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Calcipotriene and Betamethasone Dipropionate Ointment

TABLE OF CONTENTS

1. DESCRIPTION 7. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 8. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 9. MECHANISM OF ACTION
4. CONTRAINDICATIONS 10. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 11. PHARMACOKINETICS
6. ADVERSE REACTIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Calcipotriene and betamethasone dipropionate ointment, 0.005%/0.064% contains calcipotriene hydrate and betamethasone dipropionate. It is intended for topical use only.

Calcipotriene hydrate is a synthetic vitamin D3 analog. 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, and the structural formula is:

Empirical formula: C27H40O3H2O- Molecular weight: 430.6

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 following structural formula:

Empirical formula: C28H37FO7 - Molecular weight: 504.6

Betamethasone dipropionate is a white to almost white odorless powder.

Each gram of calcipotriene and betamethasone dipropionate 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 off-white to yellow paraffin ointment base of mineral oil, PPG-15 stearyl ether, dl-alpha tocopherol and white petrolatum.

2. INDICATIONS AND USAGE

2.1 Indication

Calcipotriene and betamethasone dipropionate ointment is indicated for the topical treatment of psoriasis vulgaris in adults 18 years of age and older.

2.2 Limitations of Use

• Calcipotriene and betamethasone dipropionate ointment should not be applied to the face, axillae or groin.

• Calcipotriene and betamethasone dipropionate ointment should not be used if there is skin atrophy at the treatment site.

3. DOSAGE AND ADMINISTRATION

Apply an adequate layer of calcipotriene and betamethasone dipropionate ointment to the affected area(s) once daily for up to 4 weeks. The maximum weekly dose should not exceed 100 g. Treatment of more than 30% body surface area is not recommended. Calcipotriene and betamethasone dipropionate ointment should be rubbed in gently and completely. Patients should wash their hands after applying calcipotriene and betamethasone dipropionate ointment.

Calcipotriene and betamethasone dipropionate ointment is not for oral, ophthalmic, or intravaginal use.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Effects on Calcium Metabolism

Hypercalcemia and hypercalciuria have been reported with use of calcipotriene and betamethasone dipropionate. If hypercalcemia or hypercalciuria develop, treatment should be discontinued until parameters of calcium metabolism have normalized. In the trials that included assessment of the effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism, such testing was done after 4 weeks of treatment. The effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism following treatment durations of longer than 4 weeks have not been evaluated.

5.2 Effects on Endocrine System

Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid.

HPA axis suppression has been observed with calcipotriene and betamethasone dipropionate ointment [see Pharmacodynamics (10)]. The effects of calcipotriene and betamethasone dipropionate ointment on the HPA axis following treatment durations of longer than 4 weeks have not been adequately studied.

In a trial of 32 subjects concomitantly treated with calcipotriene and betamethasone dipropionate scalp topical suspension on the scalp and calcipotriene and betamethasone dipropionate ointment on the body, adrenal suppression was identified in 5 of 32 subjects (15.6%) after 4 weeks of treatment [see Pharmacodynamics (10)].

Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent steroids, use over large surface areas, use over prolonged periods, use under occlusion, use on an altered skin barrier, and use in patients with liver failure.

An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids.

Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.

Pediatric patients may be more susceptible to systemic toxicity from use of topical corticosteroids [see Use in Specific Populations (8.4)].

5.3 Local Adverse Reactions with Topical Corticosteroids

Local adverse reactions may be more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse reactions may be irreversible.

5.4 Allergic Contact Dermatitis with Topical Corticosteroids

Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than a clinical exacerbation. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.

5.5 Allergic Contact Dermatitis with Topical Calcipotriene

Allergic contact dermatitis has been observed with use of topical calcipotriene. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.

5.6 Concomitant Skin Infections

Concomitant skin infections should be treated with an appropriate antimicrobial agent. If the infection persists, calcipotriene and betamethasone dipropionate ointment should be discontinued until the infection has been adequately treated.

5.7 Skin Irritation

If irritation develops, treatment with calcipotriene and betamethasone dipropionate ointment should be discontinued and appropriate therapy instituted.

5.8 Ultraviolet Light Exposure

Patients who apply calcipotriene and betamethasone dipropionate ointment to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use calcipotriene and betamethasone dipropionate ointment.

6. ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience

The data described below reflect exposure to calcipotriene and betamethasone dipropionate ointment in 2448 subjects, including 1992 exposed for 4 weeks, and 289 exposed for 8 weeks. Calcipotriene and betamethasone dipropionate ointment was studied primarily in placebo- and active-controlled trials (N = 1176, and N = 1272, respectively). The population was 15-97 years old, 61% males and 39% females, mostly white (97%) and had a baseline disease severity ranging from mild to very severe. Most subjects received once daily application, and the median weekly dose was 24.5 g.

The percentage of subjects reporting at least one adverse event was 27.1% in the calcipotriene and betamethasone dipropionate ointment group, 33.0% in the calcipotriene group, 28.3% in the betamethasone group, and 33.4% in the vehicle group.

Table 1: Adverse Events Reported by ≥1% of Subjects by Preferred Term

A lesional/perilesional adverse event was generally defined as an adverse event located ≤ 2 cm from the lesional border.

Table 2: Lesional/Perilesional Adverse Events Reported by ≥1% of Subjects

For subjects who reported lesional/perilesional adverse events, the median time to onset was 7 days for calcipotriene and betamethasone dipropionate ointment, 7 days for calcipotriene, 5 days for betamethasone dipropionate, and 3 days for vehicle.

Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence, folliculitis, rash papular, rash pustular, and skin hypopigmentation. Skin atrophy, telangiectasia and skin hyperpigmentation were reported infrequently (0.1%).

In a separate trial, subjects (N = 207) with at least moderate disease severity were given calcipotriene and betamethasone dipropionate ointment intermittently on an "as needed" basis for up to 52 weeks. The median use was 15.4 g per week. The effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism were not studied and the effects on the HPA axis were not adequately studied. The following adverse reactions were reported by 1% or more of the subjects: pruritus (7.2%), psoriasis (3.4%), skin atrophy (1.9%), folliculitis (1.4%), burning sensation (1.4%), skin depigmentation (1.4%), ecchymosis (1.0%), erythema (1.0%) and hand dermatitis (1.0%). One case of serious flare-up of psoriasis was reported.

6.2 Postmarketing Experience

The following adverse reactions associated with the use of calcipotriene and betamethasone dipropionate 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.

7. USE IN SPECIFIC POPULATIONS

7.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with calcipotriene and betamethasone dipropionate ointment. Calcipotriene and betamethasone dipropionate 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 calcipotriene and betamethasone dipropionate ointment. Calcipotriene and betamethasone dipropionate 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).

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 dosages 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.

8.2 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 calcipotriene and betamethasone dipropionate ointment is administered to a nursing woman.

8.3 Pediatric Use

Safety and effectiveness of the use of calcipotriene and betamethasone dipropionate 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.

8.4 Geriatric Use

Of the total number of subjects in the clinical studies of calcipotriene and betamethasone dipropionate ointment, approximately 14% were 65 years and older and approximately 3% were 75 years and over.

No overall differences in safety or effectiveness of calcipotriene and betamethasone dipropionate 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.

8.5 Unevaluated Uses

The safety and efficacy of calcipotriene and betamethasone dipropionate ointment in patients with known or suspected disorders of calcium metabolism have not been evaluated.

The safety and efficacy of calcipotriene and betamethasone dipropionate ointment in patients with erythrodermic, exfoliative, or pustular psoriasis have not been evaluated.

The safety and efficacy of calcipotriene and betamethasone dipropionate ointment in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated.

8. OVERDOSAGE

Topically applied calcipotriene and betamethasone dipropionate ointment can be absorbed in sufficient amounts to produce systemic effects [see Warnings and Precautions (5.1, 5.2)].

9. MECHANISM OF ACTION

Calcipotriene and betamethasone dipropionate 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.

10. PHARMACODYNAMICS

Vasoconstriction:

In a vasoconstrictor trial, the skin blanching response of calcipotriene and betamethasone dipropionate ointment was consistent with that of a potent corticosteroid.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:

Calcipotriene and betamethasone dipropionate 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 30minute post-stimulation cortisol level ≤ 18 mcg/dL.

However in another clinical trial of calcipotriene and betamethasone dipropionate ointment, one subject (N = 19) demonstrated adrenal 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 calcipotriene and betamethasone dipropionate scalp topical suspension on the scalp in combination with calcipotriene and betamethasone dipropionate 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 (3.1).

Effects on Calcium Metabolism:

In the combination use trial described above, the effects of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate 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.

11. PHARMACOKINETICS

Absorption

The systemic effect of calcipotriene and betamethasone dipropionate ointment in extensive psoriasis was investigated in the trial described above. In this trial, the serum levels of calcipotriene and betamethasone dipropionate and their major metabolites were measured after 4 weeks (maximum recommended duration of treatment) and also after 8 weeks of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate scalp topical suspension on the scalp. Both 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 alpha,beta-unsaturated ketone analogue of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analogue). 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 6beta-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17-propionate (B17P) is the primary metabolite.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: TACLONEX, by GLA.

b) Generic drugs: Calcipotriene and betamethasone dipropionate, by Tolmar.

2) How Supplied:

Taclonex® Ointment is off-white to yellow in color, available in collapsible tubes of:

60 gram (NDC 50222-227-04)

100 gram (NDC 50222-227-81)

3) Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15°C - 30°C (59°F - 86°F). [see USP Controlled Room Temperature].

Rx only

Rev 11/12