Use above the recommended dose may cause elevated serum calcium which subsides when treatment is discontinued. The symptoms of hypercalcemia include polyuria, constipation, muscle weakness, confusion and coma.
Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with use of topical calcipotriene.
Due to the content of calcipotriol, Дайвонекс®* is contraindicated in patients with known disorders of calcium metabolism.
Дайвонекс (calcipotriene foam) Foam should not be used by patients with known hypercalcemia.
Should not be mixed with other medicinal products.
The estimation of the frequency of adverse reactions is based on a pooled analysis of data from clinical studies and spontaneous reporting.
The most frequently reported adverse reactions during treatment are pruritus, skin irritation and erythema.
Systemic reactions (hypercalcaemia and hypercalciuria) have been reported. The risk of developing such reactions increases if the recommended total dose is exceeded.
Adverse reactions are listed by MedDRA SOC and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
| Very common Common Uncommon Rare Very rare | >1/10 >1/100 to <1/10 >1/1,000 to <1/100 >1/10,000 to <1/1,000 <1/10,000 |
Approximately 25% of the patients treated with Дайвонекс®* Ointment could experience an adverse reaction. These reactions are usually mild.
| Infections and infestations | |
| Uncommon (>1/1,000 to <1/100) | Folliculitis |
| Immune system disorders | |
| Rare (>1/10,000 to <1/1,000) | Hypersensitivity |
| Metabolism and nutrition disorders | |
| Rare (>1/10,000 to <1/1,000) | Hypercalcaemia |
| Skin and subcutaneous tissue disorders | |
| Common (>1/100 to < 1/10) | Psoriasis aggravated Dermatitis Erythema Skin exfoliation Skin burning sensation Skin irritation Pruritus |
| Uncommon (>1/1,000 to <1/100) | Rash* Dry skin |
| Rare (>1/10,000 to <1/1,000) | Photosensitivity reaction Skin oedema Urticaria Seborrhoeic dermatitis |
| Renal and urinary disorders | |
| Rare (>1/10,000 to <1/1,000) | Hypercalciuria |
| General disorders and administration site conditions | |
| Common (>1/100 to <1/10) | Application site pain |
| Uncommon (>1/1,000 to <1/100) | Application site pigmentation changes |
* Various types of rash reactions such as rash erythematous, rash maculo-papular, rash morbilliform, rash papular and rash pustular have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.Clinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Дайвонекс (calcipotriene foam) Foam was studied in three-vehicle controlled trials. Seven hundred and thirty one subjects with plaque psoriasis, including 473 exposed to Дайвонекс (calcipotriene foam) Foam were treated twice daily for 8 weeks.
Adverse events reported in greater than 1% of subjects and in a higher rate in subjects treated with Дайвонекс (calcipotriene foam) Foam compared to vehicle were limited to erythema.
The effect on calcium metabolism is approximately 100 times less than that of the hormonally active form of vitamin D3.
Calcipotriol has shown maternal and foetal toxicity in rats and rabbits when given by the oral route at doses of 54 µg/kg/day and 12 µg/kg/day, respectively. The foetal abnormalities observed with concomitant maternal toxicity included signs indicative of skeletal immaturity (incomplete ossification of the pubic bones and forelimb phalanges, and enlarged fontanelles) and an increased incidence of supernumerary ribs.
There is insufficient pharmacokinetic data available to quantify the safety margin for the embryofoetal effects.
A dermal carcinogenicity study in mice and an oral carcinogenicity study in rats revealed no special hazard to humans.
In a study where albino hairless mice were repeatedly exposed to both ultraviolet (UV) radiation and dermally administered calcipotriol for 40 weeks at dose levels corresponding to 9, 30 and 90 µg/m2/day (equivalent to 0.25, 0.84, 2.5 times the maximum recommended daily dose for a 60 kg adult, respectively), 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.
Дайвонекс®* Ointment is indicated for the topical treatment of plaque psoriasis (psoriasis vulgaris) amenable to topical therapy.
Дайвонекс (calcipotriene foam) Foam is indicated for the topical treatment of plaque psoriasis in patients aged 18 years and older.
ATC Code: D05A X02
Pharmacotherapeutic group: Antipsoriatics for topical use
Calcipotriol is a vitamin D derivative. In vitro data suggest that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.
The pharmacodynamics of Дайвонекс (calcipotriene foam) Foam are unknown.
Data from a single study containing 5 evaluable patients with psoriasis treated with 0.3-1.7 g of a 50 micrograms/g tritium labelled calcipotriol ointment suggested that less than 1% of the dose was absorbed.
However, total recovery of the tritium label over a 96 hour period ranged from 6.7 to only 32.6%, figures maximised by uncorrected chemiluminescence. There were no data on 3H tissue distribution or excretion from the lungs.
The systemic absorption of calcipotriene in psoriatic subjects was evaluated at steady state following application of Дайвонекс Foam or calcipotriene ointment. In the Дайвонекс Foam treatment group, 15 out of 16 subjects showed calcipotriene plasma concentrations below the limit of quantitation (10 pg/mL), while in the calcipotriene ointment treated group, 5 out of 16 subjects had measurable calcipotriene plasma concentrations at various time points. All measurable plasma calcipotriene concentrations were below 25 pg/mL.
The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin D. Absorbed calcipotriene is known to be converted to inactive metabolites within 24 hours of application and the metabolism occurs via a similar pathway to the natural hormone.
Effects on calcium metabolism
Due to the content of calcipotriol, hypercalcaemia may occur if the maximum weekly dose is exceeded. Care should be exercised in patients with other types of psoriasis, since hypercalcaemia has been reported in patients with generalised pustular or erythrodermic exfoliative psoriasis. Serum calcium is normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the dosage recommendations are followed. The maximum weekly dose in adults is 100 g of cream or ointment (equivalent to 5 mg of calcipotriol) or 60 ml of scalp solution (equivalent to 3 mg of calcipotriol). When cream, ointment or cutaneous solution are applied together, the total dose of calcipotriol should not exceed 5 mg per week.
Local adverse reactions
Дайвонекс®* should not be applied to the face, as it may cause skin irritation
The patient must be instructed in correct use of the product to avoid accidental transfer to the face and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.
UV exposure
During Дайвонекс®* Ointment treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Дайвонекс®* should be used with UV radiation only if the physician and patient consider that the potential benefits outweigh the potential risks.
Unevaluated use
Due to lack of data, Дайвонекс®* should be avoided in guttate, erythrodermic, exfoliative and pustular psoriasis.
Due to lack of data, Дайвонекс®* should be avoided in patients with severe liver and kidney disease.
Adverse reactions to excipients
Дайвонекс®* ointment contains propylene glycol as an excipient which may cause skin irritation.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS FlammabiUtyThe propellant in Дайвонекс (calcipotriene foam) is flammable. Instruct the patient to avoid fire, flame, and/or smoking during and immediately following application.
Effects on Calcium MetabolismTransient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.
Ultraviolet Light ExposureInstruct the patient to avoid excessive exposure of the treated areas to either natural or artificial sunlight, including tanning booths and sun lamps. Physicians may wish to limit or avoid use of phototherapy in patients who use Дайвонекс (calcipotriene foam) Foam.
Unevaluated UsesДайвонекс (calcipotriene foam) Foam has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis.
Patient Counseling InformationThe patient should be instructed as follows:
Calcipotriene topically administered to mice for up to 24 months at dose levels of 3, 10, or 30 mcg/kg/day (corresponding to 9, 30, or 90 mcg/m2/day) showed no significant changes in tumor incidence when compared to controls. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors.
The genotoxic potential of calcipotriene was evaluated in an Ames assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, and a mouse micronucleus assay. All assay results were negative.
Studies in rats at doses up to 54 mcg/kg/day (318 mcg /m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.
Use In Specific Populations Pregnancy Teratogenic Effects, Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Therefore, Дайвонекс (calcipotriene foam) Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 mcg/kg/day (132 mcg/m2/day). Rabbits administered 36 mcg/kg/day (396 mcg/m2/day) resulted in fetuses with a significant increase in the incidences of incomplete ossification of pubic bones and forelimb phalanges. In a rat study, doses of 54 mcg/kg/day (318 mcg/m2/day) resulted in a significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The maternal and fetal no-effect exposures in the rat (43.2 mcg/m2/day) and rabbit (17.6 mcg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 mcg/m2/day) from dermal application.
Nursing MothersIt is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Дайвонекс (calcipotriene foam) Foam is administered to a nursing woman.
Pediatric UseSafety and effectiveness of Дайвонекс (calcipotriene foam) Foam in pediatric patients less than 18 years of age have not been established.
Geriatric UseClinical studies of Дайвонекс (calcipotriene foam) Foam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Calcipotriol has no or negligible influence on the ability to drive and to use machines.
| Adults: | Дайвонекс®* Ointment should be applied to the affected area once or twice daily. For maximum benefit use the ointment twice daily. Maximum weekly dose should not exceed 100 g. |
| Children over 12 years: | Дайвонекс®* Ointment should be applied to the affected area twice daily. Maximum weekly dose should not exceed 75 g. |
| Children aged 6 to 12 years: | Дайвонекс®* Ointment should be applied to the affected area twice daily. Maximum weekly dose should not exceed 50 g. |
Children under 6 years: | There is limited experience of the use of Дайвонекс®* Ointment in this age group. A maximum safe dose has not been established. |
These dose recommendations are based on extensive experience in adults. In respect of children, clinical experience in children has shown Дайвонекс®* to be safe and effective over eight weeks at a mean dose of 15 g per week but with wide variability in dose among patients. Individual dose requirement depends on the extent of psoriasis but should not exceed the above recommendations. There is no experience of use of Дайвонекс®* in combination with other therapies in children.
For topical use only. Дайвонекс (calcipotriene foam) Foam is not for oral, ophthalmic, or intravaginal use.
Apply a thin layer of Дайвонекс (calcipotriene foam) Foam twice daily to the affected areas and rub in gently and completely.
No special requirements.
