CALCIPOTRIOL
DESCRIPTION:
Calcipotriol or calcipotriene monohydrate, a synthetic vitamin D3 derivative, for topical dermatological use.
Chemically, calcipotriene monohydrate is (5Z,7E,22E,24S)-24-cyclopropyl-9, 10-
secochola- 5,7,10(19), 22-tetraene-1alpha,3beta,24-triol monohydrate, with the
empirical formula C27H40O3.H2O, and a molecular weight of 430.6.
Calcipotriene monohydrate is a white or off-white crystalline substance.
ACTIONS/CLINICAL PHARMACOLOGY:
In humans, the natural supply of vitamin D depends mainly on exposure to the
ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3
(cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin
D3.
Clinical studies with radiolabelled calcipotriene ointment indicate that
approximately 6% (+/- 3%, SD) of the applied dose of calcipotriene is absorbed
systemically when the ointment is applied topically to psoriasis plaques or 5%
(+/-2.6%, SD) when applied to normal skin, and much of the absorbed active is
converted to inactive metabolites within 24 hours of application. Systemic
absorption of the cream has not been studied.
Vitamin D and its metabolites are transported in the blood, bound to specific
plasma proteins. The active form of the vitamin, 1,25-dihydroxy vitamin D3
(calcitriol) is known to be recycled via the liver and excreted in the bile.
Calcipotriene metabolism following systemic uptake is rapid and occurs via a
similar pathway to the natural hormone.
CLINICAL STUDIES:
Adequate and well-controlled trials of patients treated with CALCIPOTRIENE have
demonstrated improvement usually beginning after 2 weeks of therapy. This
improvement continued with approximately 50% of patients showing at least marked
improvement in the signs and symptoms of psoriasis after 8 weeks of therapy, but
only approximately 4% showed complete clearing.
INDICATIONS AND USAGE:
calcipotriene is indicated for the treatment of
plaque psoriasis. The safety and effectiveness of topical calcipotriene in
dermatoses other than psoriasis have not been established.
CONTRAINDICATIONS:
CALCIPOTRIENE is contraindicated in those patients with a history of
hypersensitivity to any of the components of the preparation. It should not be
used by patients with demonstrated hypercalcemia or evidence of vitamin D
toxicity. CALCIPOTRIENE should not be used on the face.
PRECAUTIONS:
GENERAL: Use of CALCIPOTRIENE may cause transient irritation of both lesions
and surrounding uninvolved skin. If irritation develops, CALCIPOTRIENE should be
discontinued.
Reversible elevation of serum calcium has occurred with use of topical
calcipotriene. If elevation in serum calcium outside the normal range should
occur, discontinue treatment until normal calcium levels are restored.
INFORMATION FOR PATIENTS: Patients using CALCIPOTRIENE should receive the
following information and instructions:
1. This medication is to be used only as directed by the physician. It is for
external use only. Avoid contact with the face or eyes. As with any topical
medication, patients should wash their hands after application.
2. This medication should not be used for any disorder other than that for which
it was prescribed.
3. Patients should report to their physician any signs of adverse reactions.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Animal studies have not
been conducted to evaluate the carcinogenic potential of calcipotriene. Studies
in rats at doses up to 54 mcgm/kg/day (318 mcgm/M(squared)/day) of calcipotriene
indicated no impairment of fertility or general reproductive performance.
Calcipotriene did not elicit any mutagenic effects in the Ames mutagenicity
assay, the mouse lymphoma TK locus assay, the human lymphocyte chromosome
aberration test, or the mouse micronucleus test.
PREGNANCY: TERATOGENIC EFFECTS: PREGNANCY CATEGORY C. 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 mcgm/kg/day (132 mcgm/M(squared)/day). Rabbits
administered 36 mcgm/kg/day (396 mcgm/M(squared)/day) resulted in fetuses with a
significant increase in the incidence of pubic bones, forelimb phalanges, and
incomplete bone ossification. In a rat study, oral doses of 54 mcgm/kg/day (318
mcgm/M(squared)/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 calculated no- effect exposures in the rat
(43.2 mcgm/M(squared)/day) and rabbit (17.6 mcgm/M(squared)/day) studies are
approximately equal to the expected human systemic exposure level (18.5
mcgm/M(squared)/day) from dermal application. There are no adequate and well-
controlled studies in pregnant women. Therefore, CALCIPOTRIENE should be used
during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
NURSING MOTHERS: There is evidence that maternal 1,25-dihydroxy vitamin D3
(calcitriol) may enter the fetal circulation, but it is not known whether it is
excreted in human milk. The systemic disposition of calcipotriene is expected to
be similar to that of the naturally occurring vitamin. Because many drugs are
excreted in human milk, caution should be exercised when CALCIPOTRIENE is
administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of CALCIPOTRIENE in pediatric patients
have not been established. Because of a higher ratio of skin surface area to
body mass, pediatric patients are at greater risk than adults of systemic
adverse effects when they are treated with topical medication.
ADVERSE REACTIONS:
In controlled clinical trials, the most frequent adverse experiences reported
for CALCIPOTRIENE were cases of skin irritation which occurred in approximately
10-15% of patients. Rash, pruritus, dermatitis, and worsening of psoriasis were
reported in 1 to 10% of patients.
OVERDOSAGE:
Topically applied calcipotriene can be absorbed in sufficient amounts to produce
systemic effects. Elevated serum calcium has been observed with excessive use of
topical calcipotriene. If elevation in serum calcium should occur, discontinue
treatment until normal calcium levels are restored (See PRECAUTIONS).
DOSAGE AND ADMINISTRATION:
Apply a thin layer of CALCIPOTRIENE to the affected skin twice daily and rub in
gently and completely. The safety and efficacy of CALCIPOTRIENE have been
demonstrated in patients treated for eight weeks.
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