Dovonex ointment 0.005%

Description

Dovonex (calcipotriene ointment) Ointment, 0.005% contains the compound calcipotriene, a synthetic vitamin D 3 derivative for topical dermatological use.

Chemically, calcipotriene is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5, 7, 10(19), 22-tetraene-1(alpha), 3(beta), 24-triol-, with the empirical formula C 27 H 40 O 3 , a molecular weight of 412.6, and the following structural formula:

images/18/63505751.jpg

Calcipotriene is a white or off-white crystalline substance. Dovonex Ointment contains calcipotriene 50 µg/g in an ointment base of dibasic sodium phosphate, edetate disodium, mineral oil, petrolatum, propylene glycol, tocopherol, steareth-2 and water.

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 D 3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D 3 .

Clinical studies with radiolabelled 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.

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 D 3 (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. The primary metabolites are much less potent than the parent compound.

There is evidence that maternal 1,25-dihydroxy vitamin D 3 (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.

Clinical Studies

Adequate and well-controlled trials of patients treated with Dovonex Ointment have demonstrated improvement usually beginning after two weeks of therapy. This improvement continued in patients using Dovonex Ointment once daily and twice daily. After 8 weeks of once daily Dovonex Ointment, 56.7% of patients showed at least marked improvement (6.4% showed complete clearing). After 8 weeks of twice daily Dovonex Ointment, 70.0% of patients showed at least marked improvement (11.3% showed complete clearing).

Subtracting percentages of patients using placebo (vehicle only) from percentages of patients using Dovonex Ointment who had at least marked improvement after 8 weeks yields 39.9% for once daily and 49.6% for twice daily. This adjustment for placebo effect indicates that what might appear to be differences between once and twice daily use may reflect differences in the studies independent from the frequency of dosing. Although there was a numerical difference in comparison across studies, twice daily dosing has not been shown to be superior in efficacy to once daily dosing.

Over 400 patients have been treated in open label clinical studies of Dovonex Ointment for periods of up to one year. In half of these studies, patients who previously had not responded well to Dovonex Ointment were excluded. The adverse events in these extended studies included skin irritation in approximately 25% of patients and worsening of psoriasis in approximately 10% of patients. In one of these open label studies, half of the patients no longer required Dovonex Ointment by 16 weeks of treatment, because of satisfactory therapeutic results.

Indications and Usage

Dovonex Ointment is indicated for the treatment of plaque psoriasis in adults. The safety and effectiveness of topical calcipotriene in dermatoses other than psoriasis have not been established.

Contraindications

Dovonex Ointment 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. Dovonex Ointment should not be used on the face.

Precautions

General:   Use of Dovonex Ointment may cause irritation of lesions and surrounding uninvolved skin. If irritation develops, Dovonex Ointment should be discontinued.

Transient, rapidly reversible elevation of serum calcium has occurred with use of Dovonex Ointment. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.

Information for Patients:   Patients using Dovonex Ointment should receive the following information and instructions:

  1. This medication is to be used 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 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 local adverse reactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been conducted to evaluate the carcinogenic potential of calcipotriene. Studies in rats at doses up to 54 µg/kg/day (318 µg/m 2 /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. In rabbits, increased maternal and fetal toxicity were noted at a dosage of 12 µg/kg/day (132 µg/m 2 /day); a dosage of 36 µg/kg/day (396 µg/m 2 /day) resulted in a significant increase in the incidence of incomplete ossification of the pubic bones and forelimb phalanges of fetuses. In a rat study, a dosage of 54 µg/kg/day (318 µg/m 2 /day) resulted in a significantly increased incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The estimated maternal and fetal no-effect exposure levels in the rat (43.2 µg/m 2 /day) and the rabbit (17.6 µg/m 2 /day) studies are approximately equal to the expected human systemic exposure level (18.5 µg/m 2 /day) from dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Dovonex Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:   It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dovonex Ointment is administered to a nursing woman.

Pediatric Use:   Safety and effectiveness of Dovonex Ointment in children have not been established. Because of a higher ratio of skin surface area to body mass, children are at greater risk than adults of systemic adverse effects when they are treated with topical medication.

Geriatric Use:   Of the total number of patients in clinical studies of calcipotriene ointment, approximately 12% were 65 or older, while approximately 4% were 75 and over. The results of an analysis of severity of skin-related adverse events showed a statistically significant difference for subjects over 65 years (more severe) compared to those under 65 years (less severe).

Adverse Reactions

In controlled clinical trials, the most frequent adverse reactions reported for Dovonex Ointment were burning, itching, and skin irritation, which occurred in approximately 10-15% of patients. Erythema, dry skin, peeling, rash, dermatitis, worsening of psoriasis including development of facial/scalp psoriasis were reported in 1 to 10% of patients. Other experiences reported in less than 1% of patients included skin atrophy, hyperpigmentation, hypercalcemia, and folliculitis. Once daily dosing has not been shown to be superior in safety to twice daily dosing.

Overdosage

Topically applied Dovonex Ointment can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with excessive use of Dovonex Ointment. (See PRECAUTIONS .)

Dosage and Administration

Apply a thin layer of Dovonex Ointment to the affected skin once or twice daily and rub in gently and completely.

How Supplied

Dovonex (calcipotriene ointment) Ointment, 0.005% is available in:

60 gram aluminum tubes (NDC 0072-2540-06)

120 gram aluminum tubes (NDC 0072-2540-12).

STORAGE

Store at controlled room temperature 15°C - 25°C (59°F - 77°F).

Do not freeze.

Manufactured by

Leo Laboratories Ltd.,

Dublin, Ireland

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 U.S.A.

E6-B001B-04-01                                           J4688B

US Patent No. 4,866,048      Revised November 2000

Hide
(web1)