Taro-Clobetasol Spray Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES..............................................................................................2

TABLE OF CONTENTS ................................................................................................................2

PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................4

1 INDICATIONS ....................................................................................................................4

1. 1. 1 Pediatrics ..................................................................................................................4
2. 1. 2 Geriatrics ..................................................................................................................4

2 CONTRAINDICATIONS ........................................................................................................4

4 DOSAGE AND ADMINISTRATION ......................................................................................4

1. 4. 1 Dosing Considerations ...............................................................................................4
2. 4. 2 Recommended Dose and Dosage Adjustment.............................................................4
3. 4. 4 Administration ..........................................................................................................5
4. 4. 5 Missed Dose ..............................................................................................................6

5 OVERDOSAGE ...................................................................................................................6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .......................................7

7 WARNINGS AND PRECAUTIONS ........................................................................................7

1. 7.

   1 Special Populations.................................................................................................. 10

   1. 7. 1. 1 Pregnant Women.................................................................................................10
   2. 7. 1. 2 Breast-feeding .....................................................................................................10
   3. 7. 1. 3 Pediatrics ............................................................................................................10
   4. 7. 1. 4 Geriatrics.............................................................................................................10

8 ADVERSE REACTIONS...................................................................................................... 11

1. 8. 1 Adverse Drug Reaction Overview ............................................................................. 11
2. 8. 2 Clinical Trial Adverse Reactions ................................................................................ 11
3. 8. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................... 12
4. 8. 5 Post-market Adverse Reactions................................................................................ 13

9 DRUG INTERACTIONS ..................................................................................................... 13

1. 9. 2 Drug Interactions Overview ..................................................................................... 13
2. 9. 4 Drug-Drug Interactions ............................................................................................ 13
3. 9. 5 Drug-Food Interactions ............................................................................................ 13
4. 9. 6 Drug-Herb Interactions ............................................................................................ 13
5. 9. 7 Drug-Laboratory Test Interactions ............................................................................ 13

10 CLINICAL PHARMACOLOGY............................................................................................. 13

1. 10. 1 Mechanism of Action ............................................................................................... 13
2. 10. 2 Pharmacodynamics ................................................................................................. 14
3. 10. 3 Pharmacokinetics .................................................................................................... 14

11 STORAGE, STABILITY AND DISPOSAL............................................................................... 14

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 14

PART II: SCIENTIFIC INFORMATION ........................................................................................ 15

13 PHARMACEUTICAL INFORMATION ................................................................................. 15

14 CLINICAL TRIALS ............................................................................................................. 16

1. 14. 1 Trial Design and Study Demographics ....................................................................... 16
2. 14. 2 Study Results ........................................................................................................... 16

15 MICROBIOLOGY.............................................................................................................. 17

16 NON-CLINICAL TOXICOLOGY ........................................................................................... 17

17 SUPPORTING PRODUCT MONOGRAPHS ......................................................................... 20

PATIENT MEDICATION INFORMATION ................................................................................... 21

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Taro-Clobetasol Spray (clobetasol propionate spray), 0.05% is a super-high potent topical corticosteroid formulation indicated for the treatment of moderate to severe plaque psoriasis in subjects 18 years of age and older.

Taro-Clobetasol Spray, 0.05% is not indicated for long-term use. Treatment should be limited to a maximum of four consecutive weeks. Intermittent use has not been studied.

1. 1. 1 Pediatrics

Use in patients under 18 years of age is not recommended. Taro-Clobetasol Spray is contraindicated in children under 2 years of age.

1. 1. 2 Geriatrics

Limited data are available in patients aged 65 years and over. Dosing selection should be made with caution in geriatric patients. See 7 WARNINGS AND PRECAUTIONS, 7.14 Geriatrics.

2 CONTRAINDICATIONS

• Patients who are hypersensitive to clobetasol propionate, to corticosteroids, or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the Product Monograph.
• Patients with skin areas affected by bacterial or mycobacterial infections (including tuberculosis of the skin), fungal infections involving the skin, certain viral diseases such as herpes simplex, chickenpox, and vaccinia, parasitic infections or ulcerous wounds.
• Must not be used in children under 2 years of age.
• Must not be applied to the eyes and eyelids (risk of glaucoma, risk of cataract).

4 DOSAGE AND ADMINISTRATION

1. 4.

   1 Dosing Considerations

   • Treatment duration should not exceed 4 consecutive weeks.
   • Taro-Clobetasol Spray, 0.05% should not be used with occlusive dressings.
2. 4. 2 Recommended Dose and Dosage Adjustment

Taro-Clobetasol Spray, 0.05% should be applied to the affected skin areas twice daily and rubbed in gently and completely. Wash hands carefully with water after application.

Taro-Clobetasol Spray, 0.05% is a super-high potent topical corticosteroid formulation. Patients should be instructed to use Taro-Clobetasol Spray for the minimum amount of time necessary. Treatment should be limited to 4 consecutive weeks. Treatment beyond two weeks should be limited to localized lesions of moderate to severe plaque psoriasis that have not sufficiently improved after the initial two weeks of treatment with Taro-Clobetasol Spray, 0.05%. If treatment with a local corticosteroid is clinically justified beyond 4 weeks, switching to a less potent corticosteroid preparation should be considered.

Total dosage of the product should not exceed 50 mL per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Therapy should be discontinued when control has been achieved. If no improvement is seen within two weeks, reassessment of diagnosis may be necessary.

Taro-Clobetasol Spray, 0.05% is not indicated for long-term use. Intermittent use has not been studied.

Pediatrics: Use in patients between 2 and 18 years of age is not recommended and is contraindicated in children below 2 years of age. See 1.1 Pediatrics.

1. 4. 4 Administration

Taro-Clobetasol Spray, 0.05% should be applied to the affected skin areas twice daily and rubbed in gently and completely.

How to use Taro-Clobetasol Spray:

The following instructions outline the proper use of Taro-Clobetasol Spray, 0.05%. The Pump Top and Directional Spray Nozzle mechanism are described in the figure below (Fig.1).

When you receive Taro-Clobetasol Spray, the Directional Spray Nozzle is in the “locked” position (see Fig. 2).

To use Taro-Clobetasol Spray follow Steps 1 through 3.

Step 1: Grip the sides of the Pump Top with one hand and use your second hand to point the Directional Spray Nozzle where you want the spray to go (see Fig. 3). The spray will be delivered through the nozzle opening at the end of the Directional Spray Nozzle.

Step 2: Push down on the Pump Top to spray Taro-Clobetasol Spray (see Fig.4).

Step 3: Spray only enough to cover affected area. Rub gently to ensure even coverage. Do not apply Taro-Clobetasol Spray to your face, underarms or groin and avoid contact with eyes and lips (see Fig. 5). In case of contact, rinse thoroughly with water.

1. 4. 5 Missed Dose

In the event of a missed dose, Taro-Clobetasol Spray, 0.05% should be applied as soon as possible after the missed dose is remembered. If this is close to the scheduled application time for the next dose, the subject should wait and apply the next scheduled dose. The usual schedule should be resumed thereafter.

5 OVERDOSAGE

In case of chronic overdose or misuse, the features of hypercortisolism may appear and in this situation, treatment should be discontinued gradually. However, because of the risk of acute adrenal suppression, this should be done gradually under medical supervision (see 7 WARNINGS AND PRECAUTIONS).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Taro-Clobetasol Spray, 0.05% is available in 59 mL (50 g) bottles. Each gram contains 0.5 mg of clobetasol propionate. Each 59 mL bottle is accompanied by a spray pump which is to be attached by the pharmacist prior to dispensing the product. Each spray from the pump delivers approximately 0.16 mL.

7 WARNINGS AND PRECAUTIONS

General

Taro-Clobetasol Spray, 0.05% should not be used under occlusive dressing, over extensive areas, or on the face, axillae, or scrotum, as sufficient absorption may occur to give rise to adrenal suppression and other systemic effects.

Clobetasol propionate belongs to the most potent class of topical corticosteroids (Class I) and prolonged use may result in serious undesirable effects (see 8.5 Post-Market Adverse Reactions). Treatment should not exceed 4 consecutive weeks (see 4 DOSAGE AND ADMINISTRATION).

Topical corticosteroids are known to potentially induce post-treatment rebound, relapses, development of tolerance (tachyphylaxis) and development of local or systemic toxicity such as skin atrophy, infection (including isolated cases of systemic infections), telangiectasia of the skin or hypothalamic-pituitary-adrenal axis suppression.

Endocrine and Metabolism

Clobetasol propionate is a highly potent topical corticosteroid that has been shown to suppress the hypothalamic-pituitary-adrenal; (HPA) axis.

Children may be more susceptible to system toxicity from use of topical corticosteroids.

Systemic absorption of topical corticosteroids has caused reversible adrenal suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.

Conditions which increase systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of adrenal suppression (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). If adrenal 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 upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see the Product Monograph for those products.

Two studies were conducted to evaluate the effect of twice daily applications of clobetasol propionate spray, 0.05% on HPA axis function in adults with plaque psoriasis covering at least 20% of their body. Study duration was two or four weeks. In the first study four of 14 (29%) patients displayed adrenal suppression after four weeks of use. In the second study, four of 19 (21%) of patients in the two week treatment group and four of 17 (24%) of patients in the four week treatment group displayed adrenal suppression. Suppression was transient, and all patients had returned to normal within 15-16 days of therapy cessation.

Hepatic/Biliary/Pancreatic

Patients with severe liver dysfunction and severe diabetes mellitus should be treated with special caution and closely monitored for side effects.

Immune

Corticosteroids have immunosuppressive properties. Topical corticosteroids may decrease resistance to infection, increase the risk of opportunistic infection and also mask some signs of infection. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Cases of systemic immunosuppression and serious infections have been reported with long-term use of clobetasol propionate beyond the maximum recommended doses (see 8.5 Post-Market Adverse Reactions). Combining clobetasol propionate with other medicines known to weaken the immune system increases the risk of systemic immunosuppression and serious infections.

Monitoring and Laboratory Tests

The following tests may be helpful in evaluating patients for HPA axis suppression:

• ACTH stimulation test
• A.M. plasma cortisol test
• Urinary free cortisol test

Musculoskeletal

Cases of osteonecrosis have been reported with long-term use of clobetasol propionate beyond the maximum recommended doses (see 8.5 Post-Market Adverse Reactions).

Ophthalmologic

Taro-Clobetasol Spray, 0.05% should not be used on plaques close to the eye because of the risk of increased intraocular pressure, glaucoma, and cataracts. Avoid any contact of the drug product with the eyes. In case of contact, the affected eye should be rinsed thoroughly with water.

Prolonged corticosteroid use may produce posterior subcapsular cataracts (especially in children), increased intraocular pressure and glaucoma with possible damage to the optic nerves, or rare diseases such as central serious chorioretinopathy (CSCR). It may also enhance secondary ocular infections due to fungi or viruses.

If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist.

Sensitivity/Resistance

Hypersensitivity to corticosteroids can be observed. Taro-Clobetasol Spray, 0.05% is not recommended in patients who are hypersensitive to other corticosteroids.

If irritation develops, Taro-Clobetasol Spray, 0.05% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by a failure to heal rather than by noting a clinical exacerbation, as is the case with most products not containing a corticosteroid.

Skin

In rare instances, treatment of psoriasis with corticosteroids (or its withdrawal) is thought to have provoked generalized pustular psoriasis in case of intensive and prolonged topical use.

Taro-Clobetasol Spray 0.05% is not recommended in patient with acne vulgaris, rosacea or perioral dermatitis.

Taro-Clobetasol Spray 0.05% must not be applied on intertriginous areas (axillae and genitoanal regions) and on other erosive skin surfaces as this could increase the risk of topical adverse events such as atrophic changes, telangiectasia or cortico-induced dermatitis.

In the presence of fungal infections, an appropriate antifungal treatment should be instituted and Taro-Clobetasol spray 0.05% should be discontinued until the fungal infection is cured. In the presence of a bacterial infection, an appropriate antibacterial agent should be instituted. If a favorable response does not occur promptly, Taro-Clobetasol Spray 0.05% should be discontinued until the bacterial infection is adequately controlled.

1. 7. 1 Special Populations
2. 7. 1. 1 Pregnant Women

There are no adequate and well-controlled studies of the teratogenic potential of clobetasol propionate in pregnant women. Taro-Clobetasol Spray, 0.05% should be used during pregnancy only if its benefit justifies the potential risk to the fetus. The extent of exposure during the clinical trials with clobetasol propionate spray, 0.05% was very limited (one case).

Corticosteroids have been shown to be teratogenic in laboratory animals when administrated systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals (see 16 NON-CLINICAL PHARMACOLOGY).

1. 7. 1. 2 Breast-feeding

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 topical administration of 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 Taro-Clobetasol Spray, 0.05% is administered to a nursing woman.

Clobetasol propionate should not be prescribed to breastfeeding women unless clearly indicated

1. 7. 1. 3 Pediatrics

Safety and effectiveness of clobetasol propionate spray, 0.05% have been established in patients 18 years and older. Insufficient data have been obtained in patients under the age of 18 years. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults for HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.

Use in patients below 18 years of age is not recommended and is contraindicated in children below 2 years of age.

HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

1. 7. 1. 4 Geriatrics

Clinical studies of clobetasol propionate spray, 0.05%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be made with caution reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8 ADVERSE REACTIONS

1. 8. 1 Adverse Drug Reaction Overview

Systemic absorption of topical corticosteroids has produced reversible HPA axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients.

The following additional local adverse reactions have been reported with topical corticosteroids in general, and they may occur more frequently with the use of occlusive dressings, use over a prolonged period of time, or use over large surface areas, especially with higher potency corticosteroids, including clobetasol propionate. These reactions include: irritation, dryness, itching, burning, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, skin atrophy, atrophy of subcutaneous tissues, telangiectasia, hypertrichosis, change in pigmentation, opportunistic infection, hypersensitivity, glaucoma, striae and miliaria. If applied to the face, acne rosacea or perioral dermatitis can occur. When occlusive dressings are used, pustules, miliaria, folliculitis and pyoderma may occur. In rare instances, treatment of psoriasis with systemic or very potent topical corticosteroids (or their withdrawal) is thought to have provoked the pustular form of the disease.

Rebound effect may occur upon treatment discontinuation.

1. 8. 2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The data presented in Table 2, below, include the combined data from two multicentre, randomized, blinded, vehicle-controlled studies conducted in patients 18 years of age or older, with moderate to severe plaque psoriasis. Clobetasol propionate spray, 0.05% or Spray Vehicle were applied twice daily to affected areas until healing, or for a maximum of four weeks.

The most common adverse reaction reported with clobetasol propionate spray, 0.05% is burning at the application site. Other common adverse reactions are local site effects as well, including pruritus, dryness, pain, hyperpigmentation around resolving plaque, irritation, and atrophy. Most local adverse events were rated as mild to moderate and were not affected by age, race or gender.

One serious, unexpected adverse event, designated as possibly related to treatment by the clinical investigator, was reported during the clinical trial programme with clobetasol propionate spray, 0.05%. This severe event was reported as paranoid delusions in a subject with a seven-year history of intermittent methamphetamine use. Although the event was thought to be related to methamphetamine use by the treating psychiatrist, the possibility of a treatment relationship to clobetasol propionate solution (i.e., spray) could not be absolutely ruled out by the investigator.

Table 2: Treatment Related Adverse Events (At Least Possibly Related) Occurring at a Frequency of ≥1% of Subjects in at Least One Group (Clinical Studies TI01-01008 and TI01-01010 Combined)

1. 8. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

One subject treated for four weeks with clobetasol propionate spray, 0.05% experienced an elevated WBC, which was designated by the investigator as possibly related to treatment.

1. 8. 5 Post-market Adverse Reactions

The following adverse reactions have been reported in clobetasol propionate during the post-marketing setting, adrenal suppression, Cushing syndrome, glaucoma, blurred vision, hypersensitivity, allergic contact dermatitis, erythema and rash.

Cases of osteonecrosis, Kaposi’s sarcoma lesions, and necrotizing fasciitis have been reported with long-term use of clobetasol propionate beyond the maximum recommended doses (see 4 DOSAGE AND ADMINISTRATION and 7 WARNINGS AND PRECAUTIONS, Immune).

9 DRUG INTERACTIONS

1. 9. 2 Drug Interactions Overview

The fact that clobetasol propionate could induce a six-fold induction of ethoxycoumarin-O-dealkylase activity in skin indicates that there is a potential drug-drug interaction with other topical drugs that could be metabolised by the same enzyme.

1. 9. 4 Drug-Drug Interactions

Interactions with other drugs have not been established.

1. 9. 5 Drug-Food Interactions

Interactions with food have not been established. However, given the topical route of administration, such interactions seem unlikely.

1. 9. 6 Drug-Herb Interactions

Interactions with herbal products have not been established.

1. 9. 7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

1. 10. 1 Mechanism of Action

Clobetasol propionate is a super-high potency topical corticosteroid. Like other topical corticosteroids, clobetasol propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

1. 10. 2 Pharmacodynamics

Results of a study in healthy volunteers have shown the vasoconstriction capacity of clobetasol propionate spray, 0.05% is comparable to that of cream formulations of clobetasol propionate and superior to that of amcinonide cream, 0.1%.

1. 10. 3 Pharmacokinetics

Absorption and Distribution

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin while inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.

Metabolism and Elimination

Topical corticosteroids are metabolized, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids, including clobetasol propionate and its metabolites, are also excreted in the bile.

If absorbed through the skin, clobetasol propionate will be metabolized by the liver and excreted primarily via bile into the feces.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15° - 30°C). Do not refrigerate. Keep tightly closed. Product is flammable, and should be kept away from heat or open flame. Keep in a safe place out of the reach and sight of children. Discard product 28 days after receipt from pharmacist.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling requirements for this product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Clobetasol propionate

Chemical name: 21-chloro-9-fluoro-11β, 17-dihydroxy-16β -methylpregna-

1, 4-diene-3, 20-dione 17-propionate

Molecular formula: C₂₅H₃₂ClFO₅ (CAS Registry Number 25122-46-7)

Molecular mass: 466.97 grams/mole

Structural formula:

Physicochemical properties: White to practically white crystalline powder that is insoluble in water, and has a melting point of approximately 196°C.

14 CLINICAL TRIALS

1. 14. 1 Trial Design and Study Demographics

Table 3: Summary of patient demographics for clinical trials in moderate to severe plaque psoriasis

Two multicentre, randomized, blinded, vehicle controlled studies were performed in patients with moderate to severe plaque psoriasis covering at least 2% of the body surface area. Patients were treated twice daily for up to four weeks with either clobetasol propionate spray, 0.05% or Spray Vehicle.

1. 14. 2 Study Results

Efficacy assessments were based on Investigator assessments of the signs and symptoms of psoriasis. The primary measure of efficacy variable was the Overall Disease Severity score, dichotomized to success or failure. Success was defined as a Grade of 2 or less on a 0-4 point scale at Week 2 or earlier and defined as a Grade of 1 or less on a 0-4 point scale at the end of treatment (Week 4 or later).

Table 4 Results of Studies TI01-01008 and TI01-01010, separately and combined, in moderate to severe plaque psoriasis

^a Success is defined as a grade of 2 or less on the 0-4 point Overall Disease Severity Scale.

^b Success is defined as a grade of 1 or less on the 0-4 point Overall Disease Severity Scale.

^c P-value from a Cochran-Mantel-Haenszel test, stratified by grouped study sites. The Week 4 analysis is considered statistically significant if and only if statistical significance is achieved for both the Week 2 and Week 4 analyses.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

Acute toxicity was determined in mice and rats using subcutaneous, oral, and intraperitoneal routes. The animals received a single dose of different concentrations of clobetasol propionate and were observed for three consecutive weeks. The LD₅₀ value obtained by the subcutaneous route in mice was 81.7 mg/kg for all animals. None of the mice died after oral administration up to 3 g/kg. The LD₅₀ value obtained by the intraperitoneal route in mice was 156 mg/kg for males and 118 mg/kg for females. The subcutaneous LD₅₀ value for male rats was 397 mg/kg and 366 mg/kg for female rats. None of the rats died after oral administration up to 3 g/kg. The LD₅₀ value by the intraperitoneal route for male rats was 414 mg/kg and 351 mg/kg for female rats.

Repeated Dose Toxicity

Using clobetasol propionate spray, 0.05%, a no observed effect dose level (NOEL) of 150 mg formulation/kg/day (safety factor of 0.9) was established for systemic toxicity in a 90-day subchronic micropig study. In a dermal toxicity study with Hanford minipigs, doses of 60, 120 and 240 mg/kg/day (safety factor 0.3, 0.65, 1.3, respectively) of clobetasol propionate spray, 0.05%, were applied for nine months followed by a one month recovery. Treatment related decreases in body weight and histopathological findings precluded the determination of a NOEL in this study.

A 90-day dermal irritation study was conducted in Sprague Dawley rats. Concentration of clobetasol propionate was varied to produce 0.001%, 0.005%, 0.015%, and 0.05% sprays. Dosing was rotated between two 20 cm² sites on the back and a constant volume of 0.16 mL/kg/dose (800 mg formulation/m²/dose) was chosen based on the results a vehicle dose range finding study that found 0.24 mL/kg/dose could be tolerated in rats for 14 days. Based on the results of this study, the no-observed- adverse-effect (NOAEL) level was considered to be the 0.001% or 0.13 mg/kg (safety factor of 0.007). The effects noted during or at the end of the treatment period were reversible and most resolved almost completely by the end of a one month recovery period.

Carcinogenicity:

Few animal studies have been performed to evaluate the carcinogenic potential of isopropyl myristate and there are no detailed systemic absorption data for this compound in humans or animals.

No classical animal studies have been performed to evaluate the carcinogenic potential of clobetasol propionate.

One 18-month study was performed in mice to evaluate the carcinogenic potential of fluticasone propionate (medium-potency corticosteroid) when given topically as a 0.05% ointment. No evidence of carcinogenicity was found in this study. No evidence of pre-neoplastic lesions was noted in a 6-month toxicity study performed with clobetasol propionate by the subcutaneous route in rats.

Genotoxicity:

Clobetasol propionate was negative in the in vivo mammalian erythrocyte micronucleus test and in the in vitro mammalian chromosome aberration test conducted.

Reproductive and Developmental Toxicology:

Segment I fertility studies in rats following oral administration at doses up to 50 μg/kg per day revealed an increase in the number of the resorbed embryos and a decrease in the number of living foetuses at the highest dose.

In another Segment I study, male rats were dosed subcutaneously twice daily beginning 70 days before cohabitation and continuing through the day before sacrifice and female rats were dosed twice daily beginning 15 days before cohabitation and continuing through Day 7 of presumed gestation. A dosage level of less than 12.5 µg /kg/day clobetasol propionate (safety factor 0.03) was considered to be the NOEL for paternal and maternal general toxicity and male reproductive toxicity. The female reproductive NOEL was 12.5 µg kg/day (safety factor 0.03).

Segment II teratogenicity studies in mice, rats and rabbits showed clobetasol propionate to be teratogenic when administered sub-cutaneously or topically. Abnormalities seen include fetal immaturity and several malformations, cleft palate, cranioschisis and skeletal abnormalities, in combination with maternal toxicity.

A Segment II study was performed in rats using Clobetasol Propionate Lotion applied dermally at dose levels of 0.05, 0.15, and 0.5 mg/kg/day. Dose-related maternal and fetal toxicity was observed, and fetal immaturity was observed at all dose levels. A variety of fetal malformations were observed at 0.15 and 0.5 mg/kg/day, in combination with maternal toxicity.

In a Segment III study, females were dosed with clobetasol propionate suspended in 0.04% Tween^® 80 in saline administered subcutaneously from Day 7 of presumed gestation through Day 20 postpartum or Day 24 presumed gestation for those rats that did not deliver a litter. The maternal NOEL for clobetasol propionate was less than 12.5 µg /kg/day (safety factor 0.03) due to reduced body weight gain and feed consumption during the gestation period. The reproductive NOEL in the dams was 25 µg /kg/day (safety factor 0.07). The NOAEL for viability and growth in the offspring was 12.5 µg /kg/day (safety factor 0.03).

Local Tolerance:

Results from special toxicity studies evaluating primary dermal and ocular irritation potential showed that clobetasol propionate spray, 0.05% is a slight skin irritant but not a skin sensitizer. It also produces moderate irritation in the Kay and Calandra Ocular Evaluation. Clobetasol propionate spray, 0.05% is not phototoxic and does not cause photoallergy reactions.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. CLOBEX® SPRAY (Clobetasol Propionate Spray, 0.05%), submission control 259690, Product Monograph, Galderma Canada Inc. (May 12, 2022)