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CLINICAL INFORMATION

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Calcipotriol Monohydrate BP

Chemical Name : (5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-

5,7,10(19),22-tetraene-1a,3b,24-triol monohydrate.

Empirical Formula : C27H40O3,H2O

Molecular Weight : 430.6

Chemical Structure :

Description : White or almost white, crystalline powder.

Solubility : Practically insoluble in water, freely soluble in

ethanol (96 per cent), slightly soluble in methylene
chloride.
It is sensitive to light.
A reversible isomerisation to pre-calcipotriol takes
place in solution, depending on temperature and
time. The activity is due to both compounds.

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Betamethasone Dipropionate BP

Chemical Name : 9-fluoro-11b-hydroxy-16b-methyl-3,20-dioxopregna-1,4-

diene-17,21-diyl dipropanoate

Empirical Formula : C28H37FO7

Molecular Weight : 504.6

Chemical Structure

Description : A white or almost white, crystalline powder.

Solubility : Practically insoluble in water, freely soluble in acetone and

in methylene chloride, sparingly soluble in ethanol (96 per
cent).

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PHARMACEUTICAL INFORMATION

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Product : Composition:
Calcipotriol Monohydrate BP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

Dosage form : External Preparation

Packing : 15 gm in a lamitube packed in laminated outer carton

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INDICATIONS

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Calcipotriol and Betamethasone Topical ointment is indicated

for the treatment of stable plaque psoriasis vulgaris

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THERAPEUTIC JUSTIFICATION FOR

THE COMBINATION OF
CALCIPOTRIOL AND BETMETHASONE
OINTMENT

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Calcipotriol and Betamethasone Topical ointment is used for the treatment of stable

plaque psoriasis vulgaris

RATIONALE FOR THE COMBINATION OF

CALCIPOTRIOL AND BETAMETHASONE IN TOPICAL OINTMENT

Composition

Calcipotriol Monohydrate BP

Equivalent to Calcipotriol anhydrous 0.005%w/w

Betamethasone Dipropionate BP

Equivalent to Betamethasone 0.05%w/w

Calcipotriol is a vitamin D analogue. In vitro data suggests that calcipotriol induces

differentiation and suppresses proliferation of keratinocytes. This is the proposed basis

for its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory,

antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing

the underlying condition. Through occlusion the effect can be enhanced due to increased

penetration of the stratum corneum (approximately by a factor of 10). The incidence of

adverse events will increase because of this. The mechanism of the anti-inflammatory

activity of the topical steroids, in general, is unclear.

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A safety study in 634 psoriasis patients has investigated repeated courses of Calcipotriol

and Betamethasone ointment used once daily as required, either alone or

alternating with Calcipotriol Ointment, for up to 52 weeks, compared with

Calcipotriol Ointment used alone for 48 weeks after an initial course of

Calcipotriol and Betamethasone ointment. Adverse drug reactions were

reported by 21.7% of the patients in the Calcipotriol and Betamethasone

ointment group, 29.6% in the Calcipotriol and Betamethasone

ointment/Calcipotriol Ointment alternating group and 37.9% in the

Calcipotriol Ointment group. The adverse drug reactions that were

reported by more than 2% of the patients in the Calcipotriol and

Betamethasone ointment group were pruritus (5.8%) and psoriasis

(5.3%). Adverse events of concern possibly related to long-term

corticosteroid use were reported by 4.8% of the patients in the Calcipotriol

and Betamethasone ointment group, 2.8% in the Calcipotriol and

Betamethasone ointment/Calcipotriol Ointment alternating group and

2.9% in the Calcipotriol Ointment group.

CONCLUSION

Therefore from the individual therapeutic role the combination of Calcipotriol and

Betamethasone topical ointment can be very well tolerated and can be used for the

treatment and management of psoriasis vulgaris.

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TOXICITY, TERATOGENECITY,
CARCINOGENECITY &
MUTAGENECITY STUDIES

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As this ointment is an external preparation no undue toxicity is reported with Calcipotriol

and Betamethasone ointment, which is used for the treatment and management of

psoriasis vulgaris.

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate,

skeletal malformations). In reproduction toxicity studies with long-term oral

administration of corticosteroids to rats prolonged gestation and prolonged and difficult

labour was detected. Moreover reduction in offspring survival, in body weight and body

weight gain was observed. There was no impairment of fertility. The relevance for

humans is unknown.

A dermal carcinogenicity study in mice revealed no special hazard to humans.

In a study where albino hairless mice were repeatedly exposed to both ultraviolet (UV)

radiation and dermally administered calcipotriol for 40 weeks at dose levels

corresponding to 9, 30 and 90 g/m 2/day (equivalent to 0.25, 0.84, 2.5 times the

maximum recommended daily dose for a 60 kg adult, respectively), a reduction in the

time required for UV radiation to induce the formation of skin tumours was observed

(statistically significant in males only), suggesting that calcipotriol may enhance the

effect of UV radiation to induce skin tumours. The clinical relevance of this finding is

unknown.

No carcinogenicity or photocarcinogenicity studies have been performed with

betamethasone dipropionate.

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DOSAGE AND ADMINISTRATION

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DOSAGE AND ADMINISTRATION

Calcipotriol and Betamethasone Ointment should be applied to the affected area once

daily. The recommended treatment period is 4 weeks. After this period repeated

treatment with Calcipotriol and Betamethasone Ointment can be initiated under medical

supervision.

The maximum daily dose should not exceed 15 g, the maximum weekly dose should not

exceed 100 g, and the treated area should not be more than 30% of the body surface.

Calcipotriol and Betamethasone Ointment is not recommended for the use in children

and adolescents below the age of 18 years.

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ADVERSE REACTIONS

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Very common >1/10

Common >1/100 and <1/10

Uncommon >1/1,000 and <1/100

Rare >1/10,000 and <1/1000

Very rare <1/10,000

The trial programme for Calcipotriol and Betamethasone Ointment ointment has so far

included more than 2,500 patients and has shown that approximately 10% of patients

can be expected to experience a non-serious undesirable effect.

Based on data from clinical trials and postmarket use the common undesirable effects

are pruritus, rash and burning sensation of skin. Uncommon undesirable effects are skin

pain or irritation, dermatitis, erythema, exacerbation of psoriasis, folliculitis and

application site pigmentation changes. Pustular psoriasis is a rare undesirable effect.

The undesirable effects are listed by MedDRA SOC and the individual undesirable effects

are listed starting with the most frequently reported.

Skin and subcutaneous tissue disorders

Common: Pruritus

Common: Rash

Common: Burning sensation of skin

Uncommon: Skin pain or irritation

Uncommon: Dermatitis

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Uncommon: Erythema

Uncommon: Exacerbation of psoriasis

Uncommon: Folliculitis

Uncommon: Application site pigmentation changes

Rare: Pustular psoriasis

Undesirable effects observed for calcipotriol and betamethasone, respectively:

Calcipotriol

Undesirable effects include application site reactions, pruritus, skin irritation, burning

and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis

aggravated, photosensitivity and hypersensitivity reactions including very rare cases of

angioedema and facial oedema.

Systemic effects after topical use may appear very rarely causing hypercalcaemia or

hypercalciuria.

Betamethasone (as dipropionate)

This product contains a potent corticosteroid.

Local reactions can occur after topical use, especially during prolonged application,

including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral

dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating

psoriasis there may be a risk of generalised pustular psoriasis.

Systemic effects due to topical use of corticosteroids are rare in adults, however they

can be severe. Adrenocortical suppression, cataract, infections and increase of intra-

ocular pressure can occur, especially after long term treatment. Systemic effects occur

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more frequently when applied under occlusion (plastic, skin folds), when applied on large

areas and during long term treatment.

DRUG INTERACTIONS

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None known for these topical preparations

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WARNINGS AND PRECAUTIONS

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The patient must be instructed in correct use of the product to avoid application and

accidental transfer to the scalp, face, mouth and eyes. Hands must be washed after each

application.

Treatment of more than 30% of the body surface should be avoided.

The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol

are fulfilled. Due to the content of calcipotriol hypercalcaemia may occur if the maximum

weekly dose (100 g) is exceeded. Serum calcium is quickly normalised, however, when

treatment is discontinued.

Calcipotriol and Betamethasone Ointment contains a strong potent group III-steroid and

concurrent treatment with other steroids must be avoided. Adverse effects found in

connection with systemic corticosteroid treatment such as adrenocortical suppression or

impact on the metabolic control of diabetes mellitus may occur also during topical

corticosteroid treatment due to systemic absorption.

Application on large areas of damaged skin and under occlusive dressings or on mucous

membranes or in skin folds should be avoided since it increases the systemic absorption

of corticosteroids. Skin of the face and genitals are very sensitive to corticosteroids.

Long-term treatment of these parts of the body should be avoided. These areas should

only be treated with the weaker corticosteroids. When lesions become secondarily

infected, they should be treated with antimicrobiological therapy. However, when

infection worsens, treatment with corticosteroids should be stopped.

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When treating psoriasis with topical corticosteroids there may be a risk of generalised

pustular psoriasis or of rebound effects when discontinuing treatment. Medical

supervision should therefore continue in the post-treatment period.

With long-term use there is an increased risk of local and systemic corticosteroid

undesirable effects. The treatment should be discontinued in case of undesirable effects

related to long-term use of corticosteroid.

There may be a risk of rebound when discontinuing a long-term treatment with

corticosteroids.

There is no experience for the use of this product on the scalp. There is no experience

with concurrent use of other anti-psoriatic products administered locally or systemically

or with phototherapy.

During Calcipotriol and Betamethasone Ointmenttreatment physicians are recommended

to advise patients to limit or avoid excessive exposure to either natural or artificial

sunlight. Topical calcipotriol should be used with UV radiation only if the physician and

patient consider that the potential benefits outweigh the potential risks.

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OVERDOSAGE

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Use above the recommended dose may cause elevated serum calcium, which should

rapidly subside when treatment is discontinued.

Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal

functions resulting in secondary adrenal insufficiency, which is usually reversible. In such

cases symptomatic treatment is indicated.

In case of chronic toxicity the corticosteroid treatment must be discontinued gradually.

It has been reported that due to misuse one patient with extensive erythrodermic

psoriasis treated with 240g of Calcipotriol and Betamethasone Ointment ointment

weekly (maximum dose 100 g weekly) for 5 months developed Cushing's syndrome and

pustular psoriasis after abruptly stopping treatment.

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CONTRA INDICATIONS

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Known hypersensitivity to the active substances or to any of the excipients.

Due to the content of calcipotriol Calcipotriol and Betamethasone Ointment is contra-

indicated in patients with known disorders of calcium metabolism.

Due to the content of corticosteroid Calcipotriol and Betamethasone Ointment is

contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the

skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in

relation to tuberculosis or syphilis, rosacea, perioral dermatitis, acne vulgaris, atrophic

skin, striae atrophicae, fragility of skin veins, ichthyosis, acne rosacea, ulcers, wounds,

perianal and genital pruritus.

Calcipotriol and Betamethasone Ointment is contraindicated in guttate, erythrodermic,

exfoliative and pustular psoriasis.

Calcipotriol and Betamethasone Ointment is contraindicated in patients with severe renal

insufficiency or severe hepatic disorders.

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MANUFACTURING PROCESS

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METHOD OF MANUFACTURE OF

CALCIPOTRIOL AND BETAMETHASONE OINTMENT

CHECKING OF INGREDIENTS:

Check the quantities and A.R.Number of the Ingrediants given in the manufacturing

work order.

a. Dispersion of drug

Calcipotriol is dispersed by White soft paraffin with Liquid paraffin. Disperse

Betamethasone dipropionate into Polyoxypropylene-15-stearyl ether under constant

stirring.

b. Mixing

The drug and other ingredients are mixed with remaining quantity of Liquid paraffin

while maintaining the pH using suitable solution at 9 to 10 and mixed for 30 minutes in

planetary mixer. Stir the solution for 5hrs until uniform ointment is obtained and proceed

for packing.

c. Testing

The ointment tubes are subjected to visual inspection to sort out the defective tubes and

a small portion of the ointment is sampled for testing.

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d. Filling

After due approval from QC the ointment is filled in 15 gm lamitube

e. Visual Checking

The tubes are again subjected to visual checking for any damage, which may occur while

filling.

f. Packing

The tubes are then packed in respective cartons and kept ready for release by the

Quality Assurance Department.

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METHOD OF ANALYSIS

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ANALYTICAL METHOD OF
RAW MATERIALS

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Calcipotriol - As per B.P

Betamethasone Dipropionate - As per B.P

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ANALYTICAL METHOD OF
CALCIPOTRIOL AND
BETAMETHASONE OINTMENT

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METHOD OF ANALYSIS OF CALCIPOTRIOL AND BETAMETHASONE OINTMENT

FINISHED PRODUCT SPECIFICATION

BRAND NAME --

GENERIC NAME Calcipotriol and Betamethasone Ointment

S. No TEST SPECIFICATION LIMITS

White color smooth White color smooth
1 Description
ointment ointment
Complies as per Complies as per
2 Identification
Specification Specification
3 Average Weight 15 gm NLT 15 gm

4 Uniformity of weight Complies 15 to 16 gm

Calcipotriol 0.005%w/w [90-110%]
5 Assay Betamethasone
0.05% w/w [90-110%]
Dipropionate

Prepared by Checked by Approved by

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FINISHED PRODUCT METHOD OF ANALYSIS

BRAND NAME --

GENERIC NAME Calcipotriol and Betamethasone Ointment

S. No TEST SPECIFICATION LIMITS

White color smooth White color smooth
1 Description
ointment ointment
Complies as per Complies as per
2 Identification
Specification Specification
3 Average Weight 15 gm NLT 15gm

4 Uniformity of weight Complies 15 to 16 gm

Calcipotriol 0.005%w/w [90-110%]
5 Assay Betamethasone
0.05% w/w [90-110%]
Dipropionate

Prepared by Checked by Approved by

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FINISHED PRODUCT METHOD OF ANALYSIS

BRAND NAME --

GENERIC NAME Calcipotriol and Betamethasone Ointment

S. No TEST SPECIFICATION

1 Description White color smooth ointment

Maximum absorbance obtained for sample
2 Identification
preparation is similar to standard preparation
3 Average Weight NLT 15gm

4 Uniformity of weight 15 to 16 gm
For Calcipotriol Monohydrate: By LC
Solution ADissolve 1.32 g of ammonium
phosphate R in water R and dilute to 10.0ml with the
same solvent.
Solvent mixtureSolution A, water R, methanol R
(3:297:700 V/V/V).
Test solution (a)Dissolve 2.00 mg of the
substance to be examined in the solvent mixture
and dilute to 5.0 ml with the solvent mixture.
Test solution (b)Dissolve 2.00 mg of the
substance to be examined in the solvent mixture
5 Assay and dilute to 20.0 ml with the same solvent mixture.
Reference solution (a)Dilute 1.0 ml of test solution
(a) to 100.0 ml with the solvent mixture.
Reference solution (b)Dilute 1.0 ml of reference
solution (a) to 10.0 ml with the solvent mixture.
Reference solution (c)Dissolve 1.0 mg of
calcipotriol monohydrate CRS (containing impurities
B, C and D) in the solvent mixture and dilute to 2.5
ml with the solvent mixture.
Reference solution (d)Dissolve 2.00 mg of
calcipotriol monohydrate CRS in the solvent mixture
and dilute to 20.0 ml with the solvent mixture.

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Prepared by Checked by Approved by

FINISHED PRODUCT METHOD OF ANALYSIS

BRAND NAME --

GENERIC NAME Calcipotriol and Betamethasone Ointment

Assay Column:
Cont.d size: l = 0.10 m, = 4.0 mm,

stationary phase: octadecylsilyl silica gel for

chromatography R (3 m).
Mobile phasewater R, methanol R(30:70 V/V).
Flow rate1.0 ml/min.
DetectionSpectrophotometer at 264 nm.
Injection: Test solution (b) and reference solution (d).
Run timeTwice the retention time of calcipotriol.
Relative retentionWith reference to calcipotriol (retention
time = about 13.5 min): impurity B = about 0.86; impurity
C = about 0.92; impurity D = about 1.3.
System suitabilityReference solution (c):
peak-to-valley ratio: minimum 1.5, where Hp = height
above the baseline of the peak due to impurity C and Hv =
height above the baseline of the lowest point of the curve
separating this peak from the peak due to calcipotriol,
the chromatogram obtained is similar to the
chromatogram supplied with calcipotriol monohydrate CRS.
Limits:
impurity B: not more than 0.5 times the area of the
principal peak in the chromatogram obtained with reference
solution (a) (0.5 per cent),
impurities C, D: for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (a) (1.0 per cent),
any other impurity: for each impurity, not more than
the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.1 per cent),
total: not more than 2.5 times the area of the principal
peak in the chromatogram obtained with reference solution
(a) (2.5 per cent),
disregard limit: 0.5 times the area of the principal peak
in the chromatogram obtained with reference solution (b)

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(0.05 per cent).
Calculate the percentage content of C27H40O3 from the areas
of the peaks and the declared content of calcipotriol
monohydrate CRS.

Prepared by Checked by Approved by

FINISHED PRODUCT METHOD OF ANALYSIS

BRAND NAME --

GENERIC NAME Calcipotriol and Betamethasone Ointment

For Betamethasone Dipropionate: by LC

Solution (1) contains 0.0125% w/v of betamethasone
Dipropionate RS and 0.010% w/v of hydrocortisone
(internal standard) in methanol (50%). For solution (2) to
a quantity of the ointment containing 2.5 mg of
Betamethasone Dipropionate add 20 ml of methanol
(50%), shake for 10 minutes and filter through a glass-
fibre filter paper (Whatman GF/C is suitable). Prepare
solution (3) in the same manner as solution (2) but use 20
Assay
ml of a 0.01% w/v solution of hydrocortisone in methanol
Cont.d
(50%) in place of the 20 ml of methanol (50%).
The chromatographic conditions described under Uniformity
of content may be used.
Calculate the content of C22H29FO5 in the ointment from the
declared content of C22H29FO5 in betamethasone
Dipropionate RS.

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Prepared by Checked by Approved by

STABILITY STUDIES

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ACCELERATED STABILITY STUDY

FOR
CALCIPOTRIOL AND
BETAMETHASONE OINTMENT

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INFORMATION CONCERNING SHELF LIFE, STABILITY AND STORAGE

CONDITIONS

ACCELARATED STABILITY STUDY OF

CALCIPOTRIOL AND BETAMETHASONE OINTMENT

LABEL CLAIM
Composition:
Calcipotriol Monohydrate BP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

BATCH NO: CB 7001 MFG.DATE: APR 2014 EXP.DATE: MAR 2016

PACKING: 30gm

Sample stored @ 45C 2C and 75% 2% relative humidity.

After 30 After 60 After 90 After 120 After 180

Tests Specification Initial
days days days days days
Appearance White color
smooth Conforms Conforms Conforms Conforms Conforms Conforms
ointment
Identification Complies as per
Specification Conforms Conforms Conforms Conforms Conforms Conforms
Average Nett content (gm)
15g5% Conforms Conforms Conforms Conforms Conforms Conforms
Calcipotriol
90% - 110% 101.67% 101.49% 99.82% 99.92% 98.98% 99.64%
Assay Anhydrous
Betamethasone 90% - 110% 100.15% 100.10% 98.92% 99.26% 99.47% 99.86%

Date APR 2014 MAY 2014 JUN2014 AUG 2014 SEP 2014 OCT 2014

SIGNATURE :

NAME :

DESIGNATION : QUALITY CONTROL INCHARGE

DATE : 18.10.2014

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INFORMATION CONCERNING SHELF LIFE, STABILITY AND STORAGE
CONDITIONS

ACCELARATED STABILITY STUDY OF

CALCIPOTRIOL AND BETAMETHASONE OINTMENT

LABEL CLAIM
Composition:
Calcipotriol Monohydrate BP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

BATCH NO: CB 7002 MFG.DATE: APR 2014 EXP.DATE: MAR 2016

PACKING: 30gm

Sample stored @ 45C 2C and 75% 2% relative humidity.

After 30 After 60 After 90 After 120 After 180

Tests Specification Initial
days days days days days
Appearance White color
smooth Conforms Conforms Conforms Conforms Conforms Conforms
ointment
Identification Complies as per
Specification Conforms Conforms Conforms Conforms Conforms Conforms
Average Nett content (mg) 30mg5% Conforms Conforms Conforms Conforms Conforms Conforms
Calcipotriol 90% - 110%
100.26% 99.94% 99.73% 98.96% 99.67% 98.87%
Assay Anhydrous
Betamethasone 90% - 110% 101.49% 100.24% 99.99% 100.17% 99.72% 98.83%
Date APR 2007 MAY 2007 JUN2007 JUL 2007 AUG 2007 OCT 2007

SIGNATURE :

NAME :

DESIGNATION : QUALITY CONTROL INCHARGE

DATE : 20.10.2014

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INFORMATION CONCERNING SHELF LIFE, STABILITY AND STORAGE

CONDITIONS

ACCELARATED STABILITY STUDY OF

CALCIPOTRIOL AND BETAMETHASONE OINTMENT

LABEL CLAIM
Composition:
Calcipotriol Monohydrate BP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

BATCH NO: CB 7003 MFG.DATE: APR 2007 EXP.DATE: JUN 2008

PACKING: 30gm

Sample stored @ 45C 2C and 75% 2% relative humidity.

After 30 After 60 After 90 After 120 After 180

Tests Specification Initial
days days days days days
Appearance White color
smooth Conforms Conforms Conforms Conforms Conforms Conforms
ointment
Identification Complies as per
Specification Conforms Conforms Conforms Conforms Conforms Conforms
Average Nett content (mg)
30mg5% Conforms Conforms Conforms Conforms Conforms Conforms
Calcipotriol 90% - 110%
99.89% 99.79% 99.28% 99.16% 98.86% 98.52%
Anhydrous
Assay
Betamethasone 90% - 110% 100.04% 99.64% 99.44% 98.73% 98.26% 99.08%
Date APR 2007 MAY 2007 JUN2007 JUL 2007 AUG 2007 OCT 2007

SIGNATURE :

NAME :

DESIGNATION : QUALITY CONTROL INCHARGE

DATE : 25.10.2007

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PROPOSED PACKAGE INSERT

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CALCIPOTRIOL AND BETAMETHASONE
[PROPOSED BRAND NAME]
Composition
Composition:
Calcipotriol MonohydrateBP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

INDICATIONS
Calcipotriol and Betamethasone Topical ointment is indicated for the treatment of stable plaque psoriasis vulgaris. Calcipotriol is a vitamin D analogue. In
vitro data suggests that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.
Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties,
however, without curing the underlying condition.

PHARMACOLOGY
Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Calcipotriol and Betamethasone
Ointment is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm 2) for 12 hours. Application to psoriasis plaques and under occlusive
dressings may increase the absorption of topical corticosteroids.
Absorption through damaged skin is approx 24%. Protein binding is approx 64%. Plasma elimination half-life after intravenous application is 5-6 hours. Due
to the formation of a depot in the skin elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in
the kidneys to glucuronide and sulphate esters. Excretion takes place by urine and faeces.

DOSAGE AND ADMINISTRATION

Calcipotriol and Betamethasone Ointment should be applied to the affected area once daily. The recommended treatment period is 4 weeks. After this period
repeated treatment with Calcipotriol and Betamethasone Ointment can be initiated under medical supervision.
The maximum daily dose should not exceed 15 g, the maximum weekly dose should not exceed 100 g, and the treated area should not be more than 30% of
the body surface.
Calcipotriol and Betamethasone Ointment is not recommended for the use in children and adolescents below the age of 18 years.

Adverse Reactions
Based on data from clinical trials and postmarket use the common undesirable effects are pruritus, rash and burning sensation of skin. Uncommon
undesirable effects are skin pain or irritation, dermatitis, erythema, exacerbation of psoriasis, folliculitis and application site pigmentation changes. Pustular
psoriasis is a rare undesirable effect.

Warning and Precautions

The patient must be instructed in correct use of the product to avoid application and accidental transfer to the scalp, face, mouth and eyes. Hands must be
washed after each application.
Treatment of more than 30% of the body surface should be avoided.
The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are fulfilled. Due to the content of calcipotriol hypercalcaemia may
occur if the maximum weekly dose (100 g) is exceeded. Serum calcium is quickly normalised, however, when treatment is discontinued.
Calcipotriol and Betamethasone Ointment contains a strong potent group III-steroid and concurrent treatment with other steroids must be avoided. Adverse
effects found in connection with systemic corticosteroid treatment such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus
may occur also during topical corticosteroid treatment due to systemic absorption.
Application on large areas of damaged skin and under occlusive dressings or on mucous membranes or in skin folds should be avoided since it increases
the systemic absorption of corticosteroids. Skin of the face and genitals are very sensitive to corticosteroids. Long-term treatment of these parts of the body
should be avoided. These areas should only be treated with the weaker corticosteroids. When lesions become secondarily infected, they should be treated
with antimicrobiological therapy. However, when infection worsens, treatment with corticosteroids should be stopped.
When treating psoriasis with topical corticosteroids there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment.
Medical supervision should therefore continue in the post-treatment period.

Contraindications
Hypersensitivity to any of the constituents of this ointment. Calcipotriol and Betamethasone Ointment is contraindicated in the following conditions: Viral (e.g.
herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis,
rosacea, perioral dermatitis, acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne rosacea, ulcers, wounds, perianal and
genital pruritus.

Pregnancy and Lactation

There are no adequate data from the use of Calcipotriol and Betamethasone Ointment in pregnant women. Studies in animals with glucocorticoids have
shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women
treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Calcipotriol and Betamethasone
Ointment should only be used when the potential benefit justifies the potential risk.
Betamethasone passes into breast milk but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion
of calcipotriol in breast milk. Caution should be exercised when prescribing Calcipotriol and Betamethasone Ointment to women who breast feed. The patient
should be instructed not to use Calcipotriol and Betamethasone Ointment on the breast when breast feeding.

STORAGE
Do not store above 25oC

Manufactured in India by
CENTRAL DRUGS AND PHARMACEUTICALS
NO: 3, MULTI INDUSTRIAL ESTATE,
GIRUGAMBAKKAM,
CHENNAI 602 101

For further information write to the above address

46
Central Drugs and
Pharmaceuticals

DRAFTS OF LABELS

47
Central Drugs and
Pharmaceuticals

30g
CALCIPOTRIOL AND BETAMETHASONE OINTMENT

(Proposed brand name)

Composition:
Calcipotriol Monohydrate BP
Equivalent to Calcipotriol anhydrous 0.005%w/w
Betamethasone Dipropionate BP
Equivalent to Betamethasone 0.05%w/w

To be applied in the affected area 3 times a day or as directed by the Physician

Do not store above 25C

Warning: To be sold by retail on the

prescription of a Registered Medical
Practitioner only

FOR EXTERNAL USE

Mfg. Lic. No : Batch No :

Mfg. Date : Exp. Date :

Maximum Retail Price:

(Inclusive of all Taxes)

Manufactured by:
CENTRAL DRUGS AND PHARMACEUTICALS
NO: 3, MULTI INDUSTRIAL NAGAR,
GIRUGAMBAKKAM,
CHENNAI 602 101

48
Central Drugs and
Pharmaceuticals

DRAFTS OF CARTONS

49
Central Drugs and
Pharmaceuticals

(Proposed Brand name)

30g

(Proposed Brand name)

CALCIPOTRIOL AND BETAMETHASONE OINTMENT

Warning: To be sold by retail on the

prescription of a Registered Medical
Practitioner only

Composition:
Mfg. Lic No: 251
(Proposed brand name)

Calcipotriol Monohydrate BP Equivalent to

Calcipotriol anhydrous 0.005%w/w Batch. No :
Betamethasone Dipropionate BP
Mfg. Date
Equivalent to Betamethasone 0.05%w/w
Ointment base Q.S Exp. Date :
To be applied in the affected area Maximum Retail Price
3 times a day (Inclusive of all Taxes)
or as directed by the Physician Manufactured by:
Do not store above 30C CENTRAL DRUGS AND PHARMACEUTICALS
NO: 3, MULTI INDUSTRIAL ESTATE,
GIRUGAMBAKKAM,
CHENNAI 600128

Pudu

50
Central Drugs and
Pharmaceuticals

CONTENTS
TITLE PAGE NO

1. Application in Form 44 duly filled and signed

2. Clinical Information 2
3. Pharmaceutical Information 5
4. Indications 7
5. Therapeutic justification for the combination 9
6. Toxicity Studies 12
7. Dosage and Administration 14
8. Adverse Reactions 16
9. Drug Interactions 19
10. Warnings 21
11. Precautions 21
12. Overdosage 24
13. Contra-Indications 26
14. Manufacturing Process 28
15. Method of Analysis of Raw Material 32
16. Method of Analysis of Finished Product 34
17. Stability Studies 40
18. Package Insert 45
19. Drafts of Labels 47
20. Drafts of Cartons 49

51