Consumer medicine information

Enstilar

Calcipotriol; Betamethasone

BRAND INFORMATION

Brand name

Enstilar

Active ingredient

Calcipotriol; Betamethasone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Enstilar.

SUMMARY CMI

Enstilar®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Enstilar®?

Enstilar® is a combination product that contains the active ingredients calcipotriol and betamethasone dipropionate. Enstilar® is a topical treatment for a skin condition called psoriasis.

For more information, see Section 1. Why am I using Enstilar®? in the full CMI.

2. What should I know before I use Enstilar®?

Do not use if you have ever had an allergic reaction to Enstilar® or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Enstilar®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Enstilar® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Enstilar®?

  • Enstilar® is designed for direct application (spray on) to your skin where it is affected by psoriasis
  • Enstilar® should be applied to dry skin on the affected areas of the body or scalp
  • Your doctor will decide how much Enstilar® you need to use and for how long

More instructions can be found in Section 4. How do I use Enstilar®? in the full CMI.

5. What should I know while using Enstilar®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Enstilar®
  • Protect the treated skin areas from sunlight and ultraviolet (UV) rays
  • Inform your doctor and pharmacist that you are using Enstilar® if you are starting any new medicine
  • Tell your doctor immediately if you become pregnant while using Enstilar®
Things you should 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
  • Do not use other topical corticosteroids on areas treated with Enstilar®
Driving or using machines
  • Enstilar® is not expected to affect your ability to drive or operate machinery
Looking after your medicine
  • Keep Enstilar® in a cool dry place. Store below 25°C
  • Enstilar® comes in a pressurised container and is extremely flammable. It may burst if heated. Protect from sunlight and do not expose to temperatures above 50°C

For more information, see Section 5. What should I know while using Enstilar®? in the full CMI.

6. Are there any side effects?

Enstilar® may cause local skin reactions or irritation to the eyes and mucous membrane. Some common side effects include skin irritation, skin pain, rash, change in skin colour, increased skin sensitivity to light, change in control of diabetes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Enstilar® Foam Spray

Active ingredient(s): Calcipotriol 50 microgram/g and Betamethasone 500 microgram/g present as dipropionate
Calcipotriol (Kal-sippo-try-all) / Betamethasone (Beet-ah-meth-ah sown)


Consumer Medicine Information (CMI)

This leaflet provides important information about using Enstilar®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Enstilar®.

Where to find information in this leaflet:

1. Why am I using Enstilar®?
2. What should I know before I use Enstilar®?
3. What if I am taking other medicines?
4. How do I use Enstilar®?
5. What should I know while using Enstilar®?
6. Are there any side effects?
7. Product details

1. Why am I using Enstilar®?

Enstilar® contains two active ingredients:

  • Calcipotriol as monohydrate (related to Vitamin D);
  • Betamethasone dipropionate (a corticosteroid)

Enstilar® is a topical treatment for psoriasis. Psoriasis is a skin disorder in which skin cells are overactive. This causes redness, scaling and thickness of your skin.

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

Enstilar® is available only with a doctor's prescription.

2. What should I know before I use Enstilar®?

Warnings

Do not use Enstilar® if:

  • you are allergic to calcipotriol, betamethasone dipropionate, or any of the ingredients listed at the end of this leaflet, or any other similar medicine such as topical corticosteroids.
  • Always check the ingredients to make sure you can use this medicine.

Do not use Enstilar® on skin affected by:

  • Viral, fungal, bacterial or parasitic skin infections
  • Tuberculosis (TB)
  • 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

Check with your doctor if you:

  • have high blood calcium levels
  • have other types of psoriasis known as generalised pustular or erythrodermic exfoliative psoriasis (your doctor will identify these conditions for you)
  • take any medicines for any other condition
  • are suffering from any illness before using Enstilar®

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

During treatment, you may be at risk of developing certain side effects. 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.

It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Do not use Enstilar® in children.

Safety and effectiveness of Enstilar® in those below 18 years of age has not been established.

3. What if I am taking other medicines?

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Enstilar®.

4. How do I use Enstilar®?

How much to use

  • Follow carefully all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.
  • Enstilar® is for topical use (on the skin). Before use, read the patient information, even if you have used Enstilar® before. Enstilar® is designed for direct application (spray on) to your skin, where it is affected by psoriasis.
  • Important: Do not use more than 15g in one day. 15g corresponds to the amount sprayed from the can when the actuator is fully pressed down for 1 minute.
  • Do not use more than 100g in one week. One 60g can should last you at least 4 days.
  • If you also use other calcipotriol containing products (e.g.: Daivobet® gel or ointment, Daivonex®) for your psoriasis, then the total amount of calcipotriol products must not exceed 15g per day or 100g per week.
  • As a guide, a short 2 second spray of Enstilar® provides 0.5g of the medication and this amount should be sufficient to cover an area of skin roughly corresponding to the area of an adult hand.
  • Follow the instructions provided and use Enstilar® until your doctor tells you to stop.

NOTE: If you use more than the recommended amount of Enstilar®, 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 Enstilar® or any other product containing calcipotriol (eg., Daivobet® gel or ointment, Daivonex®) should not be used until the calcium level has become normal again.

Blood calcium levels will quickly normalize when your doctor discontinues Enstilar® treatment.

When to use Enstilar®

  • Apply Enstilar®once a day at the most convenient time for you, and try applying it about the same time of the day each day (for example, morning, afternoon, or evening)

How long to use Enstilar®

  • Each treatment course would normally last for up to four weeks.
  • Your doctor may decide to stop treatment with Enstilar® or require you to use it twice weekly once your psoriasis has improved.
  • If using Enstilar® twice weekly, it should be applied on two non-consecutive days (e.g. Wednesday and Saturday) to areas previously affected by psoriasis. There should be 2-3 days without Enstilar® treatment.
  • If symptoms re-appear, you should use Enstilar® once daily as outlined above and contact your doctor to review your treatment.

How to use Enstilar®

  • Enstilar® should be applied to dry skin on the affected areas of the body or scalp.

For body psoriasis

  1. Shake the can for a few seconds before use and remove the cap.

  1. Apply the medication by holding the can at least 3cm (approximately 1.5 inches) from the skin and spray onto the affected area.

  1. The foam can be sprayed by holding the can in any orientation except horizontally. Apply a layer of foam only to the psoriasis plaques. Spray directly onto each affected skin area and gently rub in. If you accidentally put some of the foam on normal skin, wipe it off as soon as possible.

  1. Gently rub the foam into your affected skin areas. You will need to repeat steps 1 to 4 until all of the affected areas are covered.

  1. After applying your medication, put the cap back on the can to prevent accidental pressing of the can when not in use.
  2. Wash your hands well after using Enstilar® (unless you are using the foam to treat your hands). This will avoid accidentally spreading the foam to other parts of your body (especially face, mouth and eyes).

  1. Take care not to get the foam spray in your eyes. If this happens, rinse your eyes with clean water and seek medical advice.
  2. If you accidentally put some of the foam onto skin not affected by psoriasis, wipe it off as soon as possible.
  3. Do not bandage, tightly cover or wrap the treated area.

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

  1. Comb the hair to remove any loose scales.
  2. Shake the can for a few seconds before use and remove the cap.

  1. Hold the can at least 3 cm (1.5 inches) away. Spray directly into the palm of your hand. The foam can be sprayed holding the can in any orientation except horizontally.

  1. Scoop the foam onto your finger and apply it directly to the affected areas of the scalp. Minimise applying into the hair to make it easier to wash it out. Gently rub the foam into the scalp.

  1. After applying your medication, put the cap back on the can to prevent accidental pressing of the can when not in use.
  2. Wash your hands well after using Enstilar®. This will avoid accidentally spreading the foam to other parts of your body (especially the face, mouth and eyes).

  1. Take care not to get the foam in your eyes. If this happens, rinse your eyes with clean water and tell your doctor.
  2. If you accidentally put some of the foam onto skin not affected by psoriasis, wipe it off as soon as possible.
  3. Do not bandage, tightly cover or wrap the treated area.

For best results, do not wash your hair immediately after applying. Leave Enstilar® on during the day or night. The treated area does not need to be covered.

After applying to the scalp, the following instructions when washing your hair might be useful.

  1. Apply a mild, non-medicated shampoo to the dry hair, focusing on the areas where the foam was applied.
    It is easier to remove Enstilar® when the shampoo is applied to dry hair as water dilutes the cleansing effect of the shampoo.

  1. Massage the shampoo into the dry hair/scalp. Leave the shampoo on the scalp for a couple of minutes before washing.
  2. Rinse thoroughly with water.
  3. Repeat normal shampooing if necessary.

If you forget to use Enstilar®

Enstilar® should be used regularly at the same time each day. If you miss your dose at the usual time, use it as soon as you remember, then continue as before. Do not use an increased dose of the foam 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 Enstilar®

If you think that you have used too much Enstilar®, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Enstilar®?

Things you should do

While you are using Enstilar®, protect the treated skin areas from sunlight and ultraviolet (UV) rays, for example, by wearing protective clothing. This is particularly important if your job or lifestyle means you spend time outdoors.

Wash your hands thoroughly after applying Enstilar® on any parts of your body unless your hands are being treated.

Thoroughly wash your hands prior to handling infants or children.

Enstilar® may cause a cool sensation on the skin when applied. If any skin irritation develops, wash off the Enstilar®.

Call your doctor straight away if you:

  • If you are going to start any new medicine
  • If you become pregnant while using Enstilar®

Remind any doctor, dentist or pharmacist you visit that you are using Enstilar®.

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

Things you should not do

  • Do not use Enstilar®
    - on large areas of damaged skin;
    - in skin folds (eg., 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)
  • 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
  • Do not use other topical corticosteroids (eg., Advantan®, Diprosone®, Elocon®) on areas treated with Enstilar®.

Driving or using machines

Enstilar® is not expected to affect your ability to drive or operate machinery

Looking after your medicine

  • Keep Enstilar® in the box until required.
  • Store in a cool dry place, store below 25°C

Follow the instructions in the carton on how to take care of your medicine properly.

CAUTION: Extremely flammable

Pressurised container: May burst if heated. Protect from sunlight and do not expose to temperatures above 50°C. Do not pierce or burn, even after use. Do not spray on an open flame or other ignition source. Keep away from sparks, open flames and other ignition sources. Do not smoke while applying Enstilar®.

Keep Enstilar® in the box to protect from light.

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

Getting rid of any unwanted medicine

Ask your pharmacist what to do with any Enstilar® that is left over if

  • your doctor tells you to stop using Enstilar®, or
  • the can has been opened for more than 6 months, or
  • the expiry date has passed.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Skin irritation including:
  • Itching
  • Redness
  • Dryness
  • Swelling
  • Peeling
Other skin-related:
  • Skin pain (including burning)
  • Rash on your face or body
  • Change in skin colour
  • Skin becoming more sensitive to light
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Blood sugar-related:
  • Change in control of diabetes
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Enstilar® contains butylated hydroxytoluene. This may cause local skin reactions (eg., contact dermatitis) or irritation to the eyes and mucous membranes.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Enstilar® contains

Active ingredient
(main ingredient)
  • Calcipotriol (50 microgram/g) [as monohydrate]
  • Betamethasone dipropionate (500 microgram/g)
Other ingredients
(inactive ingredients)
  • Liquid paraffin
  • Polyoxypropylene-11 stearyl ether
  • dl-alpha-tocopherol
  • White soft paraffin
  • Butylated hydroxytoluene (included as an antioxidant in polyoxypropylene-11 stearyl ether)
  • Propellants: butane and methyl ether

Do not take this medicine if you are allergic to any of these ingredients.

What Enstilar® looks like

Enstilar® is in a pressurised can. After spraying, a white to off-white foam is formed on the skin. The foam is a non-expanding foam, which gradually collapses after spraying

The Australian Registration Number is AUST R 263292.

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

Who distributes Enstilar®

Enstilar® is supplied in Australia by:

LEO Pharma Pty Ltd
Brisbane, QLD Australia
Toll free no: 1800 991 778
Web: www.leo-pharma.com.au

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

This leaflet was prepared in March 2022.

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Enstilar

Active ingredient

Calcipotriol; Betamethasone

Schedule

S4

 

1 Name of Medicine

Calcipotriol monohydrate.
Betamethasone dipropionate.

2 Qualitative and Quantitative Composition

Enstilar contains 50 micrograms of calcipotriol (as monohydrate) and 500 microgram of betamethasone (as dipropionate) per gram.

Excipients with known effect.

Butylated hydroxytoluene.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Foam spray.
After spraying, a white to off white foam is formed. The foam has the appearance of non-expanding foam that gradually collapses after spraying.

4 Clinical Particulars

4.1 Therapeutic Indications

Topical treatment of psoriasis vulgaris in adults.

4.2 Dose and Method of Administration

Enstilar is for topical use only. Do not use if the pack shows signs of damage or tampering.

Adults.

Flare treatment.

Enstilar should be applied to the affected area once daily. The recommended treatment period is 4 weeks. If it is necessary to continue or restart treatment after this period, treatment should be continued after medical review and under regular medical supervision. Treatment of relapses has been found to be efficacious and well tolerated.

Long-term maintenance treatment.

Patients who have responded at 4 weeks treatment using Enstilar once daily are suitable for long-term maintenance treatment. See Section 5.1, Clinical trials.
Enstilar should be applied twice weekly on two non-consecutive days to areas previously affected by psoriasis vulgaris. Between applications there should be 2-3 days without Enstilar treatment.
If signs of a relapse occur, flare treatment, as described above, should be re-initiated.

Maximum dose.

The maximum daily dose of Enstilar should not exceed 15 g, i.e. one 60 g can should last for at least 4 days of treatment. 15 g corresponds to the amount administered from the can if the actuator is fully depressed for approximately one minute. A two-second application delivers approximately 0.5 g. As a guide, 0.5 g of foam should cover an area of skin roughly corresponding to the surface area of an adult hand.
The maximum weekly dose of Enstilar should not exceed 100 g. If using other calcipotriol containing products concomitantly, the total dose of all calcipotriol containing medical products, including Enstilar, should not exceed 15 g per day and 100 g per week.
The total body surface area treated should not exceed 30%.

Method of administration.

The can should be shaken before use. Enstilar should be applied by holding the can at least 3 cm (approximately 1.5 inches) from the skin and sprayed. The foam can be sprayed holding the can in any orientation except horizontally. Enstilar should be sprayed directly onto each affected skin area and rubbed in gently. If used on the scalp, Enstilar should be sprayed into the palm of the hand and then applied to the affected scalp areas with the fingertips. Hair washing instructions are provided in the Consumer Medicine Information. The hands should be washed after using Enstilar (unless Enstilar is used to treat the hands) to avoid accidentally spreading to other parts of the body. It is recommended not to take a shower or bath immediately after application of Enstilar.

4.3 Contraindications

i. Hypersensitivity to the active substances or to any of the excipients.
ii. Enstilar is contraindicated in erythrodermic and pustular psoriasis.
iii. Due to the content of calcipotriol, Enstilar is contraindicated in patients with known disorders of calcium metabolism (see Section 4.4 Special Warnings and Precautions for Use, Effects on calcium metabolism).
iv. Due to the content of corticosteroid, Enstilar is contraindicated in the following conditions if present in the treatment area: viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds.

4.4 Special Warnings and Precautions for Use

For external use only.

Effects on endocrine system.

Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impaired glycaemic 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.

Effects on calcium metabolism.

Due to the content of calcipotriol in Enstilar, hypercalcaemia may occur if the maximum weekly dose (100 g) is exceeded. Serum calcium is normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the maximum weekly dose of calcipotriol is not exceeded.

Local adverse reactions.

Enstilar contains a potent group III steroid and concurrent treatment with other steroids on the same treatment area must be avoided.
Skin of the face and genitals are very sensitive to corticosteroids. This product should not be used in these areas.
The patient must be instructed on 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.
Enstilar contains butylated hydroxytoluene which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Concomitant skin infections.

When lesions become secondarily infected, they should be treated with antimicrobial therapy. However, if the infection worsens, treatment with corticosteroids should be discontinued.

Discontinuation of treatment.

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

Long-term use.

Long term use of corticosteroids may increase the risk of local and systemic adverse reactions.
Treatment should be discontinued in case of adverse reactions related to long term use of corticosteroids.

Unevaluated use.

There is no experience with the use of Enstilar in guttate psoriasis.

UV exposure.

During Enstilar treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks.

Use in the elderly.

The safety and efficacy of Enstilar in elderly patients have not been established. No data are available.

Paediatric use.

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

Effects on laboratory tests.

There are no data available on the effects of Enstilar on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Enstilar.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Possible effects of betamethasone dipropionate in combination with calcipotriol on fertility have not been investigated in animals. Studies in rats with oral doses of calcipotriol or betamethasone dipropionate demonstrated no impairment of male and female fertility.
(Category B3)
There are no adequate data from the use of Enstilar in pregnant women. Enstilar should only be used during pregnancy when the potential benefit clearly outweighs the potential risk. Studies of corticocorticoids 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 the 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 mg/kg/day. The relevance of these findings for humans is unknown.
Betamethasone passes into breast milk. It is unknown if topical application of Enstilar 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 Enstilar to women who breastfeed. The patient should be instructed not to use Enstilar on the breast when breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Undesirable effects.

The estimation of the frequency of adverse reactions is based on a pooled analysis of data from clinical studies.
The most frequently reported adverse reactions during treatment are application site reactions.
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 (see Table 1).
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).
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 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.

Betamethasone (as dipropionate).

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 a risk of generalised pustular psoriasis.
Systemic reactions due to topical use of corticosteroids are rare in adults; however, they can be severe. Adrenocortical suppression, cataract, infections, impaired glycaemic control of diabetes mellitus and increase of intraocular pressure can occur, especially after long-term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long-term treatment.

Adverse reactions to excipients.

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

Postmarketing experience.

No data available at this time.

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

Usage above 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 result in adrenocortical suppression which is usually reversible. Symptomatic treatment may be indicated.
In case of chronic toxicity the corticosteroid treatment must be discontinued gradually.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, calcipotriol, combinations. ATC code: D05AX52.

Mechanism of action.

Enstilar combines the pharmacological effects of calcipotriol hydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid.
In combination, calcipotriol monohydrate and betamethasone dipropionate promote greater anti-inflammatory and antiproliferative effects than either component alone.

Pharmacodynamic effects.

Short-term data.

Under maximum use conditions, in subjects with extensive psoriasis on the body and scalp treated for up to 4 weeks adrenal response to ACTH was determined by measuring serum cortisol levels. None of 35 subjects had suppressed serum cortisol levels at 30 or 60 minutes post-ACTH stimulation. Thus it appears that for Enstilar, the risk of adrenal suppression is low when applied to extensive psoriasis vulgaris for 4 weeks. Similarly, there was no indication of abnormal calcium metabolism following application of Enstilar to extensive psoriasis vulgaris for 4 weeks.

Long-term data.

The adrenal response to ACTH challenge was evaluated in adult subjects with moderate to severe psoriasis vulgaris involving at least 10% of the body surface area. The subjects were randomised to receive Enstilar or foam vehicle twice weekly for up to 52 weeks (long-term maintenance treatment). Subjects experiencing a relapse were treated with Enstilar once daily for 4 weeks, then continued randomised treatment.
The trial results were in line with a low risk of adrenal suppression in subjects with extensive psoriasis (BSA 10-30%) who use Enstilar twice weekly and as outlined for up to 52 weeks. There was no clinically relevant effect on the calcium metabolism in this trial.

Clinical trials.

Efficacy.

Short-term data.

The efficacy of once daily use of Enstilar has been investigated in three randomised, double blind or investigator blind, 4 week clinical trials including more than 1100 subjects with psoriasis on the body (also scalp in Trial Two) of at least mild severity according to the Physician's Global Assessment of disease severity (PGA), affecting at least 2% body surface area (BSA) and with a modified psoriasis area severity index (m-PASI) of a least 2. The Physician's Global Assessment is made using a 5 point scale (clear, almost clear, mild, moderate and severe) based on the average psoriatic lesion. The m-PASI is a composite score assessing severity (erythema, scale and induration) and affected area (excluding face and skin folds).
In Trial One, 426 subjects were randomised to either Enstilar or the foam vehicle.
In Trial Two, 302 subjects were randomised to either Enstilar, betamethasone dipropionate (BDP) in the foam vehicle or calcipotriol in the foam vehicle.
In Trial Three, 376 subjects were randomised to either Enstilar, Daivobet ointment, foam vehicle or ointment vehicle.
The primary endpoint was subjects with 'treatment success' ('clear' or 'almost clear' for subjects with at least moderate disease at baseline, 'clear' for subjects with mild disease at baseline) according to the PGA at week 4. See Table 2 and Table 3.
Results for the primary endpoint 'treatment success' (PGA) of body at week 4 showed Enstilar to be statistically significantly more effective than all the comparators included and responses were observed in all categories of baseline disease severity.
In Trial Two the effect of Enstilar on scalp psoriasis was investigated as the percentage of subjects with 'treatment success' according to the PGA of the scalp at week 4. See Table 4.
Enstilar was statistically significantly more effective compared to calcipotriol and also associated with a higher rate of treatment success than BDP but this comparison did not reach statistical significance.
The effect of once daily use of Enstilar on itch and itch related sleep loss was investigated in Trial One by assessments with a visual analogue scale (VAS) where the range was from 0 mm (no itch at all) to 100 mm (worst itch you can imagine). Only subjects who reported itch and itch related sleep loss at baseline were evaluated. See Figures 1 and 2.
Statistically significant differences of at least 70% reduction in both itch and itch related sleep loss were observed in favour of subjects receiving Enstilar compared to those receiving foam vehicle from day 3 and throughout the treatment period.
Quality of life was investigated in Trial One by means of the generic EQ-5D-5L and the dermatologically specific DLQI. Statistically significantly greater improvement in quality of life, measured by DLQI, was demonstrated for subjects receiving Enstilar compared to those receiving foam vehicle from week 1 and throughout the treatment period. Measured by EQ-5D-5L, a statistically significantly greater improvement in favour of subjects receiving Enstilar compared to those receiving foam vehicle was demonstrated at week 4.

Long-term data.

Long-term maintenance treatment has been shown to prolong the time to first relapse, increase proportion of days in remission, reduce the number of relapses, and was well tolerated.
The efficacy and safety of treatment with Enstilar was investigated in a randomised, double-blind vehicle-controlled trial (Trial Four) in adults subjects. Subjects were treated once daily with open-label Enstilar for 4 weeks and responders were then randomised to receive Enstilar (long-term maintenance treatment) or foam vehicle twice weekly for up to 52 weeks. Subjects in both treatment arms experiencing a relapse were treated once daily with Enstilar for 4 weeks, and those responding then continued randomised treatment. See Table 5.
Subjects on long-term maintenance treatment with Enstilar had longer time to first relapse, greater proportion of days in remission during the trial, and fewer relapses than subjects using foam vehicle. Table 6 presents an overview of the effect on relapse in this trial.

5.2 Pharmacokinetic Properties

Absorption.

The extent of percutaneous absorption of the two active ingredients following topical application of Enstilar was determined in the HPA axis trial in subjects with extensive psoriasis vulgaris (see Pharmacodynamic effects). Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in most samples from 35 patients treated once daily for 4 weeks for extensive psoriasis involving the body and scalp.
Calcipotriol was quantifiable at some time point in 1 subject, betamethasone dipropionate in 5 subjects and metabolites of calcipotriol and betamethasone dipropionate were detectable in 3 and 27 subjects, respectively.

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 active ingredients, calcipotriol and betamethasone dipropionate are rapidly and extensively metabolised.

Excretion.

The main route of excretion of calcipotriol is via faeces (rats and mini pigs) and for betamethasone dipropionate it is via urine (rats and mice).

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 2 year carcinogenicity study with calcipotriol in mice showed no indications of an increase in tumours at doses up to 30 microgram/kg/day (below the clinical dose on a body surface area basis).
In a 40 week study in which albino hairless mice were exposed to both ultraviolet radiation (UVR) and topically applied calcipotriol, a reduction in the time required for UVR to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UVR to induce skin tumours.
A 2 year oral carcinogenicity study was conducted with calcipotriol in rats at doses up to 15 microgram/kg/day. A treatment related increase in benign c-cell adenomas was observed in the thyroid of males at 15 microgram/kg/day and females that received ≥ 5 microgram/kg/day. A treatment related increase in benign pheochromocytomas was observed in the adrenal glands of males receiving 15 microgram/kg/day. The relevance of these findings to patients is unknown.
When betamethasone dipropionate was applied topically to mice for up to 24 months at doses up to 8.5 microgram/kg/day in females, and 12.9 microgram/kg/day in males or administered given orally to rats for up to 24 months at doses up to 200 microgram/kg/day (estimated exposures based on AUC of the metabolite betamethasone 17-propionate at least 70 times that expected in patients), no significant changes in tumour incidence were observed when compared to control.

6 Pharmaceutical Particulars

6.1 List of Excipients

Liquid paraffin, polyoxypropylene-11 stearyl ether, dl-alpha-tocopherol, white soft paraffin, butylated hydroxytoluene (included as an antioxidant in polyoxypropylene-11 stearyl ether). Propellants: butane and methyl ether.

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.
Caution: Extremely flammable. Pressurised container. May burst if heated. Protect from sunlight and do not expose to temperatures exceeding 50°C. Do not pierce or burn, even after use. Do not spray on an open flame or other ignition source. Keep away from sparks, open flames and other ignition sources. Do not smoke while applying Enstilar.

6.5 Nature and Contents of Container

Enstilar is contained in a white aluminium can fitted with a continuous valve and a polypropylene actuator with a frosted cap. The registered pack sizes are 60 g* and 2 x 60 g.
* Marketed pack size.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Calcipotriol monohydrate.


Calcipotriol monohydrate is (5Z, 7E, 22E, 24S) -24-Cyclopropyl-9,10-secochola- 5,7,10(19),22-tetraene-1α,3β,24-triol monohydrate. 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-11 β, 17, 21-trihydroxy-16 β-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: 147657-22-5.
Betamethasone dipropionate: 5593-20-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes