Daivonex

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Calcipotriol 50 µg/g
Available from:
LEO Pharma Limited
INN (International Name):
Calcipotriol 50 µg/g
Dosage:
50 mcg/g
Pharmaceutical form:
Topical ointment
Composition:
Active: Calcipotriol 50 µg/g Excipient: Dibasic sodium phosphate dihydrate Disodium edetate dihydrate dl-Alpha tocopherol Liquid paraffin Polyoxyethylene stearyl ether Propylene glycol Purified water White soft paraffin
Units in package:
Tube, aluminium, 15g Physician sample pack, 15 g
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Leo Pharma A/S
Product summary:
Package - Contents - Shelf Life: Tube, aluminium, 15g Physician sample pack - 15 g - 24 months from date of manufacture stored at or below 25°C 6 months opened stored at or below 25°C - Tube, aluminium, 30g - 30 g - 24 months from date of manufacture stored at or below 25°C 6 months opened stored at or below 25°C - Tube, aluminium, 100g - 100 g - 6 months opened stored at or below 25°C 24 months from date of manufacture stored at or below 25°C - Tube, aluminium, 120g - 120 g - 6 months opened stored at or below 25°C 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-4924
Authorization date:
1990-07-10

Consumer Medicine Information

DAIVONEX

®

ointment, cream and

scalp solution

Calcipotriol (Kal-sippo-try-all)

Please read this leaflet carefully before you start your treatment.

Keep this leaflet. You may want to read it again.

What is in this leaflet?

This leaflet answers some common questions about using DAIVONEX. 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 DAIVONEX against the benefits it is expected to have for you.

If you have any concerns about using DAIVONEX, talk to your doctor

or pharmacist.

What DAIVONEX is used for

DAIVONEX is an anti-psoriasis medicine. DAIVONEX contains calcipotriol (related

to Vitamin D). DAIVONEX does not contain steroids.

DAIVONEX is used only on skin affected by psoriasis. Psoriasis is a skin disorder

which

skin

cells

overactive.

calcipotriol

DAIVONEX

treats

overactive skin cells.

DAIVONEX is used in the commonest type of psoriasis, where "plaques" form in the

skin. Plaques are raised, rough, reddened areas covered with fine, dry silvery scales.

Plaques are usually a centimetre or two across.

DAIVONEX preparations are available as ointment, cream and scalp solution.

DAIVONEX preparations are 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 DAIVONEX

When you must not use DAIVONEX (All Preparations)

Do not use DAIVONEX if you have an allergy to:

any medicine containing calcipotriol

any of the ingredients listed at the end of this leaflet (see Product

description).

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 DAIVONEX for severe widespread psoriasis, or the types of

psoriasis known as guttate, generalised pustular or erythrodermic exfoliative

psoriasis. Your doctor will identify these conditions for you.

Do not use DAIVONEX if you

have high blood calcium levels.

are taking calcium, vitamin D supplements or vitamin D-like medicines, for

example calcitriol.

Do not use DAIVONEX

after the expiry date printed on the pack OR

if the packaging is torn, doesn't look quite right or shows signs of

tampering.

If the DAIVONEX packaging is damaged or it is past the expiry date, return it to

your pharmacist for disposal.

Do not breast-feed if you are using DAIVONEX on your breasts.

If you are not sure whether you should start using DAIVONEX, talk to your

doctor.

When you must not use DAIVONEX Cream or Scalp Solution

Do not use DAIVONEX cream or scalp solution in children.

Safety and effectiveness of these forms of DAIVONEX in children have not

been established.

DAIVONEX ointment may be used in children (see How to use DAIVONEX).

Do not use DAIVONEX cream or scalp solution if you are having other

treatments for psoriasis.

DAIVONEX ointment may be used with some other treatments for psoriasis. Talk to

your doctor to find out if this applies to you.

Before you start to use it

Tell your doctor if you have a known allergy to DAIVONEX or any of

the ingredients listed at the end of this leaflet.

Tell your doctor if you

have kidney or liver problems.

are suffering from any other illness.

Tell your doctor if you

are pregnant

are breast-feeding

intend to breast-feed.

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 on 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 DAIVONEX.

How to use DAIVONEX

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 on the box, ask your doctor

or pharmacist for help.

How much of each DAIVONEX preparation to use

Children:

DAIVONEX ointment only

over 12 years old

- Do not use more than 75 g in one week.

6 - 12 years old

- Do not use more than 50 g in one week.

under 6 years old

- Follow your doctor's instructions.

Adults:

DAIVONEX cream and ointment:

- Do not use more than 100 g in one

week. For example, no more than

3 tubes of 30 g or

1 tube of 100 g.

Adults:

DAIVONEX scalp solution:

- Do not use more than 60 mL in one week.

For example, no more than

1 bottle containing 60 mL or

2 bottles containing 30 mL.

Adults:

Using combinations of DAIVONEX preparations

IMPORTANT: You may need to use a combination of DAIVONEX

preparations to treat your psoriasis. For example, you may use scalp solution

on your head and ointment or cream on other parts of your body.

- In one week do not use more than

60 mL of DAIVONEX scalp

solution plus one 30 g tube of

DAIVONEX cream or ointment

or

30 mL of DAIVONEX scalp solution plus two 30 g tubes of DAIVONEX

cream or ointment.

- In one week do not use more than

one 30 g tube of DAIVONEX cream and two 30 g tubes

of DAIVONEX ointment

or

two 30 g tubes of DAIVONEX cream and one 30 g tube

of DAIVONEX ointment.

NOTE: If you use more than the recommended amount, the levels of calcium in your

body may rise, and this can have serious effects.

How to use DAIVONEX preparations

NOTE: unlike certain other skin preparations which you use sparingly, use

DAIVONEX as follows:

DAIVONEX cream and ointment:

Apply DAIVONEX cream or ointment to the psoriasis plaques only.

Form a visible coating. If you accidentally get some of the cream or

ointment on normal skin, wash it off.

DO NOT use DAIVONEX cream or ointment

in skin folds,

on the genitalia,

on the scalp or

on the face.

DAIVONEX scalp solution:

Use DAIVONEX scalp solution ONLY on the scalp.

Apply DAIVONEX scalp solution, drop by drop, only to the areas of your

scalp that have psoriasis.

If any accidentally gets on your face, wash it off immediately.

Wash your hands thoroughly after applying it on any part of your body,

unless your hands are being treated.

Take care not to get DAIVONEX in your eyes. If this happens, rinse your eyes

with clean water and tell your doctor.

Avoid getting DAIVONEX on your face accidentally.

If any skin irritation develops, wash off the DAIVONEX preparation.

Do not use DAIVONEX on the face. An itchy red rash may develop.

Do not use DAIVONEX under occlusive dressings (eg a bandage). The treated area

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

When to use DAIVONEX preparations

Apply DAIVONEX twice a day (morning and night).

How long to use it

Children:

Do not use DAIVONEX ointment for more than 8 weeks.

Adults:

Continue to use DAIVONEX for as long as your doctor tells you.

If you are using DAIVONEX for longer than 3 months your doctor will probably

do blood tests to check your calcium levels and kidney function.

Your doctor may decide to stop DAIVONEX treatment once your psoriasis has

improved.

If you forget to use it

If you forget to use DAIVONEX, 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 (0800

764 766 / 03 474 7000 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 DAIVONEX

Things you must do

While you are using DAIVONEX, 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 much time out-of-doors. [An

exception is if your doctor has advised combination treatment with DAIVONEX

ointment and UV therapy.]

If you are going to start any new medicine, tell your doctor and pharmacist that

you are using DAIVONEX.

If you become pregnant while using DAIVONEX, tell your doctor immediately.

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

Your doctor may do some blood tests from time to time.

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 DAIVONEX cream or scalp solution with other treatments for

psoriasis.

Your doctor will tell you if you can use DAIVONEX ointment with other psoriasis

treatments.

Do not use more than the recommended weekly dose (see How to use

DAIVONEX).

Side effects

As with all medicines, DAIVONEX 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

DAIVONEX or

if you notice any of the following and they worry you:

- skin irritation (including rashes or peeling)

- a rash on your face

- a change in the colour of your skin

- your skin is more sensitive to light.

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 DAIVONEX

Keep DAIVONEX in the box until required.

Storage

Keep your DAIVONEX ointment or cream or scalp solution in a cool dry place

where the temperature stays below 25°C. However, do not keep DAIVONEX

cream or ointment in the refrigerator as the cream or ointment will not spread easily.

Also, keep your DAIVONEX scalp solution away from fire or flames because it

may catch fire.

Do not store DAIVONEX 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 DAIVONEX 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

If your doctor tells you to stop using DAIVONEX or the expiry date has passed,

ask your pharmacist what to do with any DAIVONEX that is left over.

Discard Daivonex

®

Ointment and Daivonex

®

Cream 6 months after opening.

Discard Daivonex

®

scalp solution 3 months after opening.

Product description

What it looks like

DAIVONEX ointment is a white to yellowish ointment.

DAIVONEX cream is a soft white cream.

DAIVONEX scalp solution is a colourless, non-runny solution.

Ingredients

DAIVONEX ointment contains the active ingredient calcipotriol (50 microgram/g). It

also contains:

dl-α-tocopherol,

disodium edetate,

sodium phosphate - dibasic dihydrate

purified water

liquid paraffin

steareth-2

propylene glycol

soft white paraffin.

DAIVONEX cream contains the active ingredient calcipotriol (50

microgram/g). It also contains

disodium edetate

quaternium-15

sodium phosphate - dibasic dihydrate

cetomacrogol 1000

glycerol

liquid paraffin

cetostearyl alcohol

soft white paraffin

purified water.

DAIVONEX scalp solution contains the active ingredient

calcipotriol (50 microgram/mL).

It also contains

menthol

hydroxypropylcellulose

sodium citrate

propylene glycol

isopropyl alcohol

purified water.

DAIVONEX does not contain lactose, sucrose, gluten, tartrazine or any

other azo products.

This is not all the information available on DAIVONEX. If you have any

more questions or are unsure about anything, ask your doctor or

pharmacist.

Supplier

DAIVONEX is supplied in New Zealand by:

LEO Pharma Ltd

Level 31, Vero Centre,48 Shortland Street,

Auckland 1010,New Zealand

DAIVONEX is manufactured by:

Leo Pharma A/S

Proprietor of the registered trademark LEO, LION Device

and DAIVONEX.

Date of Preparation: This leaflet was prepared in January 2016

NEW ZEALAND DATA SHEET

1

DAIVONEX

®

50 microgram/gram topical ointment

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Daivonex

ointment contains calcipotriol 50 microgram per gram

Daivonex

ointment contains the anhydrous form of calcipotriol.

For full list of excipients, see section 6.1 List of excipients.

3

PHARMACEUTICAL FORM

Daivonex

is a topical ointment. It is a smooth, white preservative free ointment base.

4

CLINICAL PARTICULARS

4.1

Indications

Daivonex

ointment is indicated for the topical treatment of psoriasis vulgaris, including

plaque psoriasis in adults and children (see section 4.4 Special warnings and precautions for

use - paediatric population). In adult patients, Daivonex

ointment may also be used in

combination with systemic acitretin or cyclosporin.

4.2

Dosage and method of administration

Adults

Daivonex

®

ointment therapy:

Daivonex

ointment should be applied topically to the affected area once or twice daily (i.e.

in the morning and/or in the evening). Initially, twice daily application of the ointment is

usually preferred. Application may then be reduced to once daily, provided individual clinical

response is satisfactory. After satisfactory improvement has occurred, treatment should be

discontinued.

If recurrence develops after reduction in frequency of application or after discontinuation, the

treatment may be reinstituted at the initial dosage. Experience is lacking in the use of

calcipotriol for periods longer than 1 year.

The maximum recommended weekly dose of Daivonex

®

ointment is 100 g/week.

When using a combination of ointment and cream the total maximum dose

should not exceed

100 g per week.

It should be noted that there are no long-term clinical studies assessing the safety of using

Daivonex

ointment during exposure to sunlight. Therefore, all psoriasis-affected areas

treated with calcipotriol should be, where possible, protected from direct sunlight and UV-

light with items of clothing. Furthermore, topical calcipotriol should only be used with UV

radiation if the physician and patient consider that the potential benefits outweigh the

potential risks.

Combination therapy:

Twice daily application of Daivonex

ointment in combination with systemic cyclosporin or

acitretin has been shown to enhance the efficacy of cyclosporin or acitretin (see Section 5.1

Pharmacodynamic properties Clinical efficacy and safety).

Paediatric Population:

Daivonex

®

ointment therapy:

Children under 6 years:

There is limited experience of using Daivonex

ointment in this age group. A maximum safe

dose has not been established.

Children aged 6 to 12 years:

Daivonex

ointment should be applied to the affected area twice daily. Maximum weekly

dose should not exceed 50 g.

Children over 12 years:

Daivonex

ointment should be applied to the affected area twice daily. Maximum weekly

dose should not exceed 75 g.

Combination therapy:

There is no experience of use of Daivonex

ointment in combination with other therapies for

psoriasis in children.

Daivonex

®

ointment should not be used for more than 8 weeks in children.

Method of Administration

Daivonex

ointment is indicated FOR TOPICAL USE ONLY and NOT FOR

OPHTHALMIC USE.

4.3

Contraindications

Allergic sensitisation to any constituent of Daivonex

ointment.

Patients with known disorders of calcium metabolism.

NOT FOR OPHTHALMIC USE.

4.4

Special warnings and precautions for use

In view of the risk of hypercalcaemia secondary to excessive absorption of calcipotriol when

there is extensive skin involvement, Daivonex

ointment should not be used for severe

extensive psoriasis. In children under 6 years, the maximum safe dose has not been

established; in children 6 to 12 years, the maximum weekly dose should not exceed 50 g; and

in children over 12 years, the maximum weekly dose should not exceed 75 g. In adults, the

maximum dosage of 100 g ointment per week should not be exceeded. When using a

combination of ointment and cream the total maximum dose should not exceed 100 g per

week.

Daivonex

ointment is not recommended for use in patients with generalised pustular

psoriasis, guttate psoriasis and erythrodermic exfoliative psoriasis.

Daivonex

ointment is not recommended for use on the face since it may give rise to itching

and erythema of the facial skin.

Patients should be instructed to wash

their hands after

using Daivonex

®

ointment to avoid inadvertent transfer of ointment to the face from

other body areas.

Should facial dermatitis develop in

spite of these precautions, calcipotriol

therapy should be discontinued.

Daivonex

ointment should be used cautiously in skin folds, where the natural occlusion may

give rise to an increase of any irritant effect of calcipotriol. Occlusive dressings should not be

used as they may increase absorption of calcipotriol.

Treatment with Daivonex

ointment in adults in the recommended amounts up to 100 g/week

for 1 year does not generally result in changes in laboratory values. Hypercalcaemia has been

reported rarely at the recommended dose (i.e. up to 100 g/week) of Daivonex

ointment when

used for the approved indication.

Serum

calcium and renal function should be monitored

at 3 monthly intervals during periods of usage of topical calcipotriol.

If the serum calcium

level is observed to

be elevated, treatment with Daivonex

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.

Treatment with Daivonex

ointment should be discontinued after satisfactory improvement

has occurred and may be restarted if recurrence should develop after discontinuation.

The use of Daivonex

ointment for continuous treatment periods exceeding 1 year has not

been studied.

The stability of calcipotriol in sunlight and UV light has not been demonstrated. No clinical

trials have been conducted with calcipotriol in Australia, where there is a potential to be

exposed to high levels of UV radiation. Therefore, treated areas should be protected from

sunlight and UV light, particularly where exposure may be considerable for reasons such as

occupation. Furthermore, topical calcipotriol should only be used with UV radiation if the

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

The decision to administer Daivonex

ointment in combination with systemic or physical

therapy requires careful consideration. Information on the dosages and risks associated with

systemic or physical therapies can be found in the Product Information documents for the

respective systemic therapies, or in standard texts, which should be consulted. Systemic or

physical therapy poses serious risks of toxicity, and such therapy administered in combination

with topical Daivonex

ointment should be reserved for those adults with refractory psoriasis

who are considered suitable for systemic or physical therapy.

For combination therapy with either UVA or UVB there are no safety and efficacy data

beyond 10 weeks.

Renal Impairment

Safety has not been established in patients with renal impairment.

Hepatic Impairment

Safety has not been established in patients with hepatic impairment.

Paediatric population

There are no long term efficacy and safety data in children. Daivonex

®

ointment should not

be used for more than 8 weeks in children.

Experience of the use of Daivonex

®

ointment in children under 6 years of age is limited.

A maximum safe dose has not been established.

In children 6 to 12 years, the maximum weekly dose should not exceed 50 g and in children

over 12 years, the maximum weekly dose should not exceed 75 g.

4.5

Interaction with other medicines and other forms of interaction

There is no experience of concomitant therapy with other topical antipsoriatic drugs applied to

the same skin area.

Daivonex

ointment should not be used concurrently with calcium or vitamin D supplements,

or with drugs which enhance the systemic availability of calcium.

4.6

Fertility, pregnancy and lactation

Pregnancy

Category B1

Safety for use in pregnancy has not been established. Studies 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 mg/kg/day and in rabbits (reduced skeletal

ossification) at oral doses of 36 mg/kg/day. The significance of these findings for humans is

not known. Therefore Daivonex

ointment should not be used during pregnancy unless

benefits clearly outweigh the risks.

Breastfeeding

It is not known whether calcipotriol is excreted in breast milk, therefore, Daivonex

ointment

should be used during lactation only if the benefits clearly outweigh the risks.

Daivonex

ointment should not be applied to the chest area during breast feeding to avoid

possible ingestion by infants.

Fertility

Studies in rats, at doses up to 54 µg/kg/day (318 µg/m²/day) of calcipotriol, demonstrated no

impairment of fertility or general reproductive performance.

4.7

Effects on ability to drive and use machines

Not relevant.

4.8

Undesirable effects

Adults

In the clinical trial program conducted for Daivonex

ointment, more than 1360 adult patients

were evaluated for safety of calcipotriol. Adverse reactions following treatment with

Daivonex

ointment were reported in 23% of patients and it was necessary to stop calcipotriol

therapy in 2% of patients.

The majority of adverse events reported with Daivonex

ointment were localised to the skin

at the site of application. Lesional/perilesional irritation was reported in 17% of patients,

which included irritant contact dermatitis (on and around psoriatic lesions), flaking at the edge

of lesions, increased sensitivity, tender psoriatic lesions and vesicles on psoriatic lesions.

2.5% of patients developed face and scalp irritation, including in studies which stipulated that

calcipotriol should not be used on the face and scalp, which is likely to be related to

inadvertent transfer of the ointment from other body sites. There is also the potential for

allergic and hypersensitivity reactions. Photosensitivity reaction and changes in pigmentation

have also been reported during therapy with Daivonex

ointment.

For comparison, adverse events at the site of application were reported in 9.2% of patients

receiving placebo therapy and in 10.8% of patients treated with betamethasone valerate

(0.1%) ointment and in 39% of patients treated with dithranol (up to 2%).

One unconfirmed case of Koebner phenomenon has been reported and one unconfirmed case

of allergic reaction to Daivonex

ointment. Occasionally, hypercalcaemia has been reported,

usually related to excessive (greater than 100 g/week) use of the ointment.

Paediatric population

The safety data for topical use of Daivonex

ointment in children are based on the study

described under Section 5.1 Pharmacodynamic properties – clinical efficacy and safety. The

most common adverse event was lesional and perilesional irritation, as was reported in adult

patients. Daivonex

ointment treatment was discontinued in 2.3% of paediatric patients due to

adverse events.

Adverse Events in the vehicle-controlled study

(Reported adverse events have been classified using standard WHO terms)

Adverse Event

% vehicle

(n=34)

% Daivonex

®

ointment

(n=43)

Skin and appendages disorders

lesional/perilesional irritation

23.5

16.3

facial irritation

generalised skin inflammation

Gastro-intestinal system disorders

gastroenteritis

Urinary system disorders

crystals in urine

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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.otage.ac.nz/reporting/

4.9

Overdose

Hypercalcaemia has been reported rarely at the recommended dose of Daivonex

ointment

when used for the approved indication. Excessive use may cause elevated serum calcium,

which rapidly subsides when treatment is discontinued; in such cases, the monitoring of

serum calcium levels once weekly until the serum calcium returns to normal levels is

recommended.

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

0800 POISON (0800 764 766).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Mechanism of action

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)

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.

Clinical efficacy and safety

Clinical trials with Daivonex

Ointment undertaken in adults and children are summarised

below.

Topical treatment of psoriasis in adults using twice daily calcipotriol 50 µg/g ointment

regimen

Two double-blind, multicentre, randomised studies assessed the efficacy and safety of

calcipotriol ointment 50 µg/g twice daily vs betamethasone 17-valerate ointment

0.1% twice daily in patients with psoriasis. The mean study duration was 6 weeks. The

primary efficacy endpoint was the percentage reduction of the Psoriasis Area &

Severity Index (PASI) score. The mean reduction in PASI score was statistically significant

(p<0.001) favouring calcipotriol in one study (MC 288); there was no significant difference

between treatments in the second study (MC 188).

Table 1: Twice-daily administration of calcipotriol 50 µg/g ointment in adults

Study

MC 288

MC 188

Treatment

administered:

Calcipotriol (n = 342)

Betamethasone 17-valerate

(n = 342)

Calcipotriol (n = 201)

Betamethasone 17-valerate

(n = 200)

Results:

Percentage reduction in

PASI

(mean±sd or mean

(95% CI))

Calcipotriol: 68.9±24

Betamethasone: 61.2±27.5

p<0.001

Calcipotriol:

57.7

(49.7, 59.3)

Betamethasone: 51.7

(43.4, 54.2)

p=n.s.

n.s. - not significant

Topical treatment of psoriasis in adults using once daily calcipotriol 50 µg/g regimen

Two double-blind, multicentre, randomised, vehicle-controlled studies of 8 weeks duration

assessed the efficacy and safety of calcipotriol ointment 50 µg/g once daily. Efficacy was

assessed using the Psoriasis Grading Scale to score erythema, scaling, plaque elevation and

overall severity. The primary efficacy parameter was the plaque elevation subscore. There

was a statistically significant difference (p<0.001) favouring calcipotriol.

Table 2: Once daily administration of calcipotriol 50 µg/g ointment in adults

(Intention to treat population)

Study

DE 127-007

DE 127-009

Treatment

administered:

Calcipotriol (n = 118)

Calcipotriol (n = 99)

Vehicle (n = 116)

Vehicle (n = 99)

Results (mean±sd):

Baseline

End

p

value

Baseline

End

p

value

Plaque

elevation

subscore

Calcipotriol

5.22±1.28

2.02±1.94

<0.001

5.05±1.12

2.00±1.41

<0.001

Vehicle

5.09±1.26

3.70±1.74

4.79±0.94

3.39±1.51

Erythema

subscore

Calcipotriol

4.86±1.69

2.33±1.70

<0.001

4.75±1.37

2.51±1.25

<0.001

Vehicle

4.86±1.59

3.88±1.75

4.54±1.27

3.66±1.41

Scaling

subscore

Calcipotriol

5.51±1.66

1.68±1.79

<0.001

4.96±1.47

1.68±1.14

<0.001

Vehicle

5.22±1.59

2.91±1.82

4.62±1.24

64±1.28

Overall

Severity

subscore

Calcipotriol

4.81±1.72

2.15±1.73

<0.001

4.60±1.43

2.12±1.36

<0.001

Vehicle

4.73±1.62

3.65±1.76

4.25±1.29 3.30±1.27

Calcipotriol treatment of psoriasis with cyclosporin A in adults

One double-blind, randomised, multicentre, vehicle-controlled study assessed the efficacy

and safety of calcipotriol ointment 50 µg/g twice daily with cyclosporin 2 mg/kg/day in

patients with severe psoriasis for 6 weeks. Change in PASI score was the primary efficacy

endpoint. There was a statistically significant difference (p<0.01) favouring combination

therapy.

Table 3.1: Administration of calcipotriol 50 µg/g ointment with cyclosporin A in adults

Treatment administered:

Calcipotriol + cyclosporin

Vehicle + cyclosporin

2 mg/kg/day (n = 32)

2 mg/kg/day (n = 34)

Results (mean±sd):

Baseline PASI

25.25±5.90

25.40±4.16

End PASI

4.88±6.79

10.71±8.98

Change in PASI from baseline

20.37±8.55

14.64±8.58

p<0.01

Calcipotriol treatment of psoriasis with acitretin in adults

One double-blind, multicentre, randomised, vehicle-controlled study assessed the efficacy

and safety of calcipotriol ointment 50 µg/g twice daily with acitretin (20-70 mg/day) for 12

weeks in patients with severe/extensive psoriasis unresponsive to topical treatment alone.

The percentage of patients achieving marked improvement or clearance at the end of

treatment was the primary efficacy endpoint. There was a statistically significant difference

(p<0.01) favouring combination therapy.

Table 3.2: Administration of calcipotriol 50 µg/g ointment with acitretin in adults

(Intention to treat population)

Treatment administered:

Calcipotriol +

acitretin

Vehicle +

acitretin

20-70 mg/day

(n = 76)

20-70 mg/day

(n = 59)

Results:

Patients with marked improvement or clearance

67.1%

40.7%

Baseline PASI (mean±sd)

17.8±8.9

17.4±8.6

End PASI (mean±sd)

4.6±5.4

8.6±8.4

p<0.01

Paediatric population

Topical treatment of psoriasis in children using twice daily calcipotriol 50 µg/g

ointment

One double-blind, multicentre, randomised, vehicle-controlled study assessed the safety and

efficacy of calcipotriol 50 µg/g ointment in children of 2 to 14 years with mild to moderate psoriasis

not involving more than 30% of the body surface area.

The study was of 8 weeks duration. The primary efficacy end point was the change in PASI

score. Nine of the 77 children in the trial were under the age of 7 years; 22.2% of children

below 7 years of age received calcipotriol. There was no statistically significant change

observed over placebo.

Table 4: Administration of calcipotriol 50µg/g ointment in children

(Intention to treat)

Treatment administered:

Calcipotriol

(n = 43)

Vehicle

(n =34)

Results (mean±sd):

Reduction in PASI from baseline to end

Baseline:

End:

Change:

6.70±5.80

2.89±4.49

-3.47±5.82

6.33±3.51

3.74±2.96

-2.60±3.54

p=n.s.

5.2

Pharmacokinetic properties

Pharmacokinetic studies with

H-calcipotriol have been performed in rats and minipigs. Oral

absorption of calcipotriol was approximately 60% in rats and 40% in minipigs. The half-life

of calcipotriol was 12 minutes in rats and 60 minutes in minipigs. The major metabolite of

calcipotriol, MC1080, was present in the first plasma sample at 5 minutes; its half life was 54

minutes in rats and 1.8 hours in minipigs. Drug-related radioactivity was excreted in urine and

faeces, and clearance was considered to be almost exclusively metabolic, as less than 5% of

the administered radioactivity was excreted at the time of disappearance of all calcipotriol

from plasma. Determination of the tissue distribution of calcipotriol was complicated by the

appearance of

O from the metabolic degradation of

H-calcipotriol. Autoradiography

studies performed in rats, however, established that calcipotriol concentrations were highest in

the liver, kidney and intestine. No drug-related radioactivity was present 24 hours after

administration of

H-calcipotriol.

Two main metabolites of calcipotriol, MC1046 and MC1080, were present in supernatants

from minipigs, rabbit and human liver homogenates, and in plasma samples from rats and

minipigs. Although the necessity of using very high dosages of calcipotriol precludes the

study of calcipotriol

metabolism in humans, the present evidence strongly suggests that

calcipotriol metabolism is

qualitatively similar in rats, minipigs, rabbits and humans.

Bioavailability studies of calcipotriol ointment in psoriatic and healthy patients demonstrated

that approximately 2-10% of calcipotriol from the applied dose was systemically absorbed.

5.3

Preclinical safety data

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

Mutagenicity

Calcipotriol did not elicit any genotoxic effects in

in vitro

assays for gene mutations (Ames

mutagenicity assay and mouse lymphoma TK locus assay) or chromosomal damage (human

lymphocyte chromosome aberration test or mouse micronucleus test).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dibasic sodium phosphate dihydrate

Disodium edetate dihydrate

dl-Alpha tocopherol

Liquid paraffin

Polyoxyethylene stearyl ether (also known as steareth-2)

Propylene glycol

Purified water

White soft paraffin

6.2

Incompatibilities

Not applicable

6.3

Shelf-life

Unopened container: 2 years

After first opening of container: 6 months

6.4

Special precautions for storage

Store below 25ºC.

For ease of application, do not refrigerate

6.5 Nature and contents of container

Daivonex

ointment is available in aluminium tubes of 15g, 30g or 100g.

6.6 Special precautions for disposal

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

requirements.

7

MEDICINE SCHEDULE

Prescription Medicine

8

SPONSOR

LEO Pharma Ltd

Level 31, Vero Centre

48 Shortland Street

Auckland 1010

New Zealand

Toll Free No. 0800 497 456

9

DATE OF FIRST APPROVAL

30 May 1991

10

DATE OR REVISION OF THE TEXT

29 April 2019

LEO Pharma A/S

Registered proprietor of the trademark LEO

LION Device and

Daivonex

Summary table of changes

Section changed

Summary of new information

Reformat to Medsafe SPC format

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