Consumer medicine information

Daivobet 50/500 Ointment

Calcipotriol; Betamethasone dipropionate

BRAND INFORMATION

Brand name

Daivobet 50/500 Ointment

Active ingredient

Calcipotriol; Betamethasone dipropionate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Daivobet 50/500 Ointment.

What is in this leaflet?

This leaflet answers some common questions about using the medicine Daivobet® ointment. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Daivobet® ointment against the benefits it is expected to have for you.

If you have any concerns about using Daivobet® ointment, talk to your doctor or pharmacist.

What Daivobet® ointment is used for

Daivobet® ointment is an anti-psoriasis medicine. Daivobet® ointment contains two active ingredients:

  • calcipotriol [as monohydrate] (related to Vitamin D)
  • betamethasone dipropionate (a corticosteroid).

Daivobet® ointment is used only on skin affected by plaque-type psoriasis. Psoriasis is a skin disorder in which skin cells are overactive. The calcipotriol in Daivobet® ointment treats the overactive skin cells. The betamethasone dipropionate relieves redness, swelling, itching and irritation of the skin.

Daivobet® ointment is used in the type of psoriasis, where “plaques” form in the skin. Plaques are raised, rough, reddened areas covered with fine, dry silvery scales. Plaques are usually about one to two centimetres across.

Daivobet® ointment is available only with a doctor’s prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

This medicine is not addictive.

Before you use Daivobet® ointment

When you must not use Daivobet® ointment

Do not use Daivobet® ointment if you have an allergy to:

  • calcipotriol
  • betamethasone dipropionate
  • any of the other ingredients listed at the end of this leaflet (see Product description)
  • any other similar medicine, such as topical corticosteroids.

Some of the symptoms of an allergic reaction include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or “hives” on the skin.

Do not use Daivobet® ointment for severe widespread psoriasis, or the types of psoriasis known as generalised pustular, erythrodermic or exfoliative psoriasis. Your doctor will identify these conditions for you.

Do not use Daivobet® ointment if you

  • have high blood calcium levels (ask your doctor)
  • are taking calcium supplements, drugs to treat calcium deficiency, vitamin D supplements or vitamin D-like medicines, for example, calcitriol
  • have kidney or liver problems
  • have any viral, fungal or bacterial skin infections
  • tuberculosis (TB) or syphilis
  • perioral dermatitis (red rash around the mouth)
  • thin skin, easily damaged skin, stretch marks
  • ichthyosis (dry skin with fish like scales)
  • acne
  • rosacea
  • ulcers or broken skin.

Inform your doctor if you are suffering from any illness before using Daivobet® ointment.

Do not use Daivobet® ointment

  • after the expiry date printed on the pack OR
  • if it is 12 months after the tube was first opened OR
  • if the packaging is torn, doesn’t look quite right or shows signs of tampering.

If any of these apply, return Daivobet® ointment to your pharmacist for disposal.

Do not breastfeed if you are using Daivobet® ointment on your breasts.

If you are not sure whether you should start using Daivobet® ointment, talk to your doctor.

Before you start to use it

Tell your doctor if you have a known allergy to Daivobet® ointment, calcipotriol, betamethasone dipropionate or any of the ingredients listed at the end of this leaflet.

Tell your doctor if you

  • are pregnant
  • are breastfeeding
  • intend to breastfeed.

Do not use Daivobet® ointment in children. Safety and effectiveness of Daivobet® ointment in those below 18 years of age has not been established.

If you have not told your doctor about any of the above, tell him/her before you start using this medicine.

Other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you are taking calcium supplements, drugs to treat calcium deficiency, vitamin D supplements or vitamin D-like medicines, for example calcitriol. Do not use Daivobet® ointment if you are taking these.

Your doctor and pharmacist have more information on medicines you should be careful with or avoid whilst using Daivobet® ointment.

How to use Daivobet® ointment

Follow carefully all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much Daivobet® ointment to use

Apply enough ointment to completely cover the psoriasis plaques.

One fingertip unit (FTU) is enough to cover an area of skin twice the size of your palm. For example, if the area to be treated is 2 elbows and 2 knees, you may require up to 4 FTU’s of ointment.

One fingertip unit (FTU) is the amount of ointment, squeezed out of a tube, from the tip of an adult’s index finger to the first crease in the finger.

The area treated should not be more than 30% of the body surface area (BSA). (Note: this is approximately the area on one whole leg and one whole arm.) Discuss this with your doctor.

Do not use more than 15 g in one day.

For example, no more than half (½) of a 30 g tube in one day.

Do not use more than 100 g in one week.

For example, no more than 3 tubes of 30 g in one week.

If you also use other calcipotriol containing products (e.g. Daivobet® gel, Daivonex®) on your body psoriasis, then the total amount of calcipotriol products must not exceed 15 g per day or 100 g per week and the total area treated should not exceed 30% of the total body surface.

NOTE: If you use more than the recommended amount of Daivobet® ointment, the levels of calcium in your blood may rise. This is known as “hypercalcaemia”.

Hypercalcaemia:

  • is measured by a blood test
  • may be harmful
  • may mean that Daivobet® ointment or any other product containing calcipotriol (e.g., Daivonex®) should not be used until the calcium level has become normal again.

Blood calcium levels will quickly normalise when your doctor discontinues treatment.

How to use Daivobet® ointment

NOTE: unlike certain other skin preparations, which you use very sparingly, use Daivobet® ointment as follows:

Apply Daivobet® ointment only to the psoriasis plaques in a thin layer and gently rub in. If you accidentally put some of the ointment on normal skin, wash it off as soon as possible.

Do not use Daivobet® ointment

  • on large areas of damaged skin
  • in skin folds (e.g. groin, underarm)
  • on the genitalia
  • on the scalp
  • inside the mouth, nose or in the eyes
  • on the face (an itchy red rash may develop)
  • under occlusive dressings (such as a bandage).

The treated area does not need to have a special covering. You may wear your usual clothes.

Wash your hands thoroughly after applying Daivobet® ointment on any part of your body, unless your hands are being treated.

Thoroughly wash your hands prior to handling infants or children.

Take care not to get Daivobet® ointment in your eyes. If this happens, rinse your eyes with clean water and tell your doctor.

Avoid getting Daivobet® ointment on your face, scalp, mouth or eyes accidentally (see above).

If any skin irritation develops, wash off the Daivobet® ointment.

When to use Daivobet® ointment

Apply Daivobet® ointment once a day (either morning or night), unless otherwise directed by your doctor.

How long to use it

Continue to use Daivobet® ointment for as long as your doctor tells you.

Each treatment course would normally last for up to four weeks.

Your doctor may decide to stop Daivobet® ointment treatment once your psoriasis has improved, and to recommence it as needed.

If you forget to use it

If you forget to use Daivobet® ointment, use it as soon as you remember. Then go on as before.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your doctor or pharmacist for some hints.

If you use too much or use it other than directed (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia or 0800 764 766 in New Zealand) for advice, or go to the Emergency Department at the nearest hospital, if you think that you or anyone else may have used too much or swallowed some of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Daivobet® ointment

Things you must do

While you are using Daivobet® ointment, protect the treated skin areas from sunlight and Ultra Violet (UV) rays, for example, by wearing protective clothing. This is particularly important if your job or lifestyle means you spend time out-of-doors.

If you are going to start any new medicine, tell your doctor and pharmacist that you are using Daivobet® ointment.

If you become pregnant while using Daivobet® ointment, tell your doctor immediately.

Keep all appointments with your doctor so that your progress can be checked.

Your doctor may do blood tests whilst you are using Daivobet® ointment (or any other product containing calcipotriol, for example, Daivobet® gel, Daivonex®). These tests check the levels of calcium in your blood and how well your kidneys are working (“renal function”).

Things you must not do

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not use more than the recommended daily or weekly dose (see How to use Daivobet® ointment).

Do not use other topical corticosteroids (e.g. Advantan®, Diprosone®, Elocon®) on areas treated with Daivobet® ointment.

Side effects

As with all medicines, Daivobet® ointment can cause some side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist:

  • if you have any unpleasant effects while you are using Daivobet® ointment

or

  • if you notice any of the following and they worry you:
    - skin irritation
    - skin peeling
    - itching
    - skin burning sensation
    - skin shrinkage or wasting
    - a rash on your face or body
    - skin reddening or swelling
    - worsening of psoriasis
    - infected hair roots
    - bruising of skin
    - skin pain
    - a change in the colour of your skin
    - your skin is more sensitive to light
    - change in control of diabetes mellitus.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using Daivobet® ointment

Keep Daivobet® ointment in the box until required.

Storage

Keep your Daivobet® ointment in a cool dry place where the temperature stays below 25°C. However, do not keep Daivobet® ointment in the refrigerator, as the ointment will not spread easily.

Do not store Daivobet® ointment or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep Daivobet® ointment where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Ask your pharmacist what to do with any Daivobet® ointment that is left over if:

  • your doctor tells you to stop using Daivobet® ointment or
  • the tube has been opened for more than 12 months or
  • the expiry date has passed.

Product description

What it looks like

Daivobet® ointment is an off-white to yellowish ointment.

Ingredients

Daivobet® ointment contains the active ingredients

  • calcipotriol [as monohydrate] (50 microgram/g)
  • betamethasone dipropionate (500 microgram/g).

It also contains

  • liquid paraffin
  • polyoxypropylene-11 stearyl ether
  • dl-alpha-tocopherol
  • white soft paraffin
  • butylated hydroxytoluene (E321).

This is not all the information available on Daivobet® ointment. If you have any more questions or are unsure about anything, ask your doctor or pharmacist.

Supplier

Daivobet® ointment is supplied in Australia by:

LEO Pharma Pty Ltd,
Brisbane, QLD, Australia
Australian Toll Free No: 1800 991 778

Daivobet® ointment is supplied in New Zealand by:

LEO Pharma Ltd
Auckland New Zealand
New Zealand Toll Free No: 0800 497 456

Daivobet® ointment is manufactured in Ireland.

Daivobet, LEO and LEO/lion device are registered trademarks of LEO Pharma A/S, Denmark.

This leaflet was revised in November 2019.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Daivobet 50/500 Ointment

Active ingredient

Calcipotriol; Betamethasone dipropionate

Schedule

S4

 

1 Name of Medicine

Calcipotriol monohydrate.
Betamethasone dipropionate.

2 Qualitative and Quantitative Composition

One gram of Daivobet ointment contains 50 microgram of calcipotriol (as monohydrate) and 500 microgram of betamethasone (as dipropionate).
Excipients with known effect: butylated hydroxytoluene.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ointment.
Off-white to yellow.

4 Clinical Particulars

4.1 Therapeutic Indications

Daivobet ointment is indicated for the once daily topical treatment of plaque-type psoriasis vulgaris amenable to topical therapy.

4.2 Dose and Method of Administration

Daivobet ointment is indicated for topical use only. Daivobet ointment is not for ophthalmic use. Do not use if the pack shows signs of damage or tampering.
The phototoxic effects of Daivobet ointment have not been studied in psoriasis patients. All psoriasis affected areas treated with Daivobet ointment should be, where possible, protected from direct sunlight and UV-light with items of clothing.

Adults.

Daivobet ointment should be applied topically to the affected area once daily. The maximum daily dose should not exceed 15 grams. If using other topical products containing calcipotriol in addition to Daivobet ointment, the total dose of all calcipotriol containing products should not exceed 15 g per day.
The maximum recommended weekly dose of Daivobet ointment is 100 grams/week.
The treated area should not be more than 30% of the body surface.
The use of Daivobet 50/500 ointment should be intermittent for up to one year under close medical supervision. Treatment should be limited to four week periods with calcipotriol used alone for one month between periods of use of Daivobet 50/500 ointment as needed.

Children.

Daivobet ointment is not recommended for use in children and adolescents below the age of 18 years.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed, see Section 6.1 List of Excipients.
Patients with known disorders of calcium metabolism (see Section 4.4 Special Warnings and Precautions for Use).
Due to the corticosteroid content: viral lesions of the skin (e.g. herpes or varicella), fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne rosacea, rosacea, ulceration, wounds, perianal and genital pruritus.
Erythrodermic, exfoliative and pustular psoriasis.
Patients with severe renal insufficiency or severe hepatic disorders.

4.4 Special Warnings and Precautions for Use

For external use only.

Effects on endocrine system.

Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus, may occur also during topical corticosteroid treatment due to its systemic absorption.
Application of Daivobet ointment to large areas of damaged skin, under occlusive dressings, to mucous membranes, or in skin folds should be avoided as these conditions increase the systemic absorption of both corticosteroids and calcipotriol. Elevated systemic absorption of calcipotriol could result in hypercalcaemia in some patients.

Effects on calcium metabolism.

In view of the risk of hypercalcaemia secondary to excessive absorption of calcipotriol when there is extensive skin involvement, Daivobet ointment should not be used on more than 30% of the body surface area.
The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are observed. In adults, the maximum daily dose of 15 g or the maximum weekly dose of 100 g ointment should not be exceeded.
Treatment with Daivobet ointment in adults in the recommended amounts up to 100 g per week does not generally result in changes in laboratory values.
Serum calcium and renal function should be monitored at 3 monthly intervals during periods of usage of topical calcipotriol, including that in Daivobet ointment. If the serum calcium level is elevated, treatment with Daivobet ointment should be discontinued and the condition should be treated appropriately. The levels of serum calcium should be measured once weekly until the serum calcium levels return to normal values.

Local adverse reactions.

As Daivobet ointment contains a potent corticosteroid (classified as WHO group III steroid), concurrent treatment with other steroids on the same treatment area should be avoided.
Skin of the face and genitals are very sensitive to corticosteroids. Daivobet ointment should not be used in these areas. Daivobet ointment is not recommended for use on the face since it may give rise to itching and erythema of the facial skin.
The patient must be instructed on correct use of the product to avoid application and/or accidental transfer to the scalp, face, mouth or eyes. Treatment of more than 30% of the body surface should be avoided. Patients should be instructed to wash their hands after using Daivobet ointment, to avoid inadvertent transfer of ointment to the face from other body areas.

Concomitant skin infections.

If lesions become secondarily infected, they should be treated with antimicrobial therapy. However, if infection worsens, treatment with topical corticosteroids should be stopped.

Discontinuation of treatment.

When treating psoriasis vulgaris with topical corticosteroids there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.

Long-term use.

The recommended treatment period of Daivobet ointment is 4 weeks under medical supervision, for up to 52 weeks. There is clinical trial experience with intermittent 4 weekly cycles of Daivobet ointment and calcipotriol alone used between treatment cycles (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions. Excessive prolonged use of topical corticosteroids may suppress the hypothalamic pituitary adrenal axis (HPA). The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroids (see Section 4.8 Adverse Effects (Undesirable Effects)).

Unevaluated use.

There is no experience of the use of Daivobet ointment on the scalp or in guttate psoriasis.

Concurrent treatment and UV exposure.

The stability of calcipotriol in sunlight and UV light has not been demonstrated. No clinical trials have been conducted with calcipotriol-containing products in Australia, where there is a particularly high potential to be exposed to high levels of UV radiation. In addition, the phototoxic effects of Daivobet ointment have not been studied in psoriasis patients.
Treated skin areas should be protected from sunlight and UV light (using physical covering and/or sunscreens), particularly where exposure may be considerable for reasons such as occupation. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks.

Adverse reactions to excipients.

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

Use in hepatic impairment.

Safety has not been established in patients with hepatic impairment.

Use in renal impairment.

Safety has not been established in patients with renal impairment.

Use in the elderly.

Clinical experience has not identified any differences in response in elderly patients (65 years and older). However, greater sensitivity of some elderly individuals cannot be ruled out.

Paediatric use.

Daivobet ointment is not recommended for use in children and adolescents below 18 years of age as the safety and effectiveness of Daivobet ointment in this population has not been established.

Effects on laboratory tests.

See Section 5.1 Pharmacodynamic Properties for information on effect on cortisol serum levels.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There is no experience with concurrent use of Daivobet ointment and other anti-psoriatic products applied locally or systemically or with phototherapy.
Daivobet ointment should not be used concurrently with calcium or vitamin D supplements, or with drugs that enhance the systemic availability of calcium.
No interaction studies have been performed with Daivobet ointment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Possible effects of betamethasone in combination with calcipotriol on fertility have not been investigated in animals. Studies of the oral administration of calcipotriol in rats have shown no impairment of male and female fertility.
(Category B3)
There are no adequate data from the use of Daivobet ointment in pregnant women. Daivobet ointment should only be used during pregnancy when the potential benefit clearly outweighs the potential risk.
Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). When pregnant rats were treated orally daily with betamethasone dipropionate from early gestation and throughout lactation period, prolonged gestation (at ≥ 0.3 mg/kg/day), reduced offspring survival (at ≥ 0.1 mg/kg/day) and lower offspring weights (at 1 mg/kg/day) were observed.
Studies of calcipotriol in animals have shown an increase in the incidence of skeletal variations in rats (wavy ribs, extra ribs, incomplete development of skull bones) at oral doses of 36 microgram/kg/day. The relevance of these findings for humans is unknown.
 Betamethasone is excreted into breast milk. It is unknown if topical application of Daivobet ointment could result in sufficient systemic absorption to produce significant quantities of this corticosteroid in human breast milk. There are no data on the excretion of calcipotriol in breast milk.
Caution should be exercised when prescribing Daivobet ointment to breastfeeding women. Application of Daivobet ointment to the breast area should be avoided. Daivobet ointment should only be used during lactation if the potential benefits clearly outweigh the potential risks.

Note.

In order to avoid possible direct ingestion by infants, Daivobet ointment should not be applied to the chest area of breastfeeding women. After applying Daivobet ointment to their skin, mothers should wash their hands thoroughly prior to handling their infant child.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Adverse events reported in more than 1% of subjects enrolled in early clinical trials with Daivobet ointment (in total 912 patients exposed to twice daily applications and 1,286 patients exposed to once daily applications) are listed in Table 1.
A safety study in 634 patients with at least moderate psoriasis has investigated repeated courses of Daivobet ointment used once daily as required, either alone or alternating on a four week basis with Daivonex ointment, for up to 52 weeks, compared with Daivonex ointment used alone for 48 weeks after an initial 4 week course of Daivobet ointment. The number of patients who were exposed to intermittent treatment for 52 weeks was 112 in the Daivobet ointment group, 117 in the Daivobet ointment/ Daivonex ointment alternating group and 96 in the Daivonex ointment group. Adverse drug reactions were reported by 21.7% of the patients in the Daivobet ointment group, 29.6% in the Daivobet ointment/ Daivonex ointment alternating group and 37.9% in the Daivonex ointment group. Adverse drug reactions reported in 1% or more of the patients are listed in Table 2.
Adverse effects of concern, possibly related to long-term corticosteroid use were reported by 4.8% of the patients in the Daivobet ointment group, 2.8% in the Daivobet ointment/Daivonex ointment alternating group and 2.9% in the Daivonex ointment group.
The effects of Daivobet ointment on calcium metabolism and HPA function with long term use in psoriasis patients were not adequately studied.
In total, the clinical trial programme for Daivobet ointment has so far included more than 2,500 patients, and has shown that approximately 10% of patients can be expected to experience a non serious adverse effect (see Post-marketing use section for more details).

Post-marketing use.

The estimation of the frequency of adverse reactions is based on data from clinical trials and post market use.
The most frequently reported adverse reactions during treatment are various skin reactions including pruritus and skin exfoliation, rash and skin burning sensation.
Pustular psoriasis, photosensitivity and hypercalcaemia have been reported rarely.
Adverse reactions are listed by MedDRA SOC and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Very common (≥ 1/10); Common (≥ 1/100 and < 1/10); Uncommon (≥ 1/1,000 and < 1/100); Rare (≥ 1/10,000 and < 1/1,000); Very Rare (< 1/10,000). (See Table 3.)
Single cases of serious and life threatening undesirable effects including adrenal suppression and pustular psoriasis have been reported after prolonged use (2 years or more).

Adverse reactions associated with pharmacological classes.

The following adverse reactions 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 sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity, transient changes in skin pigmentation and hypersensitivity reactions including very rare cases of angioedema and facial oedema.
Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see Section 4.4 Special Warnings and Precautions for Use).

Betamethasone (as dipropionate).

This product contains a potent corticosteroid.
Local reactions can occur after topical corticosteroid use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia.
When treating psoriasis with topical corticosteroids, there may be the risk of generalised pustular psoriasis. There may be a risk of rebound when discontinuing long term treatment with corticosteroids.
Systemic reactions due to topical use of corticosteroids are rare, in adults, however, they can be severe. HPA suppression, hypercalcaemia, cataract, infections, impact on metabolic control of diabetes mellitus and increase in intra-ocular pressure can occur, especially after long term treatment. Systemic reactions occur more frequently when applied under occlusion (e.g. plastic, skin folds), when applied on large areas or during long treatment (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Use at more than the recommended dose may cause elevated serum calcium, which subsides when treatment is discontinued. The symptoms of hypercalcaemia include polyuria, constipation, muscle weakness, confusion and coma. In such cases, the monitoring of serum calcium levels once weekly until the serum calcium returns to normal levels is recommended.
Excessive prolonged use of topical corticosteroids may suppress the hypothalamic pituitary adrenal axis (HPA) resulting in secondary adrenal insufficiency, which is usually reversible. In such cases symptomatic treatment is indicated.
In case of chronic toxicity the topical corticosteroid treatment must be withdrawn gradually.
In a reported case of misuse, one patient with extensive erythrodermic psoriasis was treated for 5 months with 240 g weekly of Daivobet ointment and received a corresponding daily dose of 34 g, which is above the recommended maximum of 15 g daily or 100 g weekly. The patient developed Cushing's syndrome during treatment and then pustular psoriasis after abruptly stopping treatment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, calcipotriol, combinations. ATC Code: DO5AX52.

Mechanism of action.

Daivobet ointment combines the pharmacological effects of calcipotriol monohydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid.
Calcipotriol is a nonsteroidal antipsoriatic agent, derived from 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 (without any evidence of a cytotoxic effect) of keratinocytes, thus reversing the abnormal keratinocyte changes in psoriasis. The therapeutic goal envisaged with calcipotriol is thus a normalisation of epidermal growth.
Betamethasone dipropionate is a potent topically active corticosteroid producing prompt, marked and prolonged anti-inflammatory, antipruritic, vasoconstrictive and immunosuppressive properties, without curing the underlying condition. These effects can be enhanced under occlusive conditions due to increased penetration of stratum corneum (by approximately a factor of 10). The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear.

Clinical trials.

Efficacy.

The pivotal clinical trials with Daivobet ointment undertaken in adults are summarised below.

Topical treatment of psoriasis in adults using combination of calcipotriol 50 microgram/g plus betamethasone (as dipropionate) 500 microgram/g ointment regimen.

Two double blind, multicentre, randomised, vehicle controlled studies assessed the efficacy and safety of the combination calcipotriol 50 microgram/g plus betamethasone (as dipropionate) 500 microgram/g ointment once daily vs calcipotriol ointment 50 microgram/g or betamethasone (as dipropionate) 500 microgram/g ointment alone once daily in patients with psoriasis. The study duration was 4 weeks. The primary efficacy endpoint was the percentage reduction of the Psoriasis Area and Severity Index (PASI) score. In both studies (MCB 0003 INT, MCB 9905 INT) there was a statistically significant difference (p < 0.001) favouring the combination group administered once daily. There was no significant difference (p = 0.052) when combination therapy was used once daily compared to twice daily after 4 weeks of treatment (MCB 9905 INT). (See Table 4.)

Safety.

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 Daivobet gel and Daivobet ointment. 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.

5.2 Pharmacokinetic Properties

Clinical studies with radiolabelled ointment demonstrated less than 1% (95% CI: -0.1% to 0.3%) of calcipotriol and betamethasone from the applied dose (2.5 g) was systemically absorbed when applied to normal skin (625 cm2) for 12 hours. When the skin is damaged absorption was increased (~ 24% of applied dose). Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Approximately 64% of the absorbed dose is protein bound. Plasma elimination half-life after intravenous administration is 5 to 6 hours. Elimination after dermal application is in order of days due to the formation of a depot in the skin.

5.3 Preclinical Safety Data

Genotoxicity.

Calcipotriol was not genotoxic in assays for gene mutations (Ames test and mouse lymphoma TK locus assay) or chromosomal damage (human lymphocyte chromosomal aberration or mouse micronucleus test).

Carcinogenicity.

The carcinogenic or mutagenic potential of topical corticosteroids has not been investigated in animal studies.
A dermal carcinogenicity study with calcipotriol in mice showed no indications of increased carcinogenic risks. Calcipotriol solution was applied topically for up to 24 months at doses of 3, 10 and 30 microgram/kg/day (corresponding to 9, 30 and 90 microgram/m2/day). The high dose was considered to be the maximum tolerated dose for dermal treatment of mice with calcipotriol. Survival was decreased at 10 and 30 microgram/kg/day, particularly in the males. The reduced survival was associated with an increased incidence of renal lesions. This is an expected effect of treatment with high doses of calcipotriol or other vitamin D analogues. There were no dermal effects and no dermal or systemic carcinogenicity.
In a study where albino hairless mice were repeatedly exposed to both ultraviolet (UV) radiation and topically applied calcipotriol for 40 weeks at the same dose levels as in the dermal calcipotriol carcinogenicity study, a reduction in the time required for UV radiation to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UV radiation to induce skin tumours. The clinical relevance of these findings is unknown.
No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

6 Pharmaceutical Particulars

6.1 List of Excipients

Liquid paraffin, polyoxypropylene-11 stearyl ether, dl-alpha-tocopherol, white soft paraffin, butylated hydroxytoluene.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Use within 12 months of opening.
Do not use beyond the expiry date on the package.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The Daivobet ointment tube container is made from aluminium.
The registered pack sizes of Daivobet ointment are 3 g (sample), 15 g, 30 g*, 60 g, 100 g, 120 g. Not all pack sizes are available.
*Marketed pack size.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Calcipotriol monohydrate.


Calcipotriol is (1S, 3R, 5Z, 7E, 22E, 24S) -24-Cyclopropyl-9, 10-secochola-5,7,10(19), 22-tetraene-1,3,24-triol. The molecular weight of calcipotriol monohydrate is 430.6.
Calcipotriol is a white or almost white crystalline substance. It is freely soluble in ethanol, soluble in chloroform and propylene glycol, particularly insoluble in liquid paraffin. Solubility in water is 0.6 microgram/mL and the melting point is 166 to 168°C. Calcipotriol is a vitamin D derivative and behaves in a similar manner to vitamin D, forming a reversible temperature-dependent equilibrium between calcipotriol and pre-calcipotriol.

Betamethasone dipropionate.


Betamethasone dipropionate is 9-fluoro-11β, 17, 21-trihydroxy-16β-methylpregna-1,4-diene-3,20 dione 17,21-dipropionate. The empirical formula is C28H37FO7. The molecular weight of betamethasone dipropionate is 504.6.
Betamethasone dipropionate is a white or almost white, crystalline powder, practically insoluble in water, freely soluble in acetone and in methylene chloride, sparingly soluble in alcohol.

CAS number.

Calcipotriol monohydrate: 112828-00-9.
Betamethasone dipropionate: 5593-20-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes