1 Name of Medicine
Calcipotriol monohydrate.
Betamethasone dipropionate.
2 Qualitative and Quantitative Composition
Klarvanta contains 50 microgram 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
The foam spray in the can is a white to off-white opalescent liquid.
After spraying, a white to off white foam is formed. The foam has the appearance of non-expanding that gradually collapses after spraying.
4.1 Therapeutic Indications
Topical treatment of psoriasis vulgaris in adults.
4.2 Dose and Method of Administration
Klarvanta is for topical use only. Do not use if the pack shows signs of damage or tampering.
Adults.
Flare treatment.
Klarvanta 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 Klarvanta once daily are suitable for long-term maintenance treatment. See Section 5.1, Clinical trials.
Klarvanta 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 Klarvanta treatment.
If signs of a relapse occur, flare treatment, as described above, should be re-initiated.
Maximum dose.
The maximum daily dose of Klarvanta 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 Klarvanta should not exceed 100 g. If using other calcipotriol containing products concomitantly, the total dose of all calcipotriol containing medical products, including Klarvanta, 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. Klarvanta 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. Klarvanta should be sprayed directly onto each affected skin area and rubbed in gently. If used on the scalp, Klarvanta 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 Klarvanta (unless Klarvanta 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 Klarvanta.4.3 Contraindications
i. Hypersensitivity to the active substances or to any of the excipients.
ii. Klarvanta is contraindicated in erythrodermic and pustular psoriasis.
iii. Due to the content of calcipotriol, Klarvanta 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, Klarvanta 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 Klarvanta, 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.
Klarvanta 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.
Klarvanta 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 Klarvanta in guttate psoriasis.
UV exposure.
During Klarvanta 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 Klarvanta in elderly patients have not been established. No data are available.
Paediatric use.
Klarvanta 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 Klarvanta on laboratory tests.4.5 Interactions with Other Medicines and Other Forms of Interactions
No interaction studies have been performed with Klarvanta.
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 Klarvanta in pregnant women. Klarvanta 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 Klarvanta 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 Klarvanta to women who breastfeed. The patient should be instructed not to use Klarvanta on the breast when breastfeeding.4.7 Effects on Ability to Drive and Use Machines
Klarvanta 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 and post-marketing experience.
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.
Klarvanta contains butylated hydroxytoluene as an excipient, which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
Post-marketing 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.
Klarvanta 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 Klarvanta, 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 Klarvanta 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 Klarvanta or foam vehicle twice weekly for up to 52 weeks (long-term maintenance treatment). Subjects experiencing a relapse were treated with Klarvanta 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 Klarvanta 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 Klarvanta 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 Klarvanta or the foam vehicle.
In Trial Two, 302 subjects were randomised to either Klarvanta, betamethasone dipropionate (BDP) in the foam vehicle or calcipotriol in the foam vehicle.
In Trial Three, 376 subjects were randomised to either Klarvanta, 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 Klarvanta 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 Klarvanta 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.
Klarvanta 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 Klarvanta 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 Klarvanta 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 Klarvanta 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 Klarvanta 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 Klarvanta was investigated in a randomised, double-blind vehicle-controlled trial (Trial Four) in adults subjects. Subjects were treated once daily with open-label Klarvanta for 4 weeks and responders were then randomised to receive Klarvanta (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 Klarvanta for 4 weeks, and those responding then continued randomised treatment. See Table 5.
Subjects on long-term maintenance treatment with Klarvanta 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 Klarvanta 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 Klarvanta.
6.5 Nature and Contents of Container
Klarvanta 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
