Topical steroid products are effective because of their anti-inflammatory, antipruritic and vasoconstrictive properties.
ratio-AMCINONIDE Cream, Ointment and Lotion are indicated for the relief of inflammatory manifestations of acute and chronic corticosteroid-responsive dermatoses, such as atopic dermatitis, contact and eczematous dermatoses, psoriasis and neuro-dermatitis. It must be remembered that steroid therapy, although responsible for remissions of dermatoses, especially of allergic origin, cannot be expected to prevent recurrence. In the case of contact or allergic dermatitis, it is important to investigate causal factors and to remove the offending material or allergen.
Topical steroid therapy is contraindicated in fungal diseases of the skin, untreated bacterial infections, in tuberculoses of the skin and certain viral diseases such as herpes simplex, vaccinia and varicella. Topical steroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the products. This topical steroid cream formulation is for ophthalmic use.
The safety of topical corticosteroids during pregnancy or lactation has not been established. The potential benefit of topical corticosteroids, if used during pregnancy or lactation, should be weighed against possible hazard to the fetus or the infant being nursed. Significant systemic absorption may occur when steroids are applied over large areas of the body, especially under occlusive dressings. To minimize this possibility, when long-term therapy is anticipated, interrupt treatment periodically, or treat one area of the body at a time.
These products should not be used in the eyes. Precautions should be taken to avoid any contact with the eyes. Although hypersensitivity reactions have been rare with topically applied steroids, the drug should be discontinued and appropriate therapy initiated if there are signs of sensitivity. The use of steroids on infected areas should be attended with caution and careful observation, bearing in mind the potential spreading of infection and the possible advisability of discontinuing steroid therapy and/or initiating antibacterial measures. If a symptomatic response is not noted within a few days to a week, the local application of corticosteroids should be discontinued until the infection is brought under control. Patients should be advised to inform subsequent physicians of prior use of corticosteroids. Occlusive dressings should not be applied if there is an elevation of body temperature. Prolonged use of topical corticosteroid products may produce atrophy of the skin and of subcutaneous tissues, particularly on flexor surfaces and on the face. If this is noted, discontinue the use of topical corticosteroids. Topical corticosteroids should be used with caution in patients with stasis dermatitis and other skin diseases associated with impaired circulation.
When occlusive dressings are used, pustules, miliaria, folliculitis, and pyoderma may occur. The following adverse skin reactions have been reported with the use of topical steroids: dryness, itching, buring, local irritation, striae, skin atrophy, atrophy of subcutaneous tissues, telangiectasia, hypertrichosis, change in pigmentation, and secondary infection. Adrenal suppression also has been reported following topical corticosteroid therapy. Posterior subcapsular cataracts have been reported following systemic use of corticosteroids.
Apply ratio-AMCINONIDE Cream, Ointment and Lotion to the affected area two or three times daily. Application twice a day is usually sufficient. Rub in gently.
ratio-AMCINONIDE 0.1% Cream is available in 15, 30 and 60 gram tubes. ratio-AMCINONIDE 0.1% Ointment is available in 15, 30 and 60 gram tubes. ratio-AMCINONIDE 0.1% Lotion is available in 20 mL and 60 mL plastic squeeze bottles.
Molecular Formula: C28H35FO7 Molecular Weight: 502.59 Chemical Name: 9-Fluoro-11S, 16a, 17, 21-tetrahydroxypregna-1, 4- diene-3, 20-dione cyclic 16, 17-acetal with cyclopentanone, 21-acetate.
Amcinonide occurs as a white to cream coloured crystalline powder, having not more than a slight odour. Its melting point range is 248 - 252oC.
ratio-AMCINONIDE Cream contains amcinonide 0.1%. The cream contains benzyl alcohol (2.2%) as the preservative and ethoxylated stearyl alcohol, isopropyl palmitate, glycerin, sorbitol solution, lactic acid and purified water as the inactive ingredients. Each gram of ratio-AMCINONIDE Ointment contains 1 mg (0.1%) of the active steroid, amcinonide, in a specially formulated base composed of white petrolatum USP, benzyl alcohol, emulsifying wax NF and TENOX II. ratio-AMCINONIDE Lotion contains amcinonide 0.1%. Benzyl alcohol is used as the preservative in the lotion vehicle containing emulsifying wax NF, isopropyl palmitate, glycerin, sorbitol solution, lactic acid and purified water.
C14 amcinonide was administered intravenously to rats and dogs at a dose of 1 mg/kg. The plasma radioactivity showed a biexponential disappearance and the major portion (86 - 90%) of the dose was excreted in the feces by both species. After six hours, plasma concentrations were in the order of 10% of those at 15 minutes, suggesting a half-life of one to two hours in these animals. Similar results were seen when C14 amcinonide was administered orally and intraperitoneally. It appears that a slower rate of excretion occurs following intramuscular and, perhaps, subcutaneous administration than following oral, intravenous or intraperitoneal dosage.
Rats and dogs were treated topically with 0.5% C14 amcinonide cream. Rabbits were treated with 0.05% C14 amcinonide cream. In rats, the data on recovery of the drug in the urine and feces showed that 6.7% to 8.7) and 8.1% (4.3 to 12.6) of the dose was excreted at the 1.0 and 5.0 mg/kg dose levels respectively. In the rabbit, percutaneous absorption of C14 amcinonide from 0.05% cream formulation was relatively high; for exposure periods of one to six hours, total excretion in urine and feces was 7 - 20% of the radioactivity applied. In the dog, the proportion of the dose excreted was similar to that in rats. When rabbits were exposed to multiple topical doses of up to 0.5 mg/kg amcinonide applied daily for three weeks in ointment form, the during-life and postmortem findings were characteristic of those associated with prolonged glucocorticoid administration and in agreement with previous results in the cream formulation studies. Similarly, when rabbits were exposed to 0.05% C14 amcinonide ointment (0.5 mg amcinonide/kg) applied to intact and abraded skin for up to 6 hours, 4 to 9% of the radioactivity was recovered in the excreta, also consistent with cream formulation studies. When rats were exposed to topical applications of 0.05% C14 amcinonide (0.5 mg/kg) in propylene carbonate ointment for up to 6 hours, 16 to 39% of the applied dose was recovered in urine and feces. The number of variables involved precluded direct comparison with previous absorption studies in rats utilizing the 0.1% amcinonide cream formulation.
The extent of metabolism of C14 amcinonide in rats and dogs was measured. In both species, there was little or no parent drug found in the urine and feces. At least five metabolites were present in the rat and four in the dog. The identities of these metabolites are not known.
The vasoconstrictor activity of 0.1% Amcinonide Cream was compared with that of 0.12% betamethasone valerate and 0.1% triamcinolone acetonide creams. Twenty-four healthy male volunteers, aged 26-47, having no history of dermatologic disease, were used in this double-blind study. Forty-eight patches, containing the test materials at various dilutions, were applied in random order to the upper backs of each subject. After four hours, they were removed and the degree of skin blanching determined at 2, 5, 20 and 24 hours following removal of the patches.
When the frequencies of positive vasoconstrictor reactions were compared at each time interval, no significant differences were found in the vasoconstrictor activities of the three 0.1% cream preparations.
When eight different dilutions of the cream preparations were compared according to the degree of blanching produced, no differences were found between the blanching activity of the eight corresponding dilutions of triamcinolone acetonide cream. Only one significant difference occurred in the comparisons of results for eight Amcinonide Cream dilutions and eight betamethasone valerate cream dilutions, that is 0.12 x 4-3% betamethasone valerate cream produced a greater degree of blanching than 0.1 x 4-3% Amcinonide Cream.
The 50% effective dose values were very similar for all three cream preparations (determined for the two hour reading):
| Drug (Cream) Amcinonide | ED 50 Conc. 2.0 x 10 -4 % | 95% Conf. Limits (0.98-4.1) x 10 -4 % |
| triamcinolone acetonide | 4.6 x 10 -4 % | (2.1-10.3) x 10 -4 % |
| betamethasone valerate | 2.7 x 10 -4 % | (0.93-7.9) x 10 -4 % |
The overall conclusion was made that there was very little difference in the vasoconstrictor activity of 0.1% Amcinonide Cream, 0.12% betamethasone valerate cream and 0.1% triamcinolone acetonide cream. In another study, the vasoconstrictor activity of 0.1% Amcinonide Cream was compared with that of 0.1% triamcinolone acetonide cream and 0.1% betamethasone valerate cream. Ten mg quantities of 0.1% Amcinonide Cream were applied to prescribed areas (2 cm) of intact skin on the forearm of 30 normal, adult volunteers. The reference formulation (0.1% triamcinolone acetonide or 0.1% betamethasone valerate cream) was applied to another test site on the same arm. Readings were made 16 and 23 hours after application. The degree of vasoconstriction observed with each steroid preparation was scored:- (no response), +, ++, +++. Activity was determined by summing the scores of all patients (+ = 1, ++ = 2, +++ = 3). Activity was expressed in two ways: (1) as the combined 16-hour and 23 -hour scores or (2) as the 23-hour scores alone. In the two assays comparing 0.1% Amcinonide Cream with 0.1% triamcinolone acetonide cream, combined scores for Amcinonide were 4 and 8 times higher than combined scores for triamcinolone acetonide, while the 23 hour scores were 3 and 7 times higher for Amcinonide than for triamcinolone acetonide. In three assays comparing 0.1% Amcinonide Cream with 0.1% betamethasone valerate cream, the combined scores and the 23-hour scores ranged from 2.2 to 2.8 times higher for Amcinonide than for betamethasone valerate. In summary, 0.1% Amcinonide Cream was found to have substantially greater vasoconstrictor activity than either 0.1% triamcinolone acetonide or 0.1% betamethasone valerate creams. This result differs from that obtained in the first study described above. The difference in results may be related to the different assay conditions employed in the two studies. A study was conducted in 30 normal volunteers comparing, in each subject, the vasoconstrictor activity of Amcinonide Ointment 0.1% in propylene carbonate base with the following topical preparations: Amcinonide Cream 0.1% Amcinonide Ointment 0.1% in benzyl alcohol base ARISTOCORT(c) Ointment 0.1% (triamcinolone acetonide) ARISTOCORT A(c) Ointment 0.1% (triamcinolone acetonide in Aquatain base) Betamethasone diproprionate ointment 0.05% Betamethasone valerate ointment 0.1% Amcinonide Ointment base - placebo Amcinonide Ointment 0.1% in propylene carbonate base exhibited the highest mean vasoconstriction score among the seven active treatments. The differences between its mean score and those of the other active preparations indicated a statistical advantage (P<0.05) for Amcinonide Ointment in propylene carbonate base over four of the treatments (betamethasone valerate ointment, Amcinonide Cream, ARISTOCORT Ointment). Vasoconstrictor activity of Amcinonide Ointment in propylene carbonate base was not statistically different from that achieved with Amcinonide Ointment in the benzyl alcohol base or betamethasone diproprionate ointment.
Rats were given large, single, oral or topical doses (22.5 - 50.0 g/kg) of 0.5% cream or ointment formulations of Amcinonide. No deaths occurred during the seven-day observation period. Slight lethargy lasting less than 24 hours followed oral dosing. Body weight gains of the drug-treated animals were less than those of the placebo cream or placebo ointment treated control animals. Body weight gains of rats treated topically with cream or ointment bases were comparable to those of the sham-treated control animals. Decreases were noted in the weights of the thymus and spleen of animals treated with Amcinonide either orally or topically. A statistically significant decrease in the weight of the adrenal glands was found only after oral administration of the cream formulation of Amcinonide. No drug-related deaths occurred in rats or mice after the single oral administration of the largest volume practical of Amcinonide Ointment at doses up to 50 mg/kg Amcinonide in mice, 42 mg/kg in rats. Depression in weight gain was exhibited by the high dose groups during the first week post dosing. In order to evaluate the hazard following an accidental ingestion by a child, Amcinonide 0.1% Cream and 0.1% Lotion were administered in massive doses by gavage to fasted adult rats of both sexes. The results indicated that both formulations, in the total amount presumably available on prescription in each supply, if ingested by a child (1 - 1.5 g/kg for a 20 kg child) would present no hazard.
Amcinonide Cream or Ointment formulations were applied to intact or abraded skin of rabbits. At 72 hours after drug application, grade 1 erythema (slight - barely perceptible) was observed in one of six rabbits that received 0.5g of amcinonide 0.5% cream formulation and in one of six rabbits that received 0.5g of amcinonide 0.5% Ointment formulation. Grade 1 erythema was observed at 24 hours, but not at 72 hours, in one of six rabbits treated with placebo cream; no irritation was observed in rabbits treated with placebo ointment. Daily application of 1g/kg placebo cream for seven days produced grade 1 erythema in one rabbit on day 3, in two animals on days 4 and 5, and in five animals on day 6; erythema was observed in all six rabbits on day 7. Reactions were seen at both abraded and non abraded sites. Rabbits tolerated the topical application of 0.5g of 0.1% Amcinonide Ointment or ointment vehicle to intact and abraded skin very well. The slight erythema noted on the abraded skin of four animals (2/6 experimental, 2/6 vehicle control) after the removel of the occlusive dressing, disappeared within 24 hours. In another study, Amcinonide 0.1% cream and 0.1% lotion as well as the vehicles alone were applied topically to abraded skin of rabbits for 7 consecutive days. The tolerance of both cream and lotion at the site of application was good and compared favourably to the response obtained with the vehicles alone. Amcinonide Ointment, 0.1%, produced no reactions that were considered irritant or allergic in 25 human subjects tested in a maximization study. It was concluded that the drug as formulated has an extremely low or negligible potential for irritation or contact sensitization.
No opacity of the cornea or inflammation of the iris or conjunctiva was produced by single doses of 0.1 mL of Amcinonide 0.5% Cream and Ointment formulations; no signs of irritation were produced by daily instillation of 0.1 mL of the 0.5% cream or ointment formulations for seven days. No findings related to treatment were noted in rabbit eyes when either a 0.1 g dose of 0.1% Amcinonide Cream or Ointment vehicle or a 0.1 g dose of 0.1% Amcinonide Lotion or lotion vehicle was introduced into the eyes.
Ninety-day topical or subcutaneous administration to the rabbit has shown that repeated topical applications of the cream or ointment formulations of Amcinonide were well tolerated; only some degree of erythema was seen at the application sites of all treated and controlled animals. The findings on liver, kidney, muscle, blood chemistry and hematology are typical of the direct and indirect effects of potent glucocorticoids. Their incidence and intensity in these studies are, in general, a function of dose, route of administration and duration of exposure. Any indication of toxicity observed in the ointment studies was limited to symptoms typically associated with glucocorticoid administration. No unique toxicity was observed with the ointment formulation.
Amcinonide, in doses up to 2000 mg/kg, had no effect on the incidence of micronuclei in rat polychromatic erythrocytes, indicating no evidence of mutagenic potential in this test system. The microbial assay was also negative with regard to a mutagenic potential for amcinonide in concentrations up to 2,500 mg/well/plate.
The findings of the studies in rats and rabbits are consistent with known teratogenic effects of glucocorticoids in laboratory animals.
Walker, B.E. : Induction of cleft palate in rats with anti-inflammatory drugs. Teratology 4:39-42, 1971.
Walker, B.E. : Induction of cleft palate in rabbits by general glucocorticoids. Proc. Soc. Exp. Biol. Med. 125:1281-1284, 1967.
McKenzie, A.W. : Percutaneous absorption of steroids. Arch. Derm. 86 :611-614, November, 1962.
Stoughton, R.B. and McKenzie, A.W. : Scientific Exhibit, American Medical Association, Florida, November 1964.
Rocha, G.L., Quinete, S.S., Dantas, F. and Faria, T.: A double blind comparative study between amcinonide and betamethasone valerate in the treatment of eczematoid conditions. Curr. Ther. Res. 19:538, 1976.
Ishihara, M.: Studies on the vasoconstrictor activity of amcinonide, a new synthetic topical corticosteroid. The Nishinihan Journal of Dermatology (Nishi-Nihon Hitu), 38: (2) 286-293, 1976.
Quinete, S.S., Dantas, F.E., Faria, T. and Rocha, G.L. : Comparison of the efficacy of amcinonide, a new topical corticosteroid, and triamcinolone acetonide. A Folha Medica 74:(1), 1977.