Daivobet

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Betamethasone dipropionate 643 µg/g equivalent to 500 µg/g betamethasone;  ; Calcipotriol 50 µg/g (as calcipotriol hydrate 52.2µg/g)
Available from:
LEO Pharma Limited
INN (International Name):
Betamethasone dipropionate 643 µg/g (equivalent to 500 µg/g betamethasone)
Dosage:
50µg/500µg/g
Pharmaceutical form:
Topical ointment
Composition:
Active: Betamethasone dipropionate 643 µg/g equivalent to 500 µg/g betamethasone   Calcipotriol 50 µg/g (as calcipotriol hydrate 52.2µg/g) Excipient: Ceteareth-15 dl-Alpha tocopherol Liquid paraffin White soft paraffin
Units in package:
Tube, aluminium, sample pack (not marketed), 3 g
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Crystal Pharma SA
Product summary:
Package - Contents - Shelf Life: Tube, aluminium, sample pack - 3 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C - Tube, aluminium, - 15 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C - Tube, aluminium, - 30 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C - Tube, aluminium, - 60 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C - Tube, aluminium, - 100 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C - Tube, aluminium, - 120 g - 24 months from date of manufacture stored at or below 25°C 12 months opened stored at or below 25°C
Authorization number:
TT50-7194
Authorization date:
2004-01-29

Daivobet

®

50/500

ointment

Daivobet

50/500 ointment

Dye-vo-bet

Calcipotriol

(Kal-sippo-try-all)/

Betamethasone

(Beet-ah-meth-ah sown )

CONSUMER MEDICINE INFORMATION (CMI)

Please read this leaflet carefully

before you start your treatment.

Daivobet

50/500 ointment is the

brand name. Calcipotriol and

betamethasone are the generic

names of the combination product,

which is Daivobet

ointment.

Keep this leaflet. You may want

to read it again.

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 (related to Vitamin

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 or

erythrodermic exfoliative

psoriasis. Your doctor will identify

these conditions for you.

Do not use Daivobet

®

ointment

if

you

have high blood calcium levels

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.

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.

Daivobet

®

50/500

ointment

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

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.

fingertip

unit

(FTU)

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 15g in one

day.

For example, no more than half (½)

of a 30g tube in one day.

Do not use more than 100g in one

week.

For example, no more than 3 tubes

of 30g 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 grams per day

or 100 grams 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 (eg,

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 (eg. 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 preparations

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

Daivobet

®

50/500

ointment

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 (including

itching, redness or burning,

swelling, bruising, rashes

or peeling)

a rash on your face or body

a change in the colour of

your skin

your skin is more sensitive

to light

headache

back pain

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 (50 microgram/g)

betamethasone dipropionate

(500 microgram/g).

It also contains

paraffin, liquid

polyoxypropylene-11 stearyl

ether

dl-alpha-tocopherol

soft white paraffin.

Daivobet

®

50/500

ointment

Daivobet

ointment does not

contain lactose, sucrose, gluten,

tartrazine or any other azo

products.

The Australian Registration

Number is AUST R 98773.

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,

Level 3, Tower 1,

25 Montpelier Road,

Bowen Hills, QLD 4006,

AUSTRALIA

Australia Toll free no: 1800 991 778

Daivobet

ointment is supplied in

New Zealand by:

LEO Pharma Ltd

Level 31, Vero Centre,

48 Shortland Street,

Auckland 1010,

New Zealand Toll Free No:

0800 497 456

Web: www.leo-pharma.com.au

Daivobet

ointment is

manufactured by:

LEO Laboratories Ltd (LEO

Pharma), Dublin, IRELAND

Daivobet, LEO and LEO/lion

device are registered trademarks

of LEO Pharma A/S, Denmark.

This leaflet was revised in June

2016.

Page 1 of 12

NEW ZEALAND DATA SHEET

1

DAIVOBET

®

50/500 OINTMENT

Daivobet

50/500 calcipotriol 50 microgram/g and betamethasone 500 microgram/g (as dipropionate)

ointment

2

QUANTITATIVE AND QUALITATIVE COMPOSITION

One gram of Daivobet

ointment contains 50 micrograms of calcipotriol (as monohydrate) and 500

micrograms of betamethasone (as dipropionate).

3

PHARMACEUTICAL FORM

Ointment

Off-white to yellow ointment.

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 in adult patients 18 years and older.

4.2 Dosage and method of administration

Daivobet

ointment is indicated FOR TOPICAL USE ONLY and NOT FOR OPHTHALMIC USE.

All psoriasis-affected areas treated with Daivobet

should be, where possible, protected from direct

sunlight and UV-light with items of clothing. Topical calcipotriol should only be used with UV radiation if

the physician and patient consider that the potential benefits outweigh the potential risks. The potential

phototoxic effects of Daivobet

over long term exposure have not been fully investigated.

Adults:

Daivobet

ointment should be applied topically to the affected area once daily. The maximum daily

dose should not exceed 15 grams.

The maximum recommended weekly dose of Daivobet

®

ointment is 100 g/week.

The treated area should not be more than 30% of the body surface.

The recommended treatment period of Daivobet

®

ointment is 4 weeks. At the completion of the

treatment period, repeated treatment with Daivobet

®

ointment can be initiated under medical

supervision. There is no clinical experience with Daivobet

®

Ointment beyond 52 weeks.

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 in section 6.1.

Patients with known disorders of calcium metabolism (see section 4.4).

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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 (see section 4.4).

Erythrodermic, exfoliative and pustular psoriasis.

Patients with severe renal insufficiency or severe hepatic disorders.

NOT FOR OPHTHALMIC USE.

4.4 Special warnings and special 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 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 (see section 4.8).

In a trial in patients with both extensive scalp and extensive body psoriasis vulgaris 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.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents

with symptoms such as blurred vision or other visual disturbances, the patient should be considered

for referral to an ophthalmologist for evaluation of possible causes which may include cataract,

glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been

reported after use of systemic and topical corticosteroid.

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 100g 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

contains potent corticosteroid (classified as WHO group III steroid), concurrent treatment

with other steroids on the same treatment area must be avoided.

Skin of the face and genitals are very sensitive to corticosteroids. Daivobet

ointment is not

recommended for use on the face since it may give rise to itching and erythema of the facial skin.

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Daivobet

ointment is not recommended for use on genitals.

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. 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 (see section 4.3)

Other

When treating psoriasis with topical corticosteroids there may be a risk of generalised pustular

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 extensively studied in the clinic.

Treated skin areas should be protected from sunlight and UV light (using physical coverings and/or

sunscreens), particularly where exposure may be considerable for reasons such as occupation. Topical

calcipotriol should only be used with UV radiation if the physician and patient consider that the potential

benefits outweigh the potential risks.

Long-term use

With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions.

The treatment should be discontinued in case of adverse reactions related to long-term use of

corticosteroids (see section 4.8).

Discontinuation of treatment

There may be a risk of generalised pustular psoriasis or rebound effects when discontinuing a 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

ointment on the scalp or in guttate psoriasis.

Adverse reactions to excipients

Daivobet

ointment contains butylated hydroxytoluene (E321) (an excipient within the excipient

polyoxypropylene stearyl ether), which may cause local skin reactions (e.g. contact dermatitis), or

irritation to the eyes and mucous membranes.

Use in Children

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.

Renal Impairment

Safety has not been established in patients with renal impairment.

Hepatic Impairment

Safety has not been established in patients with hepatic impairment.

Effects on Laboratory Tests

There are no data available on the effects of Daivobet

on laboratory tests.

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4.5 Interaction with other medicinal products 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, which enhance the systemic availability of calcium.

No interactions trials have been performed with Daivobet

ointment.

4.6 Fertility, pregnancy and lactation

Use in pregnancy (Category B1):

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). Long-term oral administration of corticosteroids in rats has been shown to prolong

gestation and make labour more difficult and prolonged. A reduction in postnatal survival and growth

was observed in the offspring of these rats.

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 18 µg/kg/day and in

rabbits (reduced skeletal ossification) at oral doses of 36 µg/kg/day. The relevance of these findings for

humans is unknown.

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.

Use in Lactation

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 when breastfeeding. 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 her

skin, mothers should wash their hands thoroughly prior to handling her 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 Undesirable effects

Clinical Trials

Adverse events reported in more than 1% of subjects enrolled in the early clinical trials with Daivobet

ointment (in total 912 patients exposed to twice daily applications and 1286 patients exposed to once

daily applications) are listed in Table 1.

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Table 1. Adverse events recorded during clinical trials with a frequency of greater than 1%.

Adverse Event

MCB 0003 INT

MCB 9905 INT

n = 486

n = 151

Pruritus NOS

Rash scaly

Back pain

Blood calcium increase

Ecchymosis

Headache NOS

Nasopharyngitis

Psoriasis

Upper respiratory tract infection NOS

A safety study in 634 psoriasis patients 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. 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. The adverse drug reactions that were reported by more than 2% of the

patients in the Daivobet

ointment group

were pruritus (5.8%) and psoriasis (5.3%). 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.

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 (spontaneous) reporting.

The most frequently reported adverse reactions during treatment are various skin reactions including

pruritus and skin exfoliation.

Pustular psoriasis 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

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Table 2: Adverse reactions listed by MedDRA SOC based on data from clinical trials and post-market

(spontaneous) reporting

Infections and infestations

Uncommon ≥1/1,000 and <1/100

Skin infection*

Folliculitis

Rare ≥1/10,000 and <1/1,000

Furuncle

Immune system disorders

Rare ≥1/10,000 and <1/1,000

Hypersensitivity

Metabolism and nutrition disorders

Rare ≥1/10,000 and <1/1,000

Hypercalcaemia

Skin and subcutaneous tissue disorders

Common ≥1/100 and <1/10

Skin exfoliation

Pruritus

Uncommon ≥1/1,000 and <1/100

Skin atrophy

Exacerbation of psoriasis

Dermatitis

Erythema

Rash**

Purpura or ecchymosis

Skin burning sensation

Skin irritation

Rare ≥1/10,000 and <1/1,000

Pustular psoriasis

Skin striae

Photosensitivity reaction

Acne

Dry skin

General disorders and administration site conditions

Uncommon ≥1/1,000 and <1/100

Application site pigmentation changes

Application site pain***

Rare ≥1/10,000 and <1/1,000

Rebound effect

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

**Various types of rash reactions such as exfoliative rash, rash popular and rash pustular have been reported.

***Application site burning is included in application site pain

Adverse reactions associated with the pharmacological classes

The following adverse reactions are considered related to the pharmacological classes of calcipotriol

and betamethasone respectively:

Calcipotriol:

Potential adverse reactions include application site reactions, pruritus, skin irritation, burning and

stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity

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).

Betamethasone (as dipropionate):

This product contains a potent corticosteroid.

Local reactions can occur after topical use, especially during prolonged application, including skin

atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis,

depigmentation and colloid milia.

When treating psoriasis with topical corticosteroids, there may be the risk of generalised pustular

psoriasis.

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Systemic reactions due to topical use of corticosteroids are rare in adults, however, they can be severe.

Adrenocortical suppression, hypercalcaemia, cataract, infections, impact on the 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 (for example plastic, skin

folds), when applied on large areas or during long treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to

report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/ .

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 of Daivobet

ointment per week (maximum recommended dose is 100 g per week)

and received a corresponding daily dose of approximately 34 g, which is above the maximum

recommended dose of 15 g daily. The patient developed Cushing’s syndrome during treatment and

then pustular psoriasis after abruptly stopping treatment..

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764 766).

5

PHARMACOLOGIAL 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 (as 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)

receptor. Calcipotriol is as potent as 1,25(OH)

, the

naturally occurring active form of vitamin D, in regulating cell proliferation and cell differentiation, but

much less active than 1,25(OH)

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.

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In vitro vitamin D has a normalising effect on human keratinocytes, arresting growth and enhancing

differentiation in inappropriately proliferating cells and stimulating normal growth in quiescent cells. The

underlying antiproliferative mechanism of vitamin D in keratinocytes is incompletely understood but is

known to involve the induction of the growth inhibitory factor transforming growth factor-

and of

cyclin-dependent kinase inhibitors, with subsequent growth arrest in the G1 phase of the cell cycle plus

down-regulation of the two proliferation factors early growth response-1 and polo-like kinase-2.

In addition, vitamin D has an immunomodulatory effect, suppressing activation and differentiation of

Th17/Th1 cells while inducing a Th2/Treg response.

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).

In psoriasis vulgaris, corticosteroids suppress the immune system, particularly proinflammatory

cytokines and chemokines, thereby inhibiting T-cell activation. At the molecular level, corticosteroids

act via the intracellular glucocorticoid receptor and the anti-inflammatory function is due to

transrepression of pro-inflammatory transcription factors such as nuclear factor

B, activator protein-1,

and interferon regulatory factor-3.

In combination, calcipotriol monohydrate and betamethasone dipropionate promote greater anti-

inflammatory and anti-proliferative effects than either component alone.

Pharmacodynamic effects

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both

extensive scalp and body psoriasis vulgaris, 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. With regard to HPA suppression, therefore, this trial shows some evidence that very high

doses of Daivobet

gel and ointment may have a weak effect on the HPA axis.

Clinical Trials

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 & Severity Index (PASI)

score. In both studies (MCB 0003 INT, MCB 9905 INT) there was a statistically significant difference

(p<0.001) favouring 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).

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Table 3: Administration of combination calcipotriol 50 microgram/g plus betamethasone (as

dipropionate) 500 microgram/g ointment in adults

Study

MCB 0003 INT

MCB 9905 INT

Treatment

administered:

Combination OD: n = 490

Calcipotriol OD: n = 480

Betamethasone OD: n = 476

Vehicle OD: n = 157

Combination OD: n = 150

Combination TD: n = 234

Calcipotriol TD n = 227

Vehicle TD: n = 207

Results:

Percentage

reduction in

PASI

(Mean ± SD)

Combination OD: -71.3 ± 25.7

Calcipotriol OD: -46.1 ± 30.9

Betamethasone OD: -57.2 ± 29.8

Vehicle OD: -22.7 ± 33.4

Combination OD: -68.6

23.6

Combination TD -73.8

21.0

Calcipotriol TD: -58.8

28.6

Vehicle TD: -26.6

31.3

Statistical

analysis of

percentage

reduction

(mean (95%

CI))

Combination OD vs calcipotriol OD:

-25.3 (-28.7 to -21.9)*

Combination OD vs Betamethasone OD:

-14.2 (-17.6 to -10.8)*

Combination OD vs Vehicle OD:

-48.3 (-53.2 to -43.4)*

*p<0.001

Combination OD vs Combination TD:

-5.4 (-10.8 to 0.1)#

Combination OD vs calcipotriol TD:

-9.8 (-15.2 to -4.3)*

Combination OD vs Vehicle TD:

-42.0 (-47.5 to -36.4)*

*p<0.001

#p=0.052

OD = Once daily:

TD = Twice daily

5.2 Pharmacokinetic properties

Absorption

Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and

betamethasone from Daivobet

ointment is less than 1% (95% CI: 0.1% to 0.3%) of the dose (2.5 g

ointment) when applied to normal skin (625 cm

) for 12 hours. When the skin was 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.

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.

Distribution

In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate,

respectively, showed that the kidney and liver had the highest level of radioactivity.

Metabolism

Following systemic exposure, both calcipotriol and betamethasone dipropionate are rapidly and

extensively metabolised.

Excretion

The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone

dipropionate it is via urine (rats and mice).

5.3 Preclinical safety data

Carcinogenicity and mutagenicity

The carcinogenic or mutagenic potential of topical corticosteroids has not been investigated in animal

studies.

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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 µg/kg/day (corresponding to 9, 30 and 90 µg/m

/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 µg/kg/day, particularly in the males. The reduced survival was associated with an increased

incidence of obstructive uropathy, most probably caused by treatment-related changes in the urinary

composition. 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 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.

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).

6

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Liquid paraffin

Polyoxypropylene stearyl ether (which contains butylated hydroxytoluene)

Alpha-tocopherol

White soft paraffin

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years.

After first opening of container: 1 year.

Do not use beyond the expiry date on the package.

Do not use if the pack shows signs of damage or tampering.

6.4 Special precautions for storage

Store below 25ºC.

6.5 Nature and contents of container

Aluminium tube with polyethylene screw cap.

Pack sizes: 3 g (sample), 15 g, 30 g, 60 g, 100 g, 120 g

Marketed pack size: 30 g

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

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6.7 Physicochemical properties

Calcipotriol (as monohydrate)

Calcipotriol is (1S, 3R, 5Z, 7E, 22E, 24S) -24-Cyclopropyl-9, 10-secochola-5,7,10(19), 22-tetraene-

1,3,24-triol (CAS No.: 112828-00-9). The molecular weight of calcipotriol hydrate 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 µg/mL

and the melting point is 166 – 168ºC. 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 (CAS No. 5593-20-4). The empirical formula is C

. 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.

7

MEDICINE SCHEDULE

Prescription Only Medicine

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8

SPONSOR

LEO Pharma Ltd

Level 31, Vero Centre

48 Shortland Street

Auckland 1010

New Zealand

Ph: 0800 497 456

9

DATE OF FIRST APPROVAL

21 April 2005

10 DATE OF REVISION OF TEXT

28 March 2019

Summary Table of Changes

Section changed

Summary of new information

Data sheet format update to SPC format

Rosacea added as a contraindication

Additional warnings due to corticosteroid content

Expansion of pharmacodynamic and pharmacokinetic properties

Daivobet

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

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