Taclonex (Page 2 of 4)

6.2 Post-marketing Experience

The following adverse reactions associated with the use of Taclonex® Ointment have been identified post-approval: pustular psoriasis and rebound effect.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with Taclonex® Ointment. Taclonex® Ointment should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with Taclonex® Ointment. Taclonex® Ointment contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically.

Teratogenicity studies with calcipotriene were performed by the oral route in rats and rabbits. In rabbits, increased maternal and fetal toxicity were noted at a dosage of 12 mcg/kg/day (144 mcg/m2 /day); a dosage of 36 mcg/kg/day (432 mcg/m2 /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 mcg/kg/day (324 mcg/m2 /day) resulted in a significantly increased incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The enlarged fontanelles are most likely due to the effect of calcipotriene upon calcium metabolism. The estimated maternal and fetal no-adverse effect levels (NOAEL) in the rat (108 mcg/m2 /day) and rabbit (48 mcg/m2 /day) derived from oral studies are lower than the estimated maximum topical dose of calcipotriene in man (460 mcg/m2 /day).


Betamethasone dipropionate has been shown to be teratogenic in mice and rabbits when given by the subcutaneous route at doses of 156 mcg/kg/day (468 mcg/m2 /day) and 2.5 mcg/kg/day (30 mcg/m2 /day), respectively. Those dose levels are lower than the estimated maximum topical dose in man (about 5950 mcg/m2 /day). The abnormalities observed included umbilical hernia, exencephaly and cleft palate.
Two oral peri- and post-natal development studies were conducted with rats:
Pregnant Wistar rats were dosed daily with calcipotriene at exposures of 0, 6, 18 or 54 mcg/kg/day from gestation day 15 through day 20 postpartum. No remarkable effects were observed on any parameter, including survival, behavior, body weight, litter parameters, or the ability to nurse or rear pups.
Betamethasone dipropionate was evaluated for effects when orally administered to pregnant rats from gestation day 6 through day 20 postpartum at dosages of 0, 100, 300, and 1000 mcg/kg/day. Mean maternal body weight was significantly reduced on gestation day 20 in animals dosed at 300 and 1000 mcg/kg/day. The mean duration of gestation was slightly, but statistically significantly, increased at 100, 300, and 1000 mcg/kg/day. The mean percentage of pups that survived to day 4 was reduced in relation to dosage. On lactation day 5, the percentage of pups with a reflex to right themselves when placed on their back was significantly reduced at 1000 mcg/kg/day. No effects on the ability of pups to learn were observed, and the ability of the offspring of treated rats to reproduce was not affected.

8.3 Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk.

Because many drugs are excreted in human milk, caution should be exercised when Taclonex® Ointment is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of the use of Taclonex® Ointment in pediatric patients have not been studied. Because of a higher ratio of skin surface area to body mass, children under the age of 12 years may be at particular risk of systemic adverse effects when they are treated with topical medication [see Warnings and Precautions (5.2) ].

HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

8.5 Geriatric Use

Of the total number of subjects in the clinical studies of Taclonex® Ointment, approximately 14% were 65 years and older and approximately 3% were 75 years and over.

No overall differences in safety or effectiveness of Taclonex® Ointment were observed between these subjects and younger subjects. All other reported clinical experience has not identified any differences in response between elderly and younger patients.

10 OVERDOSAGE

Topically applied Taclonex® Ointment can be absorbed in sufficient amounts to produce systemic effects [see Warnings and Precautions (5.1, 5.2)].

11 DESCRIPTION

Taclonex® Ointment contains calcipotriene hydrate and betamethasone dipropionate. It is intended for topical use.

Calcipotriene hydrate is a synthetic vitamin D3 analogue.

Chemically, calcipotriene hydrate is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1(alpha),3(beta),24-triol,hydrate, with the empirical formula C27 H40 O3 H2 O, a molecular weight of 430.6, and the following structural formula:Calcipotriene hydrate structure

Calcipotriene hydrate is a white to almost white crystalline compound.

Betamethasone dipropionate is a synthetic corticosteroid.

Betamethasone dipropionate has the chemical name 9-fluoro-11(beta),17,21-trihydroxy-16(beta)-methylpregna-1,4-diene-3,20-dione17,21-dipropionate, with the empirical formula C28 H37 FO7 , a molecular weight of 504.6, and the following structural formula:

betamethasone dipropionate structure

Betamethasone dipropionate is a white to almost white odorless powder.

® Ointment contains 52.18 mcg of calcipotriene hydrate (equivalent to 50 mcg of calcipotriene) and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) in an ointment base of mineral oil, PPG-15 stearyl ether, dl-alpha tocopherol and white petrolatum.

Calcipotriene hydrate structurebetamethasone dipropionate structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Taclonex® Ointment combines the pharmacological effects of calcipotriene hydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid. However, while their pharmacologic and clinical effects are known, the exact mechanisms of their actions in psoriasis vulgaris are unknown.

12.2 Pharmacodynamics

Vasoconstriction:

In a vasoconstrictor study, the skin blanching response of Taclonex® Ointment was consistent with that of a potent corticosteroid.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:

Taclonex® Ointment was applied once daily for 4 weeks to adult subjects (N = 12) with psoriasis vulgaris to study its effects on the hypothalamic-pituitary-adrenal (HPA) axis. Of eleven subjects tested, none demonstrated adrenal suppression as indicated by a 30-minute post-stimulation cortisol level 18 mcg/dL.

However in another clinical study of Taclonex® Ointment, one subject (N = 19) demonstrated adrenal suppression.

HPA axis suppression was evaluated in adult subjects (N=32) with extenisve psoriasis involving at least 30% of the scalp and, in total, 15-30% of the body surface area. Treatment consited of once daily application of Talconex Scalp® Topical Suspension on the scalp in combination with Taclonex® Ointment on the body. Adrenal suppression as indicated by a 30-minutes post-stimulation cortisol level less than or equal to 18 mcg/dL was observed in 5 of 32 subjects (15.6%) after 4 weeks of treatment as per the recommended duration of use (see Dosage and Administration (2.1).

Effects on Calcium Metabolism

In the combination use study described above, the effects of once daily application of Taclonex® Ointment on the body in combination with Taclonex Scalp® Topical Suspension on the scalp on calcium metabolism were also examined. Elevated urinary calcium levels outside the normal range were observed in 1 of 35 subjects (2.9%) after 4 weeks of treatment.

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