Taclonex Scalp (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

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

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 were 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 maximum topical dose of calcipotriene in man (460 mcg/m2 /day).

Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Betamethasone dipropionate has been shown to be teratogenic in mice and rabbits when given by the subcutaneous route at doses of 156 mcg/kg (468 mcg/m2 /day) and 2.5 mcg/kg (30 mcg/m2 /day), respectively. Those dose levels are lower than the maximum topical dose in man (about 5,950 mcg/m2 /day). The abnormalities observed included umbilical hernia, exencephaly and cleft palate.

Pregnant women were excluded from the clinical studies conducted with Taclonex Scalp® Topical Suspension.

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 Scalp® Topical Suspension is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of the use of Taclonex Scalp® Topical Suspension 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 corticosteroids. [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 patients in the controlled clinical studies of Taclonex Scalp® Topical Suspension, 334 were 65 years or older, while 84 were 75 years or older.

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

patients.

10 OVERDOSAGE

Taclonex Scalp® Topical Suspension can be absorbed in sufficient amounts to produce systemic effects [See WARNINGS AND PRECAUTIONS (5.1) ].

11 DESCRIPTION

Taclonex Scalp® Topical Suspension contains calcipotriene hydrate and betamethasone dipropionate. It is intended for topical use on the scalp.

Calcipotriene hydrate is a synthetic vitamin D3 analogue.

Chemically, calcipotriene hydrate is 9,10-Secochola-5,7,10(19),22- tetraene-1,3,24-triol,24-cyclo-propyl-, monohydrate, (1α,3ß,5Z,7E,22E,24S) with the empirical formula C27 H40 O3 ,H2 O, a molecular weight of 430.6, and the following structural formula:

image of Calcipotriene hydrate chemical structure

Calcipotriene hydrate is a white to almost white, crystalline compound.

Betamethasone dipropionate is a synthetic corticosteroid.

Betamethasone dipropionate has the chemical name Pregna-1,4- diene-3,20-dione-9-fluoro-11-hydroxy-16-methyl-17,21-bis(1-oxypropoxy)-(11ß,16ß), with the empirical formula C28 H37 FO7 , a molecular weight of 504.6, and the following structural formula:

image of Betamethasone dipropionate chemical structure

Betamethasone dipropionate is a white to almost white, crystalline powder.

Each gram of Taclonex Scalp® Topical Suspension 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 a base of hydrogenated castor oil, PPG-15 stearyl ether and mineral oil.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Taclonex Scalp® Topical Suspension 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

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:

HPA axis suppression was evaluated in adult subjects (N=32) with extensive psoriasis involving at least 30% of the scalp and, in total, 15-30% of the body surface area. Treatment consisted of once daily application of Taclonex Scalp® Topical Suspension on the scalp in combination with Taclonex® Ointment on the body for 4 to 8 weeks. Adrenal suppression as indicated by a 30-minute post-stimulation cortisol level ≤ 18 mcg/dL was observed in 5 of 32 subjects (15.6%) after 4 weeks of treatment and in 2 of 11 subjects (18.2%) who continued treatment for 8 weeks.

Effects on Calcium Metabolism:

In the study described above, the effects of once daily application of Taclonex Scalp® Topical Suspension on the scalp in combination with Taclonex® Ointment on the body for 4 to 8 weeks on calcium metabolism were also examined. Following once daily application of Taclonex Scalp® Topical Suspension on the scalp in combination with Taclonex® Ointment on the body, elevated urinary calcium levels outside the normal range were observed in two subjects (one at 4 weeks and one at 8 weeks).

12.3 Pharmacokinetics

Absorption

Taclonex Scalp® Topical Suspension:

The systemic effect of Taclonex Scalp® Topical Suspension in extensive psoriasis was investigated in the study described above. In this study, the serum levels of calcipotriene and betamethasone dipropionate and their major metabolites were measured after 4 and 8 weeks of once daily application of Taclonex Scalp® Topical Suspension on the scalp in combination with Taclonex® Ointment on the body. Calcipotriene and betamethasone dipropionate were below the lower limit of quantification in all serum samples of the 34 subjects evaluated.

However, one major metabolite of calcipotriene (MC1080) was quantifiable in 10 of 34 (29.4%) subjects at week 4 and in five of 12 (41.7%) subjects at week 8. The major metabolite of betamethasone dipropionate, betamethasone 17-propionate (B17P) was also quantifiable in 19 of 34 (55.9%) subjects at week 4 and seven of 12 (58.3%) subjects at week 8. The serum concentrations for MC1080 ranged from 20-75 pg/mL. The clinical significance of this finding is unknown.

Metabolism

Calcipotriene:

Calcipotriene metabolism following systemic uptake is rapid and occurs in the liver. The primary metabolites of calcipotriene are less potent than the parent compound.

Calcipotriene is metabolized to MC1046 (the α,ß-unsaturated ketone analog of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analog). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.

Betamethasone dipropionate:

Betamethasone dipropionate is metabolized to betamethasone 17-propionate and betamethasone, including the 6ß-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17-propionate (B17P) is the primary metabolite.

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