CALCIPOTRIENE 0.005% AND BETAMETHASONE DIPROPIONATE 0.064%- calcipotriene and betamethasone dipropionate ointment 
Sandoz Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment safely and effectively. See full prescribing information for calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment.

Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Ointment for TOPICAL use only.
Initial U.S. Approval: 2006

RECENT MAJOR CHANGES

Indications and Usage (1)                                                      12/2014
Dosage and Administration (2)                                              12/2014

INDICATIONS AND USAGE

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is a vitamin D analogue and corticosteroid combination product indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older (1).

DOSAGE AND ADMINISTRATION

  • Apply calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment to affected area(s) once daily for up to 4 weeks. Discontinue therapy when control is achieved. (2)
  • Adult patients should not use more than 100 g per week. (2)
  • Treatment of more than 30% body surface area is not recommended. (2)
  • Do not use with occlusive dressings unless directed by a physician. (2
  • Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. (2
  • Not for oral, ophthalmic, or intravaginal use. (2)

DOSAGE FORMS AND STRENGTHS

Ointment, 0.005%/0.064%

Each gram of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment contains 50 mcg of calcipotriene and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone). (3)

CONTRAINDICATIONS

None (4).

WARNINGS AND PRECAUTIONS

  • Hypercalcemia and hypercalciuria have been observed. If either occurs, discontinue treatment until parameters of calcium metabolism normalize (5.1)  
  • Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency during and after withdrawal of treatment. Risk factors include the use of high-potency topical corticosteroid, use over a large surface area or to areas under occlusion, prolonged use, concomitant use of more than one corticosteroid-containing product, altered skin barrier, liver failure, and use in pediatric patients. Modify use should HPA axis suppression develop. (5.2, 8.4)

ADVERSE REACTIONS

The most common adverse reactions (≥1%) are pruritus and scaly rash. (6.1)

 

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

 

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 1/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

​1  INDICATIONS & USAGE

2  DOSAGE & ADMINISTRATION

3  DOSAGE FORMS & STRENGTHS

4  CONTRAINDICATIONS

5  WARNINGS AND PRECAUTIONS

5.1   Hypercalcemia and Hypercalciuria     

5.2   Effects on Endocrine System

5.3   Allergic Contact Dermatitis with Topical Corticosteroids

5.4   Allergic Contact Dermatitis with Topical Calcipotriene

5.5   Skin Irritation

5.6   Risk of Ultraviolet Light Exposure

6  ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

8.3  Nursing Mothers

8.4  Pediatric Use

8.5  Geriatric Use

11  DESCRIPTION

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

12.2  Pharmacodynamics

12.3  Pharmacokinetics

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, mutagenesis, impairment of fertility

14  CLINICAL STUDIES

16  HOW SUPPLIED

16.1 How Supplied

16.2 Storage

16.3  Handling

17  INFORMATION FOR PATIENTS

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

​1  INDICATIONS & USAGE

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

2  DOSAGE & ADMINISTRATION

Apply an adequate layer of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment to the affected area(s) once daily for up to 4 weeks. Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment should be rubbed in gently and completely. Patients should wash their hands after applying calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment.  Therapy should be discontinued when control is achieved.

Patients 18 years and older should not use more than 100 g per week. Treatment of more than 30% body surface area is not recommended.

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment should not be used with occlusive dressings unless directed by a physician. Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is not for oral, ophthalmic, or intravaginal use.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

3  DOSAGE FORMS & STRENGTHS

Ointment, 0.005%/0.064%

Each gram of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment contains 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.

4  CONTRAINDICATIONS

None.

5  WARNINGS AND PRECAUTIONS

5.1   Hypercalcemia and Hypercalciuria     

Hypercalcemia and hypercalciuria have been observed with use of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment. If hypercalcemia or hypercalciuria develops, treatment should be discontinued until parameters of calcium metabolism have normalized. In the trials that included assessment of the effects of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on calcium metabolism, such testing was done after 4 weeks of treatment. The effects of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on calcium metabolism following treatment durations of longer than 4 weeks have not been evaluated. [See Clinical Pharmacology (12.2)]

5.2   Effects on Endocrine System

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, concomitant use of more than one corticosteroid-containing product, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the cosyntropin stimulation test. [See Clinical Pharmacology (12.2)]

In a trial evaluating the effects of Taclonex® Topical Suspension and calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on the HPA axis, 32 adult subjects were treated with Taclonex® Topical Suspension on the scalp and calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on the body. Adrenal suppression was identified in 5 of 32 subjects (15.6%) after 4 weeks of treatment [see Clinical Pharmacology (12.2)]. The effects of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on the HPA axis following treatment durations of longer than 4 weeks have not been adequately studied.

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid.

Cushing’s syndrome and hyperglycemia may also occur due to the systemic effects of topical corticosteroids. These complications are rare and generally occur after prolonged exposure to excessively large doses, especially of high-potency topical corticosteroids.

Pediatric patients may be more susceptible to systemic toxicity due to their higher skin surface to body mass ratios [see Use in Specific Populations (8.4), Clinical Pharmacology (12.2)].

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

5.3   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.

5.4   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.

5.5   Skin Irritation

If irritation develops, treatment with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment should be discontinued and appropriate therapy instituted.

5.6   Risk of Ultraviolet Light Exposure

Patients who apply calcipotriene 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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

Clinical Trials Conducted in Subjects 18 years and older with Plaque Psoriasis
The data described below reflect exposure to calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment in 2448 subjects with plaque psoriasis, including 1992 exposed for 4 weeks, and 289 exposed for 8 weeks. Calcipotriene 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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

Calcipotriene 0.005% and Betamethasone Dipropionate 0.064%
Ointment

N = 2448

Calcipotriene N = 3197

Betamethasone dipropionate
N = 1164

Vehicle

N = 470

Any Adverse Event

663 (27.1)

1055 (33.0)

329 (28.3)

157 (33.4)

Preferred Term

# of subjects (%)

Pruritis

75 (3.1)

183 (5.7)

38 (3.3)

43 (9.1)

Headache

69 (2.8)

75 (2.3)

44 (3.8)

12 (2.6)

Nasopharyngitis

56 (2.3)

77 (2.4)

34 (2.9)

9 (1.9)

Psoriasis

30 (1.2)

47 (1.5)

14 (1.2)

5 (1.1)

Rash scaly

30 (1.2)

40 (1.3)

0 (0.0)

1 (0.2)

Influenza

23 (0.9)

34 (1.1)

14 (1.2)

6 (1.3)

Upper respiratory

tract infection

20 (0.8)

19 (0.6)

12 (1.0)

3 (0.6)

Erythema

15 (0.6)

54 (1.7)

3 (0.3)

5 (1.1)

Application site

pruritus

13 (0.5)

24 (0.8)

10 (0.9)

6 (1.3)

Skin irritation

11 (0.4)

60 (1.9)

8 (0.7)

5 (1.1)

Pain

7 (0.3)

12 (0.4)

3 (0.3)

5 (1.1)

Burning sensation

6 (0.2)

30 (0.9)

3 (0.3)

6 (1.3)

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

Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Ointment

N = 2448

Calcipotriene N = 3197

Betamethasone dipropionate
N = 1164

Vehicle N = 470

Any Adverse Event

213 (8.7)

419 (13.1)

85 (7.3)

76 (16.2)

Preferred Term

# of subjects (%)

Pruritis

69 (2.8)

170 (5.3)

31 (2.7)

41 (8.7)

Rash scaly

29 (1.2)

38 (1.2)

0 (0.0)

0 (0.0)

Application site pruritus

12 (0.5)

24 (0.8)

10 (0.9)

6 (1.3)

Erythema

9 (0.4)

36 (1.1)

2 (0.2)

4 (0.9)

Skin irritation

9 (0.4)

51 (1.6)

8 (0.7)

5 (1.1)

Burning sensation

6 (0.2)

25 (0.8)

3 (0.3)

5 (1.1)

For subjects who reported lesional/perilesional adverse events, the median time to onset was 7 days for calcipotriene 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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.

Postmarketing reports for local adverse reactions to topical corticosteroids may also include: striae, dryness, acneiform eruptions, perioral dermatitis, secondary infection and miliaria.

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

Teratogenic Effects: Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women.  Calcipotriene 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% ointment. Calcipotriene 0.005% and betamethasone dipropionate 0.064% 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.

8.3  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 calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is administered to a nursing woman.

8.4  Pediatric Use

Safety and effectiveness of the use of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment in pediatric patients under the age of 12 years have not been established.

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids. [See Warnings and Precautions (5.2)]

Rare systemic toxicities such as Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.

Local adverse reactions including striae have also been reported with use of topical corticosteroids in pediatric patients.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5  Geriatric Use

Of the total number of subjects in the clinical studies of calcipotriene 0.005% and betamethasone dipropionate 0.064% 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 0.005% and betamethasone dipropionate 0.064% 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. However, greater sensitivity of some older individuals cannot be ruled out.

11  DESCRIPTION

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

Calcipotriene is a synthetic vitamin D3 analog.

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 C27H40O3, a molecular weight of 412.3, and the following structural formula:

3339d333-figure-01

Calcipotriene 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 C28H37FO7, a molecular weight of 504.6, and the following structural formula:

3339d333-figure-02

Betamethasone dipropionate is a white to almost white odorless powder.

Each gram of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment contains 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 caprylic/capric triglycerides, diazolidinyl urea, dl-alpha tocopherol and white petrolatum.

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment combines the pharmacological effects of calcipotriene 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 plaque psoriasis are unknown.

12.2  Pharmacodynamics

Vasoconstriction:
In a vasoconstrictor trial in healthy subjects, the skin blanching response of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment was consistent with that of a potent corticosteroid when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:
HPA axis suppression was evaluated in trials (Trial A, B, and C) following the application of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment.

In Trial A, calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment was applied once daily for 4 weeks to adult subjects (N = 12) with plaque psoriasis 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.

In Trial B, calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment was evaluated in adult subjects with plaque psoriasis (N = 19). One subject  demonstrated adrenal suppression.

In Trial C, HPA axis suppression was evaluated in adult subjects (N=32) with extensive plaque 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 calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on the body. Adrenal suppression as indicated by a 30-minutes post-stimulation cortisol level < 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 Trial C described above, the effects of once daily application of calcipotriene 0.005% and betamethasone dipropionate 0.064% 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.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

12.3  Pharmacokinetics

Absorption
In Trial C described above, the systemic effect of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment in extensive plaque psoriasis was investigated. 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 0.005% and betamethasone dipropionate 0.064% ointment on the body in combination with Taclonex 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.

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, mutagenesis, impairment of fertility

When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 mcg/kg/day (corresponding to 9, 30 and 90 mcg/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.

A 104-week oral carcinogenicity study was conducted with calcipotriene in male and female rats at doses of 1, 5 and 15 mcg/kg/day (corresponding to dosages of approximately 6, 30, and 90 mcg/m2/day). Beginning week 71, the dosage for high-dose animals of both genders was reduced to 10 mcg/kg/day (corresponding to a dosage of approximately 60 mcg/m2/day). A treatment-related increase in benign C-cell adenomas was observed in the thyroid of females that received 15 mcg/kg/day. A treatment-related increase in benign pheochromocytomas was observed in the adrenal glands of males that received 15 mcg/kg/day. No other statistically significant differences in tumor incidence were observed when compared to control. The relevance of these findings to patients is unknown.

When betamethasone dipropionate was applied topically to CD-1 mice for up to 24 months at dosages approximating 1.3, 4.2 and 8.5 mcg/kg/day in females, and 1.3, 4.2, and 12.9 mcg/kg/day in males (corresponding to dosages of up to approximately 26 mcg/m2/day and 39 mcg/m2/day, in females and males, respectively), no significant changes in tumor incidence were observed when compared to control.

When betamethasone dipropionate was administered via oral gavage to male and female Sprague Dawley rats for up to 24 months at dosages of 20, 60, and 200 mcg/kg/day (corresponding to dosages of approximately 3, 10, and 30 mcg/m2/day), no significant changes in tumor incidence were observed when compared to control.

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 indicated no impairment of fertility or general reproductive performance.  Studies in male rats at oral doses of up to 200 mcg/kg/day (1200 mcg/m2/day), and in female rats at oral doses of up to 1000 mcg/kg/day (6000 mcg/m2/day), of betamethasone dipropionate indicated no impairment of fertility.

14  CLINICAL STUDIES

Clinical Trials Conducted in Subjects 18 years and older with Plaque Psoriasis
In an international, multi-center, double-blind, vehicle- and active-controlled, parallel-group trial, 1603 subjects with mild to very severe plaque psoriasis on trunk and limbs were treated once daily for 4 weeks. Subjects were randomized to one of four treatment arms: calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment, calcipotriene 50 mcg/g in the same vehicle, betamethasone dipropionate 0.64 mg/g in the same vehicle, and vehicle alone. The mean age of the subjects was 48.4 years and 60.5% were male. Most subjects had disease of moderate severity at baseline.

Efficacy was assessed as the proportion of subjects with absent or very mild disease according to the Investigator’s Global Assessment of Disease Severity at end of treatment (4 weeks). “Absent” disease was defined as no evidence of redness, thickness, or scaling. “Very mild disease” was defined as controlled disease, but not entirely cleared: lesions with some discoloration with absolutely minimal thickness, i.e. the edges to the lesions(s) could just be felt. Table 3 contains the response rates for this trial.

Table 3

Percentage of Subjects with Absent or Very Mild Disease According to the Investigator’s Global Assessment of Disease Severity at End of Treatment (4 weeks).*

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment
N = 490

Calcipotriene N = 480

Betamethasone dipropionate

N = 476

Vehicle

N = 157

Absent or very mild disease

48.0%

16.5%

26.3%

7.6%

*Subjects with mild disease at baseline were required to have “Absent” disease to be considered a success.

In addition to the pivotal trial (N = 490), four randomized, double-blind, vehicle- or active-controlled, parallel-group trials were conducted and provided supportive evidence of efficacy. These trials included a total of 1058 subjects treated with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment once daily for up to 4 weeks.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

16  HOW SUPPLIED

16.1 How Supplied

Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Ointment is off-white to yellow in color, available in collapsible tubes of:
60 gram (NDC 0781-7165-35)
100 gram (NDC 0781-7165-95)

16.2 Storage

Store calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment at 20º - 25°C (68º - 77°F); excursions permitted to 15º - 30°C (59º - 86°F) [see USP Controlled Room Temperature].

16.3  Handling

Keep out of reach of children.

17  INFORMATION FOR PATIENTS

See FDA-approved patient labeling (Patient Information)

Inform patients of the following:

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

Taclonex® and Taclonex Scalp® are registered trademarks of LEO Pharma A/S Corporation.

Manufactured by
TOLMAR Inc.
Fort Collins, CO 80526 for
Sandoz Inc.
Princeton, NJ 08540
44584 Rev. 3 09/15



SPL PATIENT PACKAGE INSERT

Patient Information
Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Ointment
(kal si poe trye' een and bay'' ta meth' a sone dye proe' pee oh nate)

Read the Patient Information that comes with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment.  

Important information: Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is for use on the skin only (topical use only). Do not use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment on the face, under arms or on groin area. Do not swallow calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment. Another product, Taclonex® Topical Suspension contains the same medicine that is in calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment and is used to treat plaque psoriasis on the scalp. If you use both medicines to treat your plaque psoriasis, be sure to follow your doctor’s directions carefully so that you do not use too much of one or both of these medications.

What is calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is a prescription medicine that is for use on the skin only (a topical medicine). Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is used to treat plaque psoriasis in patients 18 years of age and older.  

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment has not been studied in patients under the age of 12 years.

Who should not use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
Do not use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment if you:

What should I tell my doctor before using calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
Tell your doctor about all of your health conditions, including if you:

Tell your doctor about all the medicines you take, including prescription, and nonprescription medicines, vitamins and herbal supplements. Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment and some other medicines can interact with each other. Especially tell your doctor if you use:

How should I use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?

Using calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment:
Do not bandage or tightly cover the treated skin area.

Remove the cap and check that the aluminum seal covers the tube before the first use. To break the seal, turn the cap over and punch through the seal.

What should I avoid while using calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
Avoid spending a long time in the sunlight. Avoid tanning booths and sunlamps. Use sunscreen if you have to be in the sunlight. Talk to your doctor if you get a sunburn.

What are the possible side effects of calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
The most common side effects are:

Other less common side effects with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment include:

Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment may cause serious side effects. Serious side effects are more likely to happen if you use too much calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment, use it for too long, or use it with other topical medicines that contain corticosteroids, calcipotriene, or certain other ingredients. Check with your doctor before using other topical medicines. Calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment can pass through your skin. Serious side effects may include:

Your doctor may do special blood and urine tests to check your calcium levels and adrenal gland function while you are using calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment.

Call your doctor about any side effect that bothers you or that does not go away.

These are not all of the side effects with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment. Ask your doctor or pharmacist for more information.

How should I store calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?

General information about calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment for a condition for which it was not prescribed. Do not give calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment to other people, even if they have the same symptoms you have. It may harm them. 

This leaflet summarizes the most important information about calcipotriene 0.005% and

betamethasone dipropionate 0.064% ointment. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment that is written for health professionals. 

What are the ingredients in calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment?
Active ingredients: calcipotriene, betamethasone dipropionate
Inactive ingredients: caprylic/capric triglycerides, diazolidinyl urea, dl-alpha tocopherol, white petrolatum.

Pediatric use information for patients ages 12 years and above is approved for LEO Pharma A/S’s Taclonex® (calcipotriene and betamethasone dipropionate) Ointment. However, due to LEO Pharma A/S’s marketing exclusivity rights, this drug product is not labeled with that information.

Call your doctor for medical advice about side effects.  You may report side effects to Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Rx only

Taclonex® and Taclonex Scalp® are registered trademarks of LEO Pharma A/S Corporation.

Manufactured by
TOLMAR Inc., Fort Collins, CO 80526 for
Sandoz Inc., Princeton, NJ 08540

44584 Rev. 3 09/15

PACKAGE LABEL PRINICIPAL DISPLAY PANEL

60g Tube Packaging  

60g Carton Properties
CALCIPOTRIENE 0.005% AND BETAMETHASONE DIPROPIONATE 0.064% 
calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-7165
Route of Administration TOPICAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CALCIPOTRIENE (UNII: 143NQ3779B) (CALCIPOTRIENE - UNII:143NQ3779B) CALCIPOTRIENE 50 ug  in 1 g
BETAMETHASONE DIPROPIONATE (UNII: 826Y60901U) (BETAMETHASONE - UNII:9842X06Q6M) BETAMETHASONE 0.5 mg  in 1 g
Inactive Ingredients
Ingredient Name Strength
MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
DIAZOLIDINYL UREA (UNII: H5RIZ3MPW4)  
TOCOPHERYL NICOTINATE, D-.ALPHA. (UNII: WI1J5UCY5C)  
PETROLATUM (UNII: 4T6H12BN9U)  
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:0781-7165-35 1 in 1 CARTON
1 60 g in 1 TUBE; Type 0: Not a Combination Product
2 NDC:0781-7165-95 1 in 1 CARTON
2 100 g in 1 TUBE; Type 0: Not a Combination Product
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA201615 03/31/2014
Labeler - Sandoz Inc. (110342024)
Establishment
Name Address ID/FEI Business Operations
TOLMAR Inc. 791156578 ANALYSIS(0781-7165) , LABEL(0781-7165) , MANUFACTURE(0781-7165) , PACK(0781-7165)

Revised: 1/2016
Document Id: f5ce4434-ea31-4b11-86c4-e8aa8b27ee33
Set id: 6c2ed55a-c7f2-42be-a194-bd498707ce3f
Version: 8
Effective Time: 20160114
 
Sandoz Inc.