Consumer medicine information

Daivobet 50/500 gel

Calcipotriol; Betamethasone dipropionate

BRAND INFORMATION

Brand name

Daivobet 50/500 Gel

Active ingredient

Calcipotriol; Betamethasone dipropionate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet?

This leaflet answers some common questions about using the medicine Daivobet® gel. 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® gel against the benefits it is expected to have for you.

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

What Daivobet® gel is used for

Daivobet® gel is used as topical treatment of body and scalp psoriasis. Psoriasis is a skin disorder in which skin cells are overactive. This causes redness, scaling and thickness of your skin. Daivobet® gel contains two active ingredients:

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

The calcipotriol in Daivobet® gel treats the overactive skin cells. The betamethasone dipropionate relieves redness, swelling, itching and irritation of the skin.

Daivobet® gel contains an ingredient hydrogenated castor oil.

Hydrogenated castor oil contains peanut products.

Daivobet® gel 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® gel

When you must not use Daivobet® gel

Do not use Daivobet® gel if you:

  • are allergic to calcipotriol, betamethasone dipropionate or any of the other ingredients listed at the end of this leaflet (see Product description) or any other similar medicine, such as topical corticosteroids
  • have high blood calcium levels (ask your doctor)
  • have other types of psoriasis known as generalised pustular, guttate, erythrodermic or exfoliative psoriasis (your doctor will identify these conditions for you)
  • have liver or kidney disease.

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® gel on skin affected by:

  • viral, fungal, bacterial or parasitic 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® gel.

Do not use Daivobet® gel

  • after the expiry date printed on the pack OR
  • if it is 3 months after the bottle 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 the medicine to your pharmacist for disposal.

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

Before you start to use it

Tell your doctor if you have a known allergy to Daivobet® gel, 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® gel in children. Safety and effectiveness of Daivobet® gel 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.

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

How to use Daivobet® gel

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® gel to use

Apply enough gel to completely cover the psoriasis plaques.

Usually an amount equal to 1 level teaspoon (4 g) is enough to cover an area the size of the scalp or 2 elbows, 2 knees and both hands.

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 (around 3½ teaspoons).
For example, no more than half (½) of a 30 g bottle in one day or quarter (¼) of a 60 g bottle.

Do not use more than 100 g in one week.
For example, no more than 3 bottles of 30 g in one week or no more than 1½ bottles of 60 g in one week.

If you also use other calcipotriol containing products (e.g.: Daivobet® ointment, 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® gel, 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® gel or any other product containing calcipotriol (e.g.: Daivobet® ointment, Daivonex®) should not be used until the calcium level has become normal again.

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

How to use Daivobet® gel

Apply Daivobet® gel only to areas affected by psoriasis.

Daivobet® gel should be applied on dry skin on the body and/or to the scalp when your hair is dry.

For Body Psoriasis

  1. Shake the bottle before use and remove the cap.

  1. Squeeze gel onto a clean finger.

  1. Using the finger apply enough gel to completely cover the psoriasis plaque and gently rub in. You will need to repeat steps 2 and 3 until all of the affected areas are covered.

For best results leave on during the day or night. The treated area does not need to be covered. You may wear your usual clothes however avoid contact with fabric that is easily stained by grease (e.g. silk).

For Scalp Psoriasis

Washing your hair before application of Daivobet® gel is not necessary.

  1. Comb the hair first to remove any loose scales ( part your hair before you apply the gel). Shake the bottle before use and remove the cap.

  1. Squeeze gel onto a clean finger.

  1. Using the finger apply the gel to the areas of the scalp affected by psoriasis and gently rub in with your fingertips. You will need to repeat steps 2 and 3 until all of the affected areas are covered.

To get the best results, do not wash your hair immediately after applying the gel. Let the gel remain on the scalp for a few hours, such as overnight or during the day.
  1. While your hair is still dry (prior to wetting your hair), rub a mild shampoo into the areas where the gel was applied.

  1. Leave the shampoo on the scalp for a couple of minutes before washing.

  1. Wash your hair as usual.

  • Take care not to get the gel in your eyes. If this happens, rinse your eyes with clean water and tell your doctor.
  • If you accidentally put some of the gel onto skin not affected by psoriasis, wipe it off as soon as possible.
  • Do not bandage, tightly cover or wrap the treated area
  • After applying the gel avoid contact with fabric that is easily stained by grease (e.g. silk).

Do not use Daivobet® gel

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

Wash your hands thoroughly after applying Daivobet® gel on any part of your body, unless your hands are the affected area being treated. Avoid spreading the gel to other parts of the body (especially the face, mouth and eyes).

Thoroughly wash your hands prior to handling infants or children.

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

When to use Daivobet® gel

Apply Daivobet® gel once a day at the most convenient time for you. Apply at about the same time each day.

How long to use it

Each treatment course would normally last for up to four weeks for scalp psoriasis and up to eight weeks for psoriasis on the body.

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

If you forget to use it

If you forget to use Daivobet® gel, use it as soon as you remember, then continue as before. Do not use an increased dose of the gel to make up for the forgotten doses.

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 766in 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® gel

Things you must do

While you are using Daivobet® gel, 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 outdoors.

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

If you become pregnant while using Daivobet® gel, 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® gel (or any other product containing calcipotriol, for example, Daivobet® ointment, 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® gel).

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

Side effects

As with all medicines, Daivobet® gel 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® gel

or

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

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® gel

Keep Daivobet® gel in the box until required.

Storage

Keep Daivobet® gel in a cool dry place, store below 25°C. Do not refrigerate.

Keep the bottle in the box to protect from light.

Keep Daivobet® gel 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® gel that is left over if:

  • your doctor tells you to stop using Daivobet® gel, or
  • the bottle has been opened for more than 3 months or
  • the expiry date has passed.

Product description

What it looks like

Daivobet® gel is an almost clear, colourless to slightly off-white gel.

Daivobet® gel is available as 15 g (starter pack) and 60 g bottles. Please note, not all pack sizes are marketed.

Ingredients

Daivobet® gel 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
  • hydrogenated castor oil
  • butylated hydroxytoluene

Hydrogenated castor oil contains peanut products.

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

Supplier

Daivobet® gel is supplied in Australia by:

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

Daivobet® gel is supplied in New Zealand by:

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

Daivobet® gel is manufactured in Ireland.

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

This leaflet was revised in August 2020.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Daivobet 50/500 Gel

Active ingredient

Calcipotriol; Betamethasone dipropionate

Schedule

S4

 

1 Name of Medicine

Calcipotriol monohydrate.
Betamethasone dipropionate.

2 Qualitative and Quantitative Composition

One gram of Daivobet gel contains 50 micrograms of calcipotriol (as monohydrate) and 500 micrograms of betamethasone (as dipropionate).

Excipients with known effect.

Hydrogenated castor oil*, butylated hydroxytoluene.
*Hydrogenated castor oil contains peanut products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

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

4 Clinical Particulars

4.1 Therapeutic Indications

Topical treatment of scalp psoriasis.
Topical treatment of mild to moderate plaque psoriasis on the body in adults.

4.2 Dose and Method of Administration

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

Adults.

Body psoriasis.

Daivobet gel should be applied once daily for up to 8 weeks.
If there is no response after 4 weeks, treatment should be ceased. Treatment of body psoriasis should be ceased after 8 weeks.

Scalp psoriasis.

Daivobet gel should be applied once daily for up to 4 weeks. After this period, Daivobet gel may be used according to need under medical supervision. There is experience with intermittent courses of Daivobet gel up to 52 weeks for scalp psoriasis.
All the affected scalp areas may be treated with Daivobet gel. Usually an amount between 1 g and 4 g per day is sufficient for treatment of the scalp (4 g corresponds to one teaspoon).
When using calcipotriol containing products, the maximum daily dose should not exceed 15 g and the maximum weekly dose should not exceed 100 g.
The total body surface area treated with calcipotriol should not exceed 30%. Repeated treatment of large body surface areas may result in adverse effects.
Shake the bottle before use.
In order to achieve optimal effect, it is recommended that the hair is not washed immediately after application of Daivobet gel. Daivobet gel should remain on the scalp during the night or during the day.

Children.

Daivobet gel is not recommended for use in children and adolescents below the age of 18 years due to the lack of data on safety and efficacy.

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 and wounds, perianal and genital pruritus.
Guttate, erythrodermic, exfoliative and pustular psoriasis.
Patients with severe renal insufficiency or severe hepatic disorders.

4.4 Special Warnings and Precautions for Use

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 systemic absorption.
Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids.
In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Daivobet gel (scalp application) and high doses of Daivobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment.

Effects on calcium metabolism.

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose of 15 g or the maximum weekly dose of 100 g is exceeded. Serum calcium is normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed.

Local adverse reactions.

Daivobet gel contains a potent WHO group III steroid and concurrent treatment with other steroids on the scalp must be avoided.
Treatment of more than 30% of the body surface should be avoided. Repeated treatment of large body surface areas may result in adverse effects.
Skin of the face and genitals are very sensitive to corticosteroids. Daivobet gel should not be used in these areas.
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 face, or accidentally to the eyes or conjunctives (see Section 4.8 Adverse Effects (Undesirable Effects)). The patient must be instructed in correct use of the product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas unless affected skin on the hands is being treated.

Concomitant skin infections.

When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with 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 gel should be applied to the affected areas of the scalp once daily for up to 4 weeks and affected areas of the body once daily for up to 8 weeks. If no response is observed after 4 weeks then treatment of the body psoriasis should be ceased. Treatment of body psoriasis should be ceased after 8 weeks, as there are no long-term efficacy data available beyond 8 weeks in patients treated with Daivobet gel on the body. However, there are safety data on intermittent courses of Daivobet gel used for up to 52 weeks for scalp psoriasis.
With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions, including hypothalamic pituitary adrenal (HPA) axis suppression. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid (see Section 4.8 Adverse Effects (Undesirable Effects)).
There may be a risk of rebound when discontinuing long-term treatment with corticosteroids. Medical supervision should therefore continue in the post-treatment period.

Unevaluated use.

There is no experience with the use of Daivobet gel 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 gel 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 gel 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. Daivobet is contraindicated in patients with severe hepatic impairment.

Use in renal impairment.

Safety has not been established in patients with renal impairment. Daivobet is contraindicated in patients with severe 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 gel is not recommended for use in children and adolescents below 18 years of age as the safety and effectiveness of Daivobet gel in this population has not been established.
Because of a higher ratio of skin surface area to body mass, children under the age of 12 years may be at particular risk of systemic adverse effects when they are treated with topical corticosteroids.

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

No interaction studies have been performed with Daivobet gel.
There is no experience with concurrent use of other anti-psoriatic products administered systemically or with phototherapy.

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 B1)
There are no adequate data from the use of Daivobet gel in pregnant women. Daivobet gel 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 gel 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 gel to breastfeeding women. Application of Daivobet gel to the breast area should be avoided. Daivobet gel should only be used during lactation if the potential benefits clearly outweigh the potential risks.

Note.

After applying Daivobet gel, mothers should wash their hands thoroughly prior to handling their child.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Definition of frequency of adverse events: 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.
The clinical trial programme for Daivobet gel has so far included more than 6,000 patients of whom more than 3,000 were treated with Daivobet gel.

Scalp psoriasis.

Approximately 8% of patients treated with Daivobet gel on the scalp experienced a non-serious adverse drug reaction (possibly related to study medication).
Based on the above frequency definition, data from clinical trials show that the only common adverse drug reaction is pruritus. The uncommon adverse events are burning sensation of the skin, skin pain or irritation, folliculitis, dermatitis, erythema, acne, dry skin, exacerbation of psoriasis, rash, pustular rash and eye irritation. These adverse events were all non-serious local reactions.

Body psoriasis.

Adverse drug reactions that occurred in more than 1% of patients treated with Daivobet gel on the body areas are listed in Table 1.
In a randomised, multicentre, active and vehicle controlled study where 482 patients applied Daivobet gel to affected body areas for 8 weeks, no statistically significant differences in incidence of adverse drug reactions between the Daivobet gel and vehicle were recorded.

Post marketing experience.

The estimation of the frequency of adverse reactions is based on clinical trials and post market use.
The most frequently reported adverse reaction during treatment is pruritus.
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 (Table 2).
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.

Adverse reactions associated with the 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.
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 a different formulation of Daivobet (Daivobet ointment) and received a corresponding daily dose of approximately 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 gel combines the pharmacological effects of calcipotriol monohydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid.
Calcipotriol is a non-steroidal 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 efficacy of once daily use of Daivobet gel was investigated in two randomised, double blind, 8 week clinical studies including a total of more than 2,900 patients with scalp psoriasis of at least mild severity according to the Investigator's Global Assessment of disease severity (IGA). Comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and (in one of the studies) the gel vehicle alone, all used once daily. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Daivobet gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Daivobet gel to be statistically significantly more effective than the comparators. See Table 3.
Another randomised, investigator blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA investigated use of Daivobet gel once daily compared with Daivonex Scalp Solution twice daily for up to 8 weeks. Results for the primary response criterion (clear or minimal disease according to the IGA at week 8) showed that Daivobet gel was statistically significantly more effective than Daivonex Scalp Solution. See Table 4.
One multicenter, randomised, double-blind study was conducted in subjects with psoriasis vulgaris on body areas. In this study, 1152 subjects were randomised to one of four treatment groups: Daivobet gel, betamethasone dipropionate in the same optimised vehicle, calcipotriol in the same optimised vehicle, or the optimised vehicle alone. The study enrolled subjects with mild to moderate psoriasis vulgaris on the body. The majority of subjects had disease of moderate severity at baseline. Subjects were treated once daily for 8 weeks.
Efficacy was assessed as the proportion of subjects at week 4 and week 8 who were "clear" or "almost clear" and improved at least two steps according to an Investigator's Global Assessment of Diseases Severity. Table 5 contains the response rates in this trial.

Safety.

A randomised, double blind long term clinical study including 869 patients with scalp psoriasis of at least moderate severity (according to the IGA) investigated the use of Daivobet gel compared with calcipotriol in the gel vehicle. Both treatments were applied once daily, intermittently as required, for up to 52 weeks. Adverse events possibly related to long-term use of corticosteroids on the scalp, were identified by an independent, blinded panel of dermatologists. There was no difference in the percentages of patients experiencing such adverse events between the treatment groups (2.6% in the Daivobet gel group and 3.0% in the calcipotriol group; P = 0.73). No cases of skin atrophy were reported.
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.
In another study, 43 subjects were treated with Daivobet gel on body areas and any affected areas on the scalp. Adrenal suppression was identified in 3 of 43 subjects (7%) after 4 weeks of treatment and in 0 of 36 subjects who provided data after 8 weeks treatment. The results from this limited number of subjects demonstrated that Daivobet gel may have effects on the HPA axis but the incidence was low and did not increase over time even in a maximum use setting. See Section 4.9 Overdose for additional information.
The effects on calcium metabolism were also studied in these patients. The results demonstrated that there were no changes of clinical concern regarding the effect on calcium metabolism.

5.2 Pharmacokinetic Properties

Absorption.

The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Daivobet gel is 13-45% less than Daivobet ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Daivobet 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 treated for 4 or 8 weeks with both Daivobet gel and Daivobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.

Metabolism.

Following systemic exposure, both active ingredients - calcipotriol and betamethasone dipropionate - are rapidly and extensively metabolised.

Excretion.

The main route of excretion of calcipotriol and betamethasone dipropionate is via faeces (rats, mice and minipigs).

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). Betamethasone dipropionate was not genotoxic in the Ames mutagenicity assay, the mouse lymphoma TK locus assay or in the rat micronucleus test.

Carcinogenicity.

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. In a supplementary study, mice of the same strain were treated repeatedly with either calcipotriol solution or calcipotriol/ betamethasone gel, followed by irradiation with UVR and measurement of recognised cellular indicators of skin photocarcinogenicity. This study showed a similar enhancing effect of calcipotriol alone on the photobiological response of the skin calcipotriol/ betamethasone gel increased cellular proliferation but did not increase other markers indicative of enhancement of photocarcinogenesis. 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, butylated hydroxytoluene, hydrogenated castor oil*.
*Hydrogenated castor oil contains peanut products.

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 6 months of opening.
Do not use beyond the expiry date on the package.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate.
Keep the bottle in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

The Daivobet gel bottle container is made from high density polyethylene.
The registered pack sizes of Daivobet gel are 15 g (starter pack), 30 g, 60 g*, 2 x 60 g. Not all pack sizes are available.
*Marketed trade pack sizes.

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