dose of DOVOBET ointment is 100 g per week.

Missed Dose

If a dose is missed, the patient should apply DOVOBET as soon as he/she remembers and then continue on as usual.

Overdosage

Due to the calcipotriol component of DOVOBET (calcipotriol and betamethasone dipropionate), excessive administration (i.e. more than the recommended weekly amount of 100 g) may cause elevated serum calcium, which rapidly subsides when treatment is discontinued. In such cases, it is recommended to monitor serum calcium levels once weekly until they return to normal.

Excessive or prolonged use of topical corticosteroids can suppress pituitary-adrenal function, resulting in secondary adrenal insufficiency and manifestations of hypercorticoidism, including Cushing's disease. Recovery is usually prompt and complete upon steroid discontinuation. In cases of chronic toxicity, slow withdrawal of corticosteroids is recommended.

Action and Clinical Pharmacology

Mechanism of Action

DOVOBET 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, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity is generally unclear. However, corticosteroids are thought to induce phospholipase A2 inhibitor proteins, preventing arachidonic acid release and the biosynthesis of potent mediators of inflammation.

Clinical Pharmacology

A large multicentre, randomized, double-blind clinical trial has shown DOVOBET ointment (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate)) administered twice daily to be more efficacious and to provide faster onset of action than either of the individual components alone (calcipotriol or betamethasone dipropionate) for the treatment of plaque psoriasis. These findings were supported by a second large, multicentre, randomised, double-blind trial comparing DOVOBET twice daily to calcipotriol and betamethasone dipropionate, each in their currently marketed formulations. A third large, multicentre, randomised, double-blind trial found DOVOBET once daily to be more efficacious than vehicle alone and calcipotriol twice daily (betamethasone alone was not evaluated). It was also demonstrated that once daily DOVOBET was similar to twice daily DOVOBET for most of the efficacy measures. In all three studies, DOVOBET was effective in terms of reducing PASI (Psoriasis Area and Severity Index) score and thickness of target lesions. Furthermore, a significant proportion of patients on DOVOBET achieved marked improvement or clearance at the end of 4 weeks of treatment. Clinical improvement occurred rapidly and a significant improvement was evident within 1 week of treatment. DOVOBET was well tolerated with the most common adverse reaction being mild pruritus. In one additional study, patients were treated with DOVOBET once daily for 8 weeks. Optimal population results in this study were seen between 4 and 5 weeks of treatment. The therapeutic goal envisioned with DOVOBET is to provide an effective, rapid acting topical agent for initial treatment of psoriasis and/or for treatment of flare-ups of psoriasis.

Pharmacokinetics

A pharmacokinetic study of calcipotriol ointment demonstrated that the apparent systemic absorption over 12 hours is approximately 5.5% of the dose in normal subjects and in psoriatic patients. Topical application of corticosteroids to normal skin results in minimal absorption. Only small amounts of drug reach the dermis and are then absorbed into the systemic circulation. However, absorption may be greater when corticosteroids are applied to certain areas of the body (such as the axilla and scrotum) or if the epidermis is damaged by disease or inflammation. Continued absorption of corticosteroids may occur, even after washing, due to retention of the drug in the stratum corneum. The individual pharmacokinetics of calcipotriol and betamethasone dipropionate, are not affected by their combined presence in DOVOBET ointment. Under normal conditions of use, systemic absorption of calcipotriol and/or betamethasone from DOVOBET is not expected to have any effects.

Storage and Stability

Store at 5 to 25°C. Use within 12 months of first opening the tube.

For easy application do not refrigerate, this is to prevent pulling of delicate skin.

Dosage Forms, Composition and Packaging

Dosage Form

Ointment (faintly translucent white to yellowish ointment)

Composition

50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate)

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

Packaging

Available in 30 g, 60 g, and 120 g lacquered aluminium tubes (equipped with an aluminium membrane).