Fluocinolone acetonide 0.01% Topical Oil House Standard Topical Corticosteroid Manufacturer: Hill Dermaceuticals, Inc. 2650 South Mellonville Ave. Sanford, Florida 32773 U.S.A. www.hillderm.com Canadian Distributor: Hill Dermaceuticals, Inc. 3045 Southcreek Road, Unit #4 Mississauga, Ontario L4X 2X6 Date of Preparation: Canada December 21, 2006 Control Number 111174 March 05, 2007
Table of Contents
SUMMARY PRODUCT INFORMATION 1 INDICATIONS AND CLINICAL USE 1 CONTRAINDICATIONS 1 WARNINGS AND PRECAUTIONS 1 ADVERSE REACTIONS 5 DRUG INTERACTIONS 7 DOSAGE AND ADMINISTRATION 7 OVERDOSAGE 7 ACTION AND CLINICAL PHARMACOLOGY 8 STORAGE AND STABILITY 9 DOSAGE FORMS, COMPOSITION AND PACKAGING 9
PHARMACEUTICAL INFORMATION 10 CLINICAL TRIALS 11 DETAILED PHARMACOLOGY 18 MICROBIOLOGY 18 TOXICOLOGY 18 REFERENCES 19
PRODUCT MONOGRAPH
Fluocinolone acetonide 0.01% Topical Oil House Standard Topical Corticosteroid | ||
|---|---|---|
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Topical | Topical Oil / 0.01% | Refined Peanut Oil NF, Mineral Oil Light, Oleth-2, Isopropyl Myristate, Isopropyl Alcohol, Cream Fragrance, Balsam Pine Fragrance. For a complete listing see Dosage Forms, Composition and Packaging section. |
Derma-Smoothe/FS(r) Topical Oil (fluocinolone acetonide 0.01%) is a low to medium potency corticosteroid indicated for:
Treatment of atopic eczema in adults.
Treatment of moderate to severe atopic dermatitis in children 2 to 12 years of age. It may be used for a maximum duration of 4 weeks on the body. It is not indicated for use on the face.
Derma-Smoothe/FS(r) Topical Oil is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. This product contains refined peanut oil NF (see WARNINGS AND PRECAUTIONS section). For a complete listing see Dosage Forms, Composition and Packaging section. Topical application to the eye is contraindicated, especially in the presence of ophthalmologic infections.
General
Systemic absorption of topical corticosteroids can produce reversible hypothalamic- pituitary-adrenal (HPA) axis suppression and the potential for adrenal insufficiency after sudden withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glycosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Derma-Smoothe/FS(r) is formulated with 48% refined peanut oil NF. Physicians should use caution in prescribing Derma-Smoothe/FS(r) for peanut-sensitive individuals. One peanut- sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma-Smoothe/FS(r) (see CLINICAL TRIALS section). If irritation develops, Derma-Smoothe/FS(r) Topical Oil should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch test. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Derma-Smoothe/FS(r) Topical Oil should be discontinued until the infection has been adequately controlled. Derma-Smoothe/FS(r) should not be used in intertriginous areas or under occlusion.
Carcinogenesis and Mutagenesis
Long term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of Derma-Smoothe/FS(r) Topical Oil. Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide, the active ingredient in Derma-Smoothe/FS(r). Some corticosteroids have been found to be genotoxic in various genotoxicity tests (i.e. the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay).
Endocrine and Metabolism
Glucocorticoids decrease the hypoglycemic activity of insulin and oral hypoglycemics, so that a change in dose of the antidiabetic drugs may be necessitated. In high doses, glucocorticoids also decrease the response to somatotropin. The usual doses of mineralocorticoids and large doses of some glucocorticoids cause hypokalemia and may exaggerate the hypokalemic effects of thiazides and high-ceiling diuretics. In combination with amphotericin-B, they also may cause hypokalemia. Glucocorticoids appear to enhance the ulcerogenic effects of non-steroidal anti-inflammatory drugs. They decrease the plasma levels of salicylates, and salicylism may occur on discontinuing steroids. Glucocorticoids may increase or decrease the effects of prothrombopenic anticoagulants. Estrogens, phenobarbital, phenytoin and rifampin increase the metabolic clearance of adrenal steroids and hence necessitate dose adjustments.
Immune
Cortisol and the synthetic analogs of cortisol have the capacity to prevent or suppress the development of the local heat, redness, swelling, and tenderness by which inflammation is recognized. At the microscopic level, they inhibit not only the early phenomena of the inflammatory process (edema, fibrin deposition, capillary dilation, migration of leukocytes into the inflamed area, and phagocytic activity) but also the later manifestations (capillary proliferation, fibroblast proliferation, deposition of collagen, and, still later, cicatrization).
Neurologic
Patients receiving a large dose of a higher potency topical steroid applied to a large surface area or under occlusion should be evaluated periodically for evidence of Hypothalamic- Pituitary-Adrenal (HPA) axis suppression. This may be done by using the ACTH (Adrenocorticotropic hormone) stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids.
Ophthalmologic
Avoid contact with the eyes. In case of contact, wash eyes liberally with water.
Sensitivity/Resistance
Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS-Paediatrics section).
Skin
The following local adverse reactions have been reported infrequently with topical corticosteroids, including fluocinolone acetonide. They may occur more frequently with the use of occlusive dressing, especially with higher potency corticosteroids. The reactions are listed in approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae and miliaria.
Special Populations
Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. No studies have been done on Derma-Smoothe/FS(r) Topical Oil to show teratologic effects on animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from Derma-Smoothe/FS(r). Therefore, Derma-Smoothe/FS(r) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 secreted in human milk, caution should be exercised when Derma-Smoothe/FS(r) Topical Oil is administered to a nursing woman.
Derma-Smoothe/FS(r) is not indicated for use on the face or in the diaper or anogenital areas. Derma-Smoothe/FS(r) may be used twice daily for up to 4 weeks in paediatric patients 2 years and older with moderate to severe atopic dermatitis. Derma-Smoothe/FS(r) should not be used under the age of 2 years. Application to intertriginous areas should be avoided due to the increased possibility of local adverse events such as striae, atrophy, and telangiectasia, which may be irreversible. The smallest amount of drug needed to cover the affected areas should be applied. Long term safety (over 28 days) in the paediatric population has not been established. Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment, and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to system toxicity from equivalent doses due to their larger skin surface to body mass ratios. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headache, and bilateral papilledema. Derma-Smoothe/FS(r) is formulated with 48% refined peanut oil NF, in which peanut protein is not detectable at 2.5 ppm. Physicians should use caution in prescribing Derma- Smoothe/FS(r) for peanut-sensitive children.
:
Clinical studies have not been conducted in populations >65 years of age.
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
Adverse Drug Reaction Overview
The following local adverse reactions have been reported infrequently with topical corticosteroids, including fluocinolone acetonide. They may occur more frequently with the use of occlusive dressing, especially with higher potency corticosteroids. The reactions are listed in an approximate decreasing order of occurrence: dryness, folliculitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria, burning, itching, irritation, and hypopigmentation. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma-Smoothe/FS(r).
Deaths and other Serious Adverse Events
No deaths or serious adverse events were reported in any of the studies.
Withdrawals Due to Adverse Events
There were 7 withdrawals from the primary efficacy studies in pediatric patients with atopic dermatitis. Six (6) withdrawals were due to adverse events (disease exacerbation), 4 from the placebo group and 2 from the active group. One patient from the active group was removed due to a protocol violation.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Atopic Dermatitis Studies
Table 1: Study 25 and Study 25-S
| Derma-Smoothe/FS (r) N = 76 * (%) | Derma-Smoothe/FS (r) Vehicle N = 52 (%) | |
| Integumentary Hypopigmentation Erythema Papules Pustules Burning Itching Irritation | 1 (1.3) 2 (2.6) 6 (7.9) 6 (7.9) 4 (5.3) 4 (5.3) 4 (5.3) | 0 0 0 0 0 0 0 |
Combined Study 25 and Study 25-S (Open-Label)
Study 25
Study 25 was a double-blind safety and efficacy study of Derma-Smoothe/FS(r) versus the Derma-Smoothe/FS(r) vehicle in the treatment of atopic dermatitis in children 2 years and older. Derma-Smoothe/FS(r) was applied twice daily for 28 days. Only one adverse event was noted in Study 25. This adverse event was slight hypopigmentation, noted at the final evaluation, 2 weeks after stopping treatment with Derma-Smoothe/FS(r). In Study 25, a total of 84 patients completed the study.
Study 25-S
Study 25-S was an open-label safety study of Derma-Smoothe/FS(r) for the treatment of atopic dermatitis. Derma-Smoothe/FS(r) was applied twice daily for 28 days. No adverse events were observed in Study 25-S California. Four patients in Study 25-S Chicago, Cleveland, and Miami had at least one adverse event. All patients with reported adverse events were at the Chicago site: two patients had severe papules, pustules, burning, itching, and irritation at the final visit (2 weeks after stopping study medication), and two patients had mild papules and pustules at the 4th week of treatment (the last week of treatment with study medication), and moderate erythema, papules, pustules, burning, itching, and irritation at the final visit (2 weeks after stopping study medication). All adverse events had resolved soon after the end of the study, as determined by an informal follow-up by the sponsor to each investigator after termination of the study. Seven placebo treated patients had exacerbation of the disease. In Study 25-S, a total of 25 subjects completed the study.
Study 26
Study 26 was a post-marketing (open label) safety study to evaluate the effects of Derma- Smoothe/FS(r) on HPA axis suppression. A total of 15 people were enrolled in the safety study. One subject withdrew before week two evaluations and one subject was eliminated for a lack of cortisol levels at week four. No local adverse events were reported during Study 26. In Study 26 a total of 13 subjects completed the study.
Post-Market Adverse Drug Reactions
Only 30 adverse events overall have been reported to the sponsor, including (in decreasing order of frequency): allergic reaction, alopecia, skin irritation, erythema, transient corneal irritation due to accidental exposure, nausea, and vertigo.
Study 26
Study 26 was a post-marketing (open label) safety study to evaluate the effects of Derma- Smoothe/FS(r) on HPA axis suppression. No local adverse events were reported during Study 26.
Peanut Hypersensitivity Safety Study Chicago Peanut Allergy Study
A phase 4, controlled, open label clinical study was conducted to assess the safety of Derma-Smoothe/FS(r), which contains refined peanut oil NF, on subjects with known peanut allergies. The study enrolled 13 patients with atopic dermatitis, 6 to 17 years of age. Of the 13 patients, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). One of the 9 peanut-sensitive patients experienced an exacerbation of atopic dermatitis after 5 days of treatment with Derma-Smoothe/FS(r) (see CLINICAL TRIALS section). In the Chicago Peanut Allergy Study, a total of 12 patients completed the study.
Overview
There are no known genetic differences in response to Derma-Smoothe/FS(r) Topical Oil for treatment of atopic dermatitis, and there are no known clinically relevant interactions with other medicinal products. There were insufficient numbers of patients in the clinical trials of Derma-Smoothe/FS(r) Topical Oil to examine potential drug-drug, drug- demographic, or drug-disease interactions.
Drug-Drug Interactions
There have been no clinical studies conducted to assess the safety of Derma- Smoothe/FS(r) Topical Oil used in combination therapy. It is recommended that Derma- Smoothe/FS(r) Topical Oil be used without the use of other medications.
Dosing Considerations
Paediatrics: Children have a larger surface to body mass area leading to a higher susceptibility to HPA axis suppression; however, there have been no reported cases during clinical studies or post-marketing experience of HPA axis suppression. Parents of paediatric patients should be advised not to use Derma-Smoothe/FS(r) Topical Oil in the treatment of facial or diaper dermatitis. Derma-Smoothe/FS(r) Topical Oil is not indicated for use on the face or anogenital areas. Derma-Smoothe/FS(r) Topical Oil is not indicated for use in the diaper area as diapers or plastic pants may constitute occlusive dressing. Parents of paediatric patients should be advised that use of Derma-Smoothe/FS(r) Topical Oil is for topical use only, not for oral, ophthalmic, or intravaginal use.
Geriatrics: Clinical studies have not been conducted in population ages >65 years of age.
Recommended Dose
Atopic Eczema in Adults: Wet or dampen the affected area and apply a thin film of Derma-Smoothe/FS(r) Topical Oil two to three times daily, massaging in gently. Atopic Dermatitis in Children 2 to 12: Moisten skin and apply a thin film of Derma- Smoothe/FS(r) Topical Oil over the affected areas, massaging in gently twice daily for up to a maximum of 4 weeks. If no improvement is seen within 2 weeks, contact the physician.
Missed Dose
If a dose of this medication is missed, it is not necessary to make up the missed dose. Skip the missed dose and continue with the next scheduled dose.
It is unlikely that overdose could occur following topical administration of Derma- Smoothe/FS(r) Topical Oil, even if it were applied to most of the body. Paediatric studies with patients suffering from atopic dermatitis on >50% of the body did not demonstrate any signs of overdosing or HPA axis suppression. If an overdose should occur, there is no antidote.
Mechanism of Action
Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids 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.
Pharmacodynamics
The pathways by which topical steroids improve atopic dermatitis are not clearly understood. No studies involving the pharmacodynamics of the active fluocinolone acetonide or the drug product Derma-Smoothe/FS(r) Topical Oil have been performed.
Pharmacokinetics
No studies in pharmokinetics, absorption, distribution, excretion, or metabolism involving the active fluocinolone acetonide or the drug product Derma-Smoothe/FS(r) Topical Oil have been performed. Pharmacokinetic properties of the drug class of topically applied corticosteroids remain incompletely understood.
Topically applied corticosteroids may be absorbed percutaneously; percutaneous absorption of topical steroids is determined by many factors including the vehicle, thickness of the stratum corneum, presence of skin disease, skin hydration, and integrity of the epidermal barrier. Topical corticosteroids can be absorbed through normal skin.
Dermally applied corticosteroids are distributed throughout the skin, although the distribution in the skin depends on their percutaneous absorption. Percutaneously absorbed corticosteroids can also be distributed throughout the body, entering the systemic circulation via the dermal microcirculation.
The viable epidermis is known to be metabolically active and contains many of the enzymes also found in the liver, including a cytochrome P450 system which may be inducible. Steroids may undergo hydrolysis within the epidermis; sulphate conjugation also occurs. The importance of dermal metabolism of steroids to their mechanism of action is unknown. Systemically, 90% or more of glucocorticoids is reversibly bound to protein under normal circumstances. Corticosteroid-binding globulin and albumin account for most of the plasma steroid-binding capacity. Topically applied corticosteroids undoubtedly undergo further systemic metabolic processes. All of the biologically active adrenocortical steroids and their synthetic cogeners have a double bond in the 4,5 position and a ketone group at C 3. Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites, yielding inactive compounds. Reduction of the 3-ketone constituent occurs only in the liver.
Systemically distributed steroids are excreted in the urine as water-soluble esters and glucuronides. Neither biliary nor fecal excretion is of quantitative importance in humans. Topical steroids may also remain on the surface of the skin and may be eliminated by washing them off the skin.
Recommended storage condition for Derma-Smoothe/FS(r) Topical Oil is at controlled room temperature of approximately 25o C excursions permitted to 15deg-30degC (59deg-86degF). Derma- Smoothe/FS(r) Topical Oil has a full shelf life of 24 months under the required storage conditions.
Dosage Forms: Topical Oil
Balsam Pine Fragrance # 5124 Cream Fragrance # 73457 Isopropyl Alcohol USP Isopropyl Myristate NF Mineral Oil Light NF Oleth-2 Peanut Oil Refined NF
Derma-Smoothe/FS(r) Topical Oil is supplied in bottles containing 118.28ml (4 fl. oz.)
PART II: SCIENTIFIC INFORMATION
Fluocinolone acetonide
: (6a, 11b, 16a)-6,9-Difluoro-11b, 16a, 17, 21-tetrahydroxypregna-1,4-diene-3, 20-dione, cyclic 16, 17-acetal with acetone
Molecular Formula and Molecular Mass: C24H30F2O6 , 452.50
:
White, crystalline powder that is odorless; stable in light.
Fluocinolone acetonide is soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water.
Melts at about 270degC, with decomposition.
Store in well-closed containers, protected from light, at temperatures not exceeding 25degC
Study 25 Double-Blind Comparative Efficacy and Safety Study Comparing Derma- Smoothe/FS(r) Topical to its Vehicle in the Treatment of Atopic Dermatitis in Pediatric Patients A phase 3 double-blind clinical study was conducted to assess the efficacy and safety of Derma- Smoothe/FS(r) Topical Oil in the treatment of Atopic Dermatitis in children 2 years and older. Of the 102 subjects who were enrolled in the study, 4 did not return after the 2-week washout (and did not receive the study drug) and one did not return after the baseline visit. Six subjects suffered disease exacerbation during the study and were terminated because of protocol violations (required disallowed medications). Of the subjects included in the Intend-To-Treat (ITT) population, 46/49 (94%) of the active subjects completed the study, as did 41/45 (91%) of the vehicle-treated subjects. All seven subjects who did not complete the study did so because of disease exacerbation, which required treatment with disallowed medication. Derma-Smoothe/FS Topical Oil(r) was applied to the affected areas twice daily for 28 days.
| Table 1: Demographic and Baseline Information | |||||||
| Parameter | Treatment Group | Miami | Atlanta | p-value | Chicago | St. Louis | p-value |
| Age (yrs) ( M +- SE) | Active | 6.14 +- 3.05 | 5.53 +- 2.50 | 0.530 a | 6.57 +- 1.83 | 3.50 +- 2.26 | 0.024 a |
| Vehicle | 6.76 +- 3.58 | 6.27 +- 4.03 | 0.714 a | 4.71 +- 1.98 | 3.50 +- 1.38 | 0.233 a | |
| Sex | Active Male Female | 8 13 | 6 9 | 0.908 b | 2 5 | 5 1 | 0.048 b |
| Active Male Female | 10 7 | 8 7 | 0.755 b | 2 5 | 4 2 | 0.170 b | |
| Race | Active White Black Hispanic | 6 14 1 | 2 13 0 | 0.351 b | 3 1 2 | 2 4 0 | 0.135 b |
| Active White Black Hispanic | 2 13 2 | 1 14 0 | 0.324 b | 3 3 1 | 1 5 0 | 0.296 b | |
a
t-test
b
chi square test
| Table 2: Subjects Enrolled in Study 25. | |||||||
| Subject Status | Treatment Group | Miami | Atlanta | Chicago | St. Louis | East | West |
| Enrolled | Active | 21 | 15 | 7 | 7 | 36 | 14 |
| Vehicle | 22 | 15 | 8 | 7 | 37 | 15 | |
| Did not return after washout | Active | 0 | 0 | 0 | 1 | 0 | 1 |
| Vehicle | 2 | 0 | 1 | 0 | 2 | 1 | |
| Did not return after baseline | Active | 0 | 0 | 0 | 0 | 0 | 0 |
| Vehicle | 0 | 0 | 0 | 1 | 0 | 10 | |
| No evaluations after baseline | Active | 0 | 0 | 0 | 0 | 0 | 0 |
| Vehicle | 3 | 0 | 0 | 0 | 3 | 0 | |
| ITT analysis population | Active | 21 | 15 | 7 | 6 | 36 | 13 |
| Vehicle | 17 | 15 | 7 | 6 | 32 | 13 | |
| Did not complete study a | Active | 1 | 0 | 1 | 1 | 1 | 2 |
| Vehicle | 0 | 0 | 4 | 0 | 0 | 4 | |
| Completed Study | Active | 20 | 15 | 6 | 5 | 35 | 11 |
| Vehicle | 17 | 15 | 3 | 6 | 32 | 9 | |
a
subjects experienced disease exacerbation and required disallowed medications
Data Source: Module 5 Volume 1 Section 5.3.5.1 Study 25 Appendix III, Listings 1 and 2.
Study Results
After one week of treatment (week 1 visit), there were statistically significant differences between the active (Derma-Smoothe/FS(r)) and vehicle groups for all four parameters, all in favor of the active group: erythema (p=0.006); scaling (p=0.0021); lichenification (p= <0.0001); and pruritus (p=0.009).
| Table 3: East Study: Summary of Efficacy Parameter Scores at Baseline, Week 1, and Week 2 a | |||||||
| Parameter | Treatment Group | Baseline | Week 1 (mean +- SD) (median) | Week 1 (mean +- SD) (median) | |||
| Erythema | Active (N=36) | 1.11 +- 0.91 1.00 | p = 0.76 | 0.29 +- 0.50 0.00 | p = 0.0062 b | 0.09 +- 0.25 0.00 | p = 0.0274 b |
| Vehicle (N=32) | 1.06 +- 0.84 1.00 | 0.73 +-0.68 0.87 | 0.50 +- 0.56 0.25 | ||||
| Scaling | Active (N=36) | 1.80 +- 0.51 2.00 | p = 0.608 | 0.92 +- 0.58 1.00 | p = 0.0021 | 0.46 +- 0.49 0.33 | p = 0.0012 |
| Vehicle (N=32) | 1.92 +- 0.72 2.00 | 1.55 +- 0.89 1.87 | 1.06 +- 0.77 1.00 | ||||
| Lichenification | Active (N=36) | 1.92 +- 0.54 2.00 | p = 0.084 | 1.28 +- 0.73 1.00 | p = 0.0027 | 0.84 +- 0.54 1.00 | p = <0.0001 |
| Vehicle (N=32) | 2.23 +- 0.68 2.00 | 1.89 +- 0.79 2.00 | 1.65 +- 0.80 2.00 | ||||
| Pruritus | Active (N=36) | 1.62 +- 0.87 2.00 | p = 0.406 | 0.53 +- 0.64 0.29 | p = 0.0009 | 0.19 +- 0.32 0.00 | p = 0.0001 |
| Vehicle (N=32) | 1.85 +-0.85 2.00 | 1.23 +- 0.91 1.00 | 0.87 +- 0.86 1.00 | ||||
a
Difference in mean values tested by Mann Whitney U test
b
p-value based on testing differences from baseline: Data Source Module 5 Volume 1 Section 5.3.5.1 Appendix IV, Tables A, K.i, and K.iii
Except for the parameter erythema, the between group differences at week 1 were significantly in favor of the active group: scaling (p=0.0136); lichenification (p= 0.0057); and pruritus (p=0.0382). These differences remained statistically in favor of the active group at week 2: scaling (p=0.0079); lichenification (p= 0.0085); and pruritus (p=0.0324). The between group differences for erythema at both week 1 and week 2 were numerically in favor of the active group, but were not statistically significant. The lack of significance may be due to the small number of subjects in the analysis
| Table 4: West Study: Summary of Efficacy Parameter Scores at Baseline, Week 1, and Week 2 | |||||||
| Parameter | Treatment Group | Baseline | Week 1 (mean +- SD) (median) | Week 1 (mean +- SD) (median) | |||
| Erythema | Active (N=36) | 1.46 +- 0.60 1.50 | p = 0.7373 | 1.09 +- 0.61 1.00 | P = 0.1137 | 0.91 +- 0.74 0.75 | p = 0.1578 |
| Vehicle (N=32) | 1.49 +- 0.65 1.67 | 1.46 +-0.69 1.33 | 1.37 +- 0.88 1.33 | ||||
| Scaling | Active (N=36) | 1.60 +- 0.61 1.75 | p = 0.7952 | 1.11 +- 0.69 1.00 | P = 0.0136 | 0.93 +- 0.71 0.75 | P = 0.0079 |
| Vehicle (N=32) | 1.73 +- 0.42 1.83 | 1.73 +- 0.50 2.00 | 1.68 +- 0.63 2.00 | ||||
| Lichenification | Active (N=36) | 1.34 +- 0.84 1.50 | p = 0.6601 | 1.03 +- 0.55 1.13 | P = 0.0057 | 0.84 +- 0.62 0.75 | P = 0.0085 |
| Vehicle (N=32) | 1.63 +- 0.38 1.67 | 1.62 +- 0.39 1.67 | 1.51 +- 0.61 1.75 | ||||
| Pruritus | Active (N=36) | 1.82 +- 0.64 2.00 | p = 0.4195 | 1.05 +- 0.68 1.00 | P = 0.0382 | 0.82 +- 0.71 0.80 | P = 0.0324 |
| Vehicle (N=32) | 1.63 +-0.86 1.83 | 1.56 +- 0.73 2.00 | 1.54 +- 0.86 1.83 | ||||
Data Source: Module 5 Volume 1 Section 5.3.5.1: Study 25 Appendix IV, Tables B and K.ii
The Global Assessment at Week 1 and Week 2 indicate a statistically significant differences between the active (Derma-Smoothe/FS(r)) and vehicle groups for disease clearing, in favor of the active group: Week 1 (p=<0.0001) and Week 2 (p=0.003).
| Table 5: East Study: Global Assessment at Week 1 and Week 2 | ||||||||
| Treatment Group | Cleared (1) | Excellent (2) | Good (3) | Fair (4) | Slight (5) | No Change (6) | Exacerbation (7) | p- value a |
| Week 1 | ||||||||
| Active (N=36) | 0 | 10 | 11 | 8 | 5 | 0 | 0 | <0.001 |
| Vehicle (N=32) | 0 | 0 | 5 | 6 | 12 | 5 | 3 | |
| Week 2 b | ||||||||
| Active (N=36) | 4 | 15 | 11 | 1 | 3 | 0 | 1 | 0.003 |
| Vehicle (n=32) | 1 | 3 | 10 | 4 | 13 | 1 | 0 | |
a
the p-values represented are those obtained from the chi-square analysis the above matrices, which contain empty cells. A second analysis was performed after coalescing the cleared-excellent-good cells and the slight-no change- exacerbation cells for the above matrices (see Module 5 Volume 1 Section 5.3.5.1 Study 25 Appendix IV, Table E, Analysis for wk 1mod and wk 2mod). The p-values were <0.0001 and 0.0014, respectively.
b
Week 1: 2 active and 1 vehicle subject had no assessment Week 2: 1 active subject had no assessment
Data Source: Module 5 Volume 1 Section 5.3.5.1 Study 25 Appendix IV, Table E
| Table 6: West Study: Global Assessment at Week 1 and Week 2 | ||||||||
| Treatment Group | Cleared (1) | Excellent (2) | Good (3) | Fair (4) | Slight (5) | No Change (6) | Exacerbation (7) | p- value a |
| Week 1 b | ||||||||
| Active (N=13) | 1 | 1 | 6 | 3 | 0 | 0 | 1 | 0.0156 |
| Vehicle (N=13) | 0 | 1 | 0 | 1 | 1 | 4 | 5 | |
| Week 2 b | ||||||||
| Active (N=13) | 1 | 5 | 4 | 0 | 0 | 0 | 1 | 0.065 |
| Vehicle (n=13) | 0 | 1 | 1 | 0 | 1 | 3 | 3 | |
a
the p-values represented are those obtained from the chi-square analysis the above matrices, which contain empty cells. A second analysis was performed after coalescing the cleared-excellent-good cells and the slight-no change- exacerbation cells for the above matrices (see Module 5 Volume 1 Section 5.3.5.1 Study 25 Appendix IV, Table F, Analysis for wk 1mod and wk 2mod). The p-values were 0.0001 and 0.0018, respectively.
b
Week 1: 1 active and 1 vehicle subject had no assessment Week 2: 2 active and 4 vehicle subjects had no assessment
Data Source: Module 5 Volume 1 Section 5.3.5.1 Study 25 Appendix IV, Table F
Study 25-S Open-Label Safety Study on Derma-Smoothe/FS(r) Topical Oil on Pediatric Patients with Atopic Dermatitis Study 25-S assessed suppression of the hypothalamic-pituitary-adrenal (HPA) axis in the paediatric population with atopic dermatitis. Twenty-six Patients were exposed to Derma- Smoothe/FS(r) only as part of the open-label study design. Patients were to apply Derma- Smoothe/FS(r) twice daily for a total of 4 weeks; at the end of 4 weeks Cortisol testing was conducted to evaluate HPA axis suppression. Of the 26 subject who were enrolled, 25 subjects completed the study. Of the 25 who completed the study, only 21 subjects had evaluable Cortisol results. No evidence of suppression of the HPA axis was observed in pediatric patients following treatment with Derma-Smoothe/FS(r) Topical Oil twice daily for 4 weeks.
| Table 7: Cortisol Concentrations (ug/dL) Before and After Adrenal Stimulation: Start of Study and After 4 Weeks of Treatment with Derma-Smoothe/F (r) S Study 25-S California | |||
| At Start of Study (N=11) | After 4 Weeks of Treatment (N=11) | Week 0 vs. Week 4 c p value a | |
| Cortisol Concentration at Baseline (SD) b | 12.09 (3.87) | 10.73 (1.96) | 0.185 |
| Cortisol Concentration Following Stimulation (SD) | 25.30 (3.60) | 24.51 (1.93) | 0.408 |
| Increase in Cortisol After Stimulation | 13.21 (5.00) | 13.78 (2.25) | 0.742 |
p-value from paired t-test
Baseline value is value prior to stimulation
Data Source: Study 25 Statistical Report, Table 11
c
Day 28: 7 day post-treatment evaluation
| Table 8: Cortisol Concentrations (ug/dL) Before and After Adrenal Stimulation: Start of Study and After 4 Weeks of Treatment with Derma-Smoothe/F (r) S Study 25-S Chicago, Cleveland, and Miami | |||
| At Start of Study (N=10) | After 4 Weeks of Treatment (N=10) | Week 0 vs. Week 4 c p value a | |
| Cortisol Concentration at Baseline (SD) b | 11.00 (3.95) | 11.76 (3.28) | 0.444 |
| Cortisol Concentration Following Stimulation (SD) | 28.84 (6.74) | 26.07 (5.20) | 0.056 |
| Increase in Cortisol After Stimulation | 17.84 (9.67) | 14.28 (5.60) | 0.091 |
p-value from paired t-test
Baseline value is value prior to stimulation
Data Source: Study 25 Statistical Report, Table 12
c
Day 28: 7 day post-treatment evaluation
Study 26 HPA Axis Open-Label Safety Study on Derma-Smoothe/FS(r) on Pediatric Patients with Atopic Dermatitis (2 to 5 years) A phase 4, open label clinical study was conducted to assess the safety of Derma-Smoothe/FS(r) Topical Oil was used twice daily for 28 days in children 2 years and older with Atopic Dermatitis. Fifteen subjects between the ages of 2 and 5 were enrolled in Study 26. Of the 15 enrolled, 13 completed the study. No HPA axis suppression was observed following treatment of Derma-Smoothe/FS(r) Topical Oil.
| Table 9: Cortisol Concentrations (ug/dL) Before and After Adrenal Stimulation: Start of Study and After 4 Weeks of Treatment with Derma-Smoothe/F (r) S Study 26 | |||
| At Start of Study (N=13) | After 4 Weeks of Treatment (N=13) | Week 0 vs. Week 4 p value a | |
| Cortisol Concentration at Baseline (SD) b | 10.73 (5.01) | 9.35 (3.82) | 0.376 |
| Cortisol Concentration Following Stimulation (SD) | 26.12 (2.97) | 24.20 (3.79) | 0.153 |
| Increase in Cortisol After Stimulation | 15.39 (4.81) | 14.85 (3.10) | 0.647 |
p-value from paired t-test
Baseline value is value prior to stimulation Data Source: Study 26 Report, Table 2
Chicago Peanut Allergy Study A phase 4 controlled, open label clinical study was conducted to assess the safety of Derma- Smoothe/FS(r), which contains refined peanut oil NF, on subjects with known allergies. The study enrolled 13 patients with atopic dermatitis, 6 to 17 years of age. Of the 13 patients, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The study evaluated the responses to both prick test and patch test utilizing refined peanut oil NF, Derma-Smoothe/FS(r) and histamine/saline controls, on the 13 individuals. These subjects were also treated with Derma-Smoothe/FS(r) twice daily for 7 days. Prick test and patch test results for all 13 patients were negative to Derma-Smoothe/FS(r) and the refined peanut oil NF. One of the 9 peanut-sensitive patients experienced an exacerbation of atopic dermatitis after 5 days of Derma-Smoothe/FS(r). Importantly, the bulk peanut oil NF, used in Derma-Smoothe/FS(r) is heated at 475degF for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins.
Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids in general is unclear. One factor may be the ability of the glucocorticoids to inhibit the recruitment of neutrophils and monocyte-macrophages into the affected area. Glucocorticoid also decreases the adherence of neutrophils to nylon fibers, indicating decreased tendency of neutrophils to adhere to capillary endothelial cells in areas of inflammation. Although steroids do not affect the production of macrophage migratory inhibitory factor (MIF), it blocks the effect of MIF on macrophages so that the movements of these cells are no longer restricted hence they do not accumulate locally. Evidence also show that glucocorticoids induce the production of a protein that inhibits phospholipase A2, reducing the release of arachidonic acid from phospholipids, in turn decreasing the formation of prostaglandins, leukotrienes, endoperoxides and thromboxane which plays an important role in chemotaxis and inflammation.
Investigative studies showing pharmacokinetic, toxicology and microbiological aspects have not been carried out for Derma-Smoothe/FS(r).
No nonclinical studies were performed to assess the toxicology, genotoxicity, carcinogenicity, reproductive or developmental toxicity, or local tolerance of fluocinolone acetonide or Derma-Smoothe/FS(r) Topical Oil. However, some corticosteroids are associated with several toxic effects; they are summarized below.
Genotoxicity
Some corticosteroids have been found to be genotoxic in various genotoxicity tests (e.g., the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test, and the in vitro mouse lymphoma gene mutation assay). Reproductive and Developmental Toxicity Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. The relationship between corticosteroid use and teratogenicity in humans is unclear. Local Tolerance Skin thinning (atrophy) has been shown after fluocinolone acetonide administration on mouse tail epidermis and on the dorsal skin of hairless dogs. This activity may correlate with the activity of fluocinolone acetonide in treating atopic dermatitis.
Balow JE. Glucocorticoid suppression of macrophage migration inhibitory factor. J. Exp. Med. 1973; 137(4): 1031-41
Blackwell GJ. Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature 1980; 287(5778):147-9.
Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999; 86:242-4.
Fauci AS. Immunosupressive and anti-inflammatory effects of glucocorticoids.
Monographs on Endocrinology 1979; 12:449-65. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs 1988; 36:51-61. Hirata F. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci USA 1980; 77(5): 2533-6. Kimura T, Doi K. Dorsal skin reactions of hairless dogs to topical treatment with corticosteroids. Toxicol Pathol 1999; 27:528-35. McKenzie AW, Stoughton RB. Method for comparing percutaneous absorption of steroids. Arch Dermatol 1962; 86:608-10. Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In Goodman & Gilman's the pharmacological basis of therapeutics. New York: The Mc Graw-Hill Companies; 2001. p. 1649-77. Spearman RIC, Jarrett A. Bio-assay of corticosteroids for topical application. Br J Dermatol 1975; 92:581-4. Stoughton RB. Vasoconstrictor assay-specific applications. In: Maibach HI, Surber C (eds). Topical corticosteroids. Basel: S Karger AG; 1992. p. 42-52. Wester RC, Bucks DAW, Maibach HI. In vivo percutaneous absorption of hydrocortisone in psoriatic patients and normal volunteers. J Amer Acad Dermatol 1983; 8:645-7. Wester RC, Maibach HI. Cutaneous pharmacokinetics: 10 steps to percutaneous absorption. Drug Metab Rev 1983; 14:169-205. Gilman AG, Goodman LS, Rall TW, Murad F (eds). Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985. Maibach HI, Surber C (eds). Topical corticosteroids. Basel: S Karger AG; 1992.
PART III: CONSUMER INFORMATION
Derma-Smoothe/FS(r) Topical Oil Fluocinolone acetonide 0.01%
This leaflet is part III of a three-part "Product Monograph" published when Derma-Smoothe/FS(r) Topical Oil was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Derma-Smoothe/FS(r) Topical Oil. Contact your doctor or pharmacist if you have any questions about the drug.
should not be applied to the diaper area as diapers or plastic pants may constitute occlusive dressing.
Derma-Smoothe/FS(r) Topical Oil should not be used on the underarm or groin.
This medication is not recommended for use on the face.
INTERACTIONS WITH THIS MEDICATION
There are no known drug interactions with Derma- Smoothe/FS(r) Topical Oil.
ABOUT THIS MEDICATION
PROPER USE OF THIS MEDICATION
What the medication is used for:
Derma-Smoothe/FS(r) Topical Oil is indicated for adult atopic eczema and atopic dermatitis in children 2 to 12 years. Derma- Smoothe/FS(r) is not to be used on the face.
What it does:
Derma-Smoothe/FS(r) is a topical corticosteroid. When applying to the affected area, corticosteroids work to stop inflammation
(swelling), redness and itching.
When it should not be used:
If you (or your child) are allergic to Fluocinolone Acetonide or to any of the other ingredients in Derma-Smoothe/FS(r). Derma-Smoothe/FS(r) contains refined peanut oil.
This medication should not be used on the underarm or groin.
This medication should not be used on the eye or eye area.
This medication should not be used if having untreated bacterial or fungal or viral infections such as chicken pox, herpes simplex or vaccination.
What the medicinal ingredient is:
Fluocinolone acetonide 0.01%
What the important nonmedicinal ingredients are:
Refined Peanut Oil NF, Mineral Oil Light, Oleth-2, Isopropyl
Myristate, Isopropyl Alcohol, Cream Fragrance, and Balsam Pine Fragrance.
What dosage forms it comes in:
Topical Oil
WARNINGS AND PRECAUTIONS
BEFORE you use Derma-Smoothe/FS(r) Topical Oil talk to your doctor or pharmacist if:
You (or your child) have a history of allergic reactions to any of the ingredients in Derma-Smoothe/FS(r). Derma- Smoothe/FS(r) Topical Oil contains refined peanut oil.
Other untreated bacterial or fungal skin infections.
You are nursing or pregnant.
Derma-Smoothe/FS(r) Topical Oil should not be used to treat diaper dermatitis. Derma-Smoothe/FS(r) Topical Oil
Usual dose:
For Adult Atopic Eczema:
Moisten the affected area with water. Apply a thin film of Derma- Smoothe/FS(r) Topical Oil to the affected area and massage in gently. Use two to three times daily.
For Atopic Dermatitis in Children 2 to 12:
Moisten the affected area with water. Apply a thin film of Derma- Smoothe/FS(r) Topical Oil to the affected area and massage in gently. Use twice daily for a maximum of 4 weeks. If no improvement is seen within 2 weeks, contact your child's doctor.
Overdose:
Wash thoroughly with water.
Missed Dose:
If a dose of this medication is missed, it is not necessary to make up the missed dose. Skip the missed dose and continue with the
next scheduled dose.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: (common) burning, itching, irritation, dryness, (uncommon) hair follicle infection, acne, skin litening, rash around the mouth, allergic contact dermatitis, (rare) secondary infection, skin thinning, stretch mark, and bumps. If a raised area and flare type reactions (which may be limited to intense itching) or other manifestations of allergic reaction develop, Derma-Smoothe/FS(r) Topical Oil should be discontinued immediately and appropriate therapy instituted. If side effects persist please contact your doctor or pharmacist.
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | |||
| Symptom / effect There have been no reported Serious Side Effects during clinical trials or post-marking experience. If a serious side effect does occur, discontinue the drug and call your doctor or pharmacist. | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist | |
| Only if severe | In all cases | ||
| Allergic Reaction: Flare up of existing condition | T | ||
MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor: Hill Dermaceuticals, Inc.
At: 1-800-344-5707
This leaflet was prepared by Hill Dermaceuticals, Inc. Last revised: March 2007
This is not a complete list of side effects. For any unexpected effects while taking Derma-Smoothe/FS(r) Topical Oil, contact your doctor or pharmacist.
HOW TO STORE IT
Keep tightly closed. Store at 25degC (77degF); excursions permitted to 15deg-30degC (59deg-86degF) [see USP Controlled Room Temperature].
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca
By regular mail: National AR Centre
Marketed Health Products Safety and Effectiveness Information Division
Marketed Health Products Directorate
Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9
NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.