Taclonex (Topical application)

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment (calcipotriene 0.005% and betamethasone dipropionate 0.064%) is available in 60 gram collapsible tubes (NDC 0430-3230-15).

Store Taclonex® (calcipotriene and betamethasone dipropionate) Ointment between 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F).

Keep out of reach of children.

Manufactured by: LEO Laboratories Ltd. (LEO Pharma) Dublin, Ireland. FDA Rev date: 9/25/2007

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment is indicated for the topical treatment of psoriasis vulgaris in adults 18 years of age and above 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.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should not be applied to the face, axillae or groin.

Apply an adequate layer of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment to the affected area(s) once daily for up to 4 weeks. Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should be rubbed in gently and completely. The maximum weekly dose should not exceed 100 g. Treatment of more than 30% body surface area is not recommended. Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should not be applied to the face, axillae or groin.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment is contraindicated in patients with known or suspected disorders of calcium metabolism.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment is contraindicated in patients with erythrodermic, exfoliative and pustular psoriasis.

WARNINGS

No information provided.

PRECAUTIONS

General

Hypercalcemia has been observed with use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. If elevation of serum calcium outside the normal range occurs, discontinue treatment until normal calcium levels are restored. In the trials that included assessment of the effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism, such testing was done after 4 weeks of treatment. The effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism following treatment durations of longer than 4 weeks are not known.

Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Use of more than one corticosteroid-containing product at the same time may increase total systemic glucocorticoid exposure. (See DOSAGE AND ADMINISTRATION).

Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area should be evaluated periodically for evidence of HPA axis suppression by using the Cosyntropin Stimulation Test. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the topical corticosteroid.

The use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment has not been studied in patients with severe renal insufficiency or severe hepatic disorders.

HPA axis suppression has been observed with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

If irritation develops, Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should be discontinued and appropriate therapy instituted.

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than by noting any clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.

If concomitant skin infections are present or develop after treatment initiations, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should be discontinued until the infection has been adequately controlled.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should not be used in the presence of pre-existing skin atrophy at the treatment site.

Taclonex® (calcipotriene and betamethasone dipropionate) Ointment should not be used on the face, axillae or groin.

Information for Patients

This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Patients using Taclonex® (calcipotriene and betamethasone dipropionate) 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 has been prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive, unless directed by the physician.
4. Patients should report any signs of adverse reactions to their physician.
5. Other products containing calcipotriene or a corticosteroid should not be used with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment without first talking to the physician.
6. Patients who apply Taclonex® (calcipotriene and betamethasone dipropionate) Ointment to exposed portions of the body 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 Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

Laboratory Tests

See PRECAUTIONS, General.

Carcinogenesis, mutagenesis, impairment of fertility:

When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 µg/kg/day (corresponding to 9, 30 and 90 µg/m²/day), no significant changes in tumor incidence were observed when compared to control.

In a study in which albino hairless mice were exposed to both ultra-violet radiation (UVR) and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. Patients who apply Taclonex® (calcipotriene and betamethasone dipropionate) Ointment to exposed portions of the body 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 that use Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of betamethasone dipropionate.

Calcipotriene did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, the human lymphocyte chromosome aberration test, or the mouse micronucleus test.

Betamethasone dipropionate did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, or in the rat micronucleus test.

Studies in rats with oral doses of up to 54 mcg/kg/day (324 mcg/m²/day) of calcipotriene demonstrated no impairment of fertility or general reproductive performance.

Studies in rats with oral doses of up to 0.2 mg/kg/day (1,200 mcg/m²/day) of betamethasone dipropionate demonstrated no impairment of male fertility.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. Taclonex® (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. There are no adequate and well-controlled studies in pregnant women. Taclonex® (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.

Teratogenicity studies with calcipotriene were performed by the oral route in rats and rabbits. In rabbits, increased maternal and fetal toxicity were noted at 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 calcipotriene's effect upon calcium metabolism. The estimated maternal and fetal no-effect levels in the rat (108 mcg/m²/day) and rabbit (48 mcg/m²/day) studies are lower than the estimated maximum topical dose in man (approximately 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/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 (5,948 mcg/m²/day). The abnormalities observed included umbilical hernia, exencephaly and cleft palates.

Pregnant women were excluded from the clinical trials conducted with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

Nursing mothers

Safety of the use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment during lactation has not been established.

Nursing women were excluded from the clinical trials conducted with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

It is not known whether topically administered calcipotriene is excreted in human milk.

It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk.

Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant.

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

Pediatric use

Safety and effectiveness of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment 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.

Geriatric use

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

No overall differences in safety or effectiveness of Taclonex® (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.

SIDE EFFECTS

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to Taclonex® (calcipotriene and betamethasone dipropionate) Ointment in 2448 patients, including 1992 exposed for 4 weeks, and 289 exposed for 8 weeks. In the trials that included assessment of the effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism, such testing was done after 4 weeks of treatment. The effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism following treatment durations of longer than 4 weeks are not known (See PRECAUTIONS). The effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on the HPA axis following treatment durations of longer than 4 weeks have not been adequately studied. Taclonex® (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 patients 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 Taclonex® (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.

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.

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 Taclonex® (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 study, patients (N=207) with at least moderate disease severity were given Taclonex® (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 Taclonex® (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 patients: 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 a serious flare-up of psoriasis was reported.

Development of pustular psoriasis has been reported as an adverse reaction during and following use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

DRUG INTERACTIONS

No information provided.

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. Taclonex® (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. There are no adequate and well-controlled studies in pregnant women. Taclonex® (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.

Teratogenicity studies with calcipotriene were performed by the oral route in rats and rabbits. In rabbits, increased maternal and fetal toxicity were noted at 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 calcipotriene's effect upon calcium metabolism. The estimated maternal and fetal no-effect levels in the rat (108 mcg/m²/day) and rabbit (48 mcg/m²/day) studies are lower than the estimated maximum topical dose in man (approximately 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/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 (5,948 mcg/m²/day). The abnormalities observed included umbilical hernia, exencephaly and cleft palates.

Pregnant women were excluded from the clinical trials conducted with Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to Taclonex® (calcipotriene and betamethasone dipropionate) Ointment in 2448 patients, including 1992 exposed for 4 weeks, and 289 exposed for 8 weeks. In the trials that included assessment of the effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism, such testing was done after 4 weeks of treatment. The effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on calcium metabolism following treatment durations of longer than 4 weeks are not known (See PRECAUTIONS). The effects of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment on the HPA axis following treatment durations of longer than 4 weeks have not been adequately studied. Taclonex® (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 patients 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 Taclonex® (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.

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.

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 Taclonex® (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 study, patients (N=207) with at least moderate disease severity were given Taclonex® (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 Taclonex® (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 patients: 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 a serious flare-up of psoriasis was reported.

Development of pustular psoriasis has been reported as an adverse reaction during and following use of Taclonex® (calcipotriene and betamethasone dipropionate) Ointment.

Topically applied Taclonex® (calcipotriene and betamethasone dipropionate) Ointment can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS).