Fucidin H Cream
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Fucidin H Cream - Scientific Information

Manufacture: LEO Pharma
Country: Ireland
Condition: Atopic Dermatitis, Staph Skin Infection (Skin or Soft Tissue Infection)
Class: Topical antibiotics, Topical steroids
Form: Cream
Ingredients: fusidic acid, hydrocortisone acetate, butylhydroxyanisole (E320), cetyl alcohol, glycerol, liquid paraffin, potassium sorbate, polysorbate 60, all-rac-α-tocopherol, water and white soft paraffin

Pharmaceutical Information

Drug Substance

Proper Name:fusidic acid / hydrocortisone acetate
Fusidic acidHydrocortisone acetate
Chemical Name:ent-(17Ζ)-16α-(Acetyloxy)-3β,11β-
dihydroxy-4β,8,14-trimethyl-18-
nor-5β,10α-cholesta-17(20),24-
dien-21-oic acid hemihydrate
11β,17-dihydroxy-3,20-dioxopregn-4-
en-21-yl acetate
Structural Formula:





Molecular Formula:C31H48O6, ½ H2OC23H32O6
Molecular Weight:525.7404.5
Description:White or almost white crystalline
powder.
White or almost white crystalline
powder.
Solubility:Insoluble in water. Freely soluble
in alcohol or chloroform.
Slightly soluble in ethanol or
chloroform

Composition

FUCIDIN H contains fusidic acid (hemihydrate) and hydrocortisone acetate. Non-medicinal ingredients: Butylated hydroxyanisol, cetyl alcohol, glycerol (85%), liquid paraffin, potassium sorbate, polysorbate 60, white soft paraffin and purified water.

Storage Recommendation

Store below 30 °C. Use within 3 months of first opening the tube.

Availability of Dosage Form

FUCIDIN H (fusidic acid and hydrocortisone acetate) cream is available in lacquered aluminum tubes of 30 g.

Information for the Consumer

What is Atopic Dermatitis?

Atopic dermatitis is a common skin disease. It is characterized by unpredictable relapses, severe itching, and unpleasant looking lesions (crusting, erythema, serous discharge, and oedema). Atopic dermatitis is believed to be inherited, but its development and severity are influenced by a variety of environmental factors (ie. skin irritation, inflammation, psychological stress, allergies, and bacterial skin colonization). Although there is presently no cure for atopic dermatitis, it can be successfully managed.

Management of Atopic Dermatitis

The skin functions as a barrier against the environment, preventing water loss, infection and physical damage. Atopic dermatitis presents as dry, irritable skin which results in disruption of the skins barrier function. This leads to itch, dermatitis, and infection. Therefore, management of the disease involves preventative treatments such as skin moisturization and avoidance of skin irritants, as well as symptomatic treatment of the lesions. However, patient compliance is an important component of treatment. Management of atopic dermatitis must, as a rule, be continued intermittently over several years.

Skin Moisturization

Short baths, in lukewarm water containing bath oil, are useful both for cleansing and hydrating the skin. However, soaps and detergents may act as irritants by removing the natural lipid from the skin surface. A cleansing cream may, therefore, be used as a soap substitute to cleanse the skin. Extreme or skin-irritating cleansing procedures should be avoided. After bathing, pat the skin dry as opposed to rubbing it. Frequent and liberal use of emollients provides a surface lipid film, which prevents water loss from the skin surface. Emollients are most effective when applied immediately after bathing.

Avoid Skin Irritation

The skin of individuals with atopic dermatitis is often highly sensitive to irritation. Extremes of temperature should be avoided, nails should be kept short and scratching avoided. Irritant clothing such as wool and fully synthetic textiles should not be worn next to the skin. Some sources suggest that emollients with as little artificial fragrance and chemical stabalizers are most appropriate.

Treatment of Lesions

Symptomatic treatment is primarily directed at inflammation of the lesions and involves topical corticosteroids. However, patients with atopic dermatitis often have large numbers of bacteria on their skin, particularly Staph. aureus which is not normally found on the skin. The presence of these bacteria may provoke the symptoms of dermatitis.

What is FUCIDIN H?

FUCIDIN H is a combination of the mild potency corticosteroid, hydrocortisone acetate, and the antibiotic fusidic acid. The hydrocortisone component reduces inflammation while fusidic acid eliminates Staph. aureus which may prevent provocation and/or worsening of dermatitis.

Indication

FUCIDIN H is indicated for the treatment of mild to moderately severe atopic dermatitis where Staph. aureus is suspected as a contributing factor. The presence of Staph. aureus may be associated with crusting of lesions and/or erythema. FUCIDIN H has antibacterial activity which results in the eradication of Staph. aureus from the skin lesions of atopic dermatitis. In addition, FUCIDIN H also has anti-inflammatory activity.

Dosage and Administration

FUCIDIN H should be applied 3 times daily (or as prescribed by your doctor) and gently massaged into the affected areas. The treatment period is generally 2 weeks, shorter if symptoms improve.

Precautions

Contact your doctor if there are no signs of improvement after 14 days of treatment.

Use only as directed and for the duration prescribed by your doctor. Application to extensive areas, too frequent or prolonged application or application under occlusive (plastic) dressings may lead to adverse effects associated with topical hydrocortisone. Thinning of the skin at the site of application, striae (streaks or red lines in the skin) or telangiectasia (marks on the skin due to dilation of small blood vessels) may develop following prolonged or excessive use, particularly on skin folds and on the face.

FUCIDIN H should not be used in or near the eye because of irritation or the possibility of glaucoma.

Inform your doctor if you are pregnant or if you become pregnant during treatment with FUCIDIN H. Inform your physician if you are breast feeding or intent to breast feed. Report any signs of local adverse reactions to your physician.

Storage

Store below 30 °C. Use within 3 months of first opening the tube.

Microbiology

The microbiological effect of FUCIDIN H (fusidic acid and hydrocortisone acetate) is attributed to fusidic acid.

In Vitro Studies with Fusidic Acid

Fusidic acid has potent antibacterial activity toward Gram-positive bacteria and Neisseria species. Fusidic acid is most notable for its activity against Staphylococci, whether coagulase-positive or negative, and regardless of resistance to methicillin and related penicillins. It is also active against Corynebacteria and against many genera of strict anaerobes and microaerophiles. The efficacy of fusidic acid against different microorganisms is outlined in Table 1. However, fusidic acid has almost no antibacterial activity against Gram-negative organisms such as E. Coli, Proteus, Klebsiella and Salmonella. Fungi are also insensitive to fusidic acid.

Table 1. Antimicrobial Spectrum of Fusidic Acid
MicroorganismsMIC90%*MIC-range*MBC-range*
SENSITIVE
Gram-positive
Staph. aureus (methicillin-susceptible)0.060.007-0.1950.097-25.0
Staph. aureus (methicillin-resistant)0.120.015-8.00.040-12.5
Staph. epi. (methicillin-susceptible)0.250.024-8.00.024-12.5
Staph. epi. (methicillin-resistant)0.500.03-≥32ND
Corynebacterium diptheriae0.0044 (a)NDND
Clostridium tetani0.05 (a)NDND
Clostridium perfringens0.50.06-1.0ND
Propionibacterium acnes1.0≤0.06- 2.0ND
Other Corynebacterium spp.2.0≤0.04- 12.5ND
Clostridium difficile2.0≤0.25- 64ND
Other Clostridium spp.≤1.0≤0.06- 1.0ND
Staphylococcus saprophyticus3.120.048-6.250.097-12.5
Streptococcus faecalis6.251.56- 6.251.56 -50.0
Streptococcus pyogenes12.5<1.6 - 50ND
Streptococcus pneumoniae25.0<0.25->64ND
JK diphteroids32.0
Gram-negative
Neisseria meningitidis0.120.015- 0.5ND
Legionella pneumophila≤0.25 (a)NDND
Neisseria gonorrhoeae1.0≤0.03- 8.0ND
Bacteroides fragilis2.00.5- 4.0ND
Other Bacteroides spp.≤2.0≤0.06- 8.0ND
Others
Mycoplasma spp.≤0.8 (a)NDND
Mycobacterium tuberculosis3.0 (a)NDND
Nocardia asteroids16.0≤0.5 - 32.0ND
Other Nocardia spp.32.0≤0.5 - >32.0ND
RESISTANT
Other Gram-Negative
E. coli
Pseudomonas
Klebsiella
Proteus
Salmonella
Shigella
Pasteurella

*ug/mL (a) MIC-value ND - No data

Resistance to Fusidic Acid

During more than 30 years of therapeutic use of fusidic acid, resistance by Staph. aureus has remained extremely low (<2%). An ongoing Canadian program has monitored resistance of clinical isolates of Staph. aureus to fusidic acid since 1986. As of 1994, over 12,500 strains of Staph. aureus have been tested with an overall resistance rate of 1.47%. The annual resistance rate has never exceeded 2%, indicating the stability of the anti-staphylococcal activity of fusidic acid.

Two mechanisms explain emergence of resistance to fusidic acid in Staph. aureus strains. The first one is chromosomal mutation. All populations of Staph. aureus produce resistant variants by chromosomal mutation at a frequency of 1 in 106 to 107. This type of resistance is readily detected in vitro, and is due to a modification of elongation factor G, the target at which fusidic acid inhibits bacterial protein synthesis. Such variants appear to be defective in that they grow more slowly than the parent strain, have a lower pathogenicity and subsequently revert to full sensitivity in the absence of fusidic acid. This type of mutation occurs at a high rate in vitro, but emergence of resistance in the clinical setting occurs less readily than is indicated by this observation. The second mechanism is plasmid-mediated resistance. These strains have been shown to be distinct from the chromosomal variants, as they do not have a modification of elongation factor G. Protein synthesis of cell free extracts is still inhibited by fusidic acid and there is no evidence of enzyme-mediated inactivation of fusidic acid. However, it has been suggested that there may be a permeability barrier at the cell surface, which reduces entry of the antibiotic. This theory is supported by the fact that they grow normally and are pathogenic. However, some plasmids that confer resistance to fusidic acid are unstable, which may make them inefficient at transmitting resistance.

No cross resistance between fusidic acid and other antibiotics has been found.

Pharmacology

Vickers (1969), using excised human skin, demonstrated that fusidic acid is able to penetrate intact skin at a rate similar to that achieved by glucocorticoids. As much as 2.2% of fusidic acid penetrates intact skin. These results were confirmed by Knight (1969). Using radiolabeled commercial preparations of fusidic acid, Stuttgen and Bauer (1988) demonstrated that penetration of the entire skin thickness occurs in damaged skin. The concentration of sodium fusidate achieved in the subcutaneous tissue 30 minutes after an initial application of FUCIDIN 2% cream to excised skin with the horny layer artificially damaged by Telsafilm stripping was 2.6 g/ml, which is 43 times the MIC90 for methicillin-susceptible Staph. aureus. Dermal absorption of hydrocortisone is considered to be approximately 1-5% of the administered dose. Absorption of both fusidic acid and hydrocortisone may be higher on injured skin.

Toxicology

Acute Toxicity of Fusidic Acid

The following table summarizes the acute toxicity data obtained for mice and rats.

Drug
Substance
SpeciesRoute of
Administration
LD50
(mg/kg b.w.)
Na FusidateMiceOral860
Intravenous180
RatsOral3000
Intravenous140
Fusidic AcidMiceOral5400
Intravenous355
Rats
- AdultsOral2263
- PupsOral443

The signs and symptoms of toxicity of fusidic acid and its salts in mice were decreased activity, ataxia, staggering, tremors, convulsions and increased respiratory rate in a few cases; in rats, the only symptoms preceding death were decreased activity, slight salivation and in some cases coma and increased respiration.

Dogs

Sodium fusidate was administered as a 10% solution by stomach tube to 2 fasted dogs in single doses of 250 and 500 mg/kg, respectively. Two other fasted dogs received the drug in the form of gelatin capsules in doses of 500 and 1500 mg/kg, respectively. No effects were noted in the dog receiving 500 mg/kg by capsules. The remaining 3 dogs vomited within 8 to 60 minutes; the dog given 1500 mg/kg was lethargic for 12 hours, but no other effects were observed during a 7-day observation period. A dose dependent increase in BSP retention times was observed.

Subacute Toxicity of Sodium Fusidate

Rats

Sodium fusidate was administered in the diet of 2 groups composed of 5 male and 5 female rats at doses of 0 or 270 mg/kg/day for 4 weeks. A similar group received 500 mg/kg/day for 1 week and subsequently 1200 mg/kg/day for 3 weeks. None of the animals died during testing and no significant lesions attributable to the drug were found. Except for a slight to moderate weight retardation in males in the high dose group, the average rates of growth of the treated animals were comparable to that of the controls.

In a more recent study, sodium fusidate was administered intravenously for 2 weeks to 2 groups of rats composed of 10 males and 10 females in a dose of 21.5 mg/kg per day diluted with saline to a concentration of 2.15 mg/mL. There were no mortalities and no changes in appearance or behaviour in any of the animals. No toxic or other adverse effects attributable to the drug were seen.

Dogs

Sodium fusidate was administered in the diet of 3 groups of 2 dogs each. One group served as the control, another group was dosed at 110 mg/kg/day for 4 weeks and the third group at 250 mg/kg/day for 1 week followed by 470 mg/kg/day for the next 3 weeks. None of the dogs showed any significant gross or micropathological alterations which were considered to be drug-related.

During the second and third weeks, the 2 dogs on the low dose showed reductions in appetite which were apparently due to poor palatability of the drug. One of the 2 dogs showed a slight weight loss. In the high dose group reductions in appetite limited drug intake to an average of 470 mg/kg/day. Both these animals had small weight losses, probably associated with reduced food intake.

Sodium fusidate was also administered intravenously to 2 male and 2 female dogs for 2 weeks at a dose of 21.5 mg/kg per day given in two equal doses of 62.5 mL each. Apart from local swelling at the site of catherization, no changes were seen which were considered to be related to the administration of the sodium fusidate compound by gross or histopathological examination.

In a further study, 2 male dogs received daily, for 2 weeks, 2 infusions of 10.75 mg/kg of sodium fusidate in a volume of 62.5 mL administered by slow infusion over a period of 90 minutes. The infusion of sodium fusidate provoked a local intolerance manifested by a reddening and swelling at the site of cannulation. At the histological level, a venous intolerance reaction was noted.

Chronic Toxicity of Sodium Fusidate

Rats

Sodium fusidate was administered in the diet to 4 groups of 40 rats at doses of 0, 200, 420 or 840 mg/kg daily for 34 weeks. High dose females and to a lesser degree, high dose males showed a small retardation of weight gain. Slight neutrophilia was also noted in both high dose males and females. Ten of the 14 high dose males showed mild fatty metamorphosis of the liver without significant cytopathological change.

In another study, rats received sodium fusidate administered orally at a dose of 200 mg/kg/day for 24 weeks. No influence on growth or haematology and no other toxic effects were observed.

In a final study, fusidic acid was administered orally to a group of 25 male and 25 female rats at a dose of 400 mg/kg/day, 6 days a week for 5 months. No haematological changes or other toxic effects were noted.

Guinea Pigs

No toxic effects were seen when sodium fusidate was administered orally to guinea pigs at doses of 80 mg/kg/day for 50 days.

Dogs

Sodium fusidate was included daily in the diet of 4 groups of 5 dogs in amounts to result in doses of 0, 90, 190 or 300 mg/kg for 26 weeks. Significant changes observed were: i) weight loss with significantly reduced appetite in one animal on the high dose; however, all other test animals maintained or gained weight comparable to the control group in spite of slightly reduced food intake ascribed by the investigator to poor palatability, ii) one dog on the high dose showed definite increases in plasma bilirubin and BSP; one dog on the intermediate dose showed slight to moderate increases in BSP, SGPT and alkaline phosphatase; one dog on the low dose showed a moderate increase in alkaline phosphatase and a slight increase in plasma bilirubin.

In another study, post-mortem examination revealed mild to moderate liver cell damage in one high dose dog (400 mg/kg/day) at 26 weeks, but the other animals showed no morphological changes with this dose attributable to the drug.

Fertility and Reproduction Studies with Sodium Fusidate

Rats

Two groups, each comprised of 20 male and 20 female rats, received either 0 or 400 mg/kg sodium fusidate per day from 2 weeks before mating to weaning. Caesarian sections were performed on half the dams on the 20th day; the remainder were allowed to deliver naturally.

There were no significant differences between the treated and control dams with respect to percent resorptions, the condition of the uteri or the number and weights of the pups. No soft tissue abnormalities were found in the pups of either group but skeletal anomalies (control group 2 pups missing ribs and dosed group 1 pup occipital bone formation incomplete and 1 pup rib deformities) appeared in 4% of the pups in both groups. These rates were similar to that seen in the control group. The viability and lactation indices, reflecting neonatal development, were higher in the treated group than the control group, but all values were within normal limits.

Teratology Studies with Sodium Fusidate

Mice

Pregnant mice were divided into 3 groups of 16-19 animals each and given daily doses of 20, 100 and 200 mg/kg sodium fusidate by gavage from the 6th to 15th day of gestation. Another group of 23 pregnant mice, serving as controls, received just water by gavage. On the 18th day of pregnancy, half the dams were sacrificed. The remainder were allowed to go to term.

Sex distribution of fetuses and young, fetal weight, birth weight and weight increase were normal and similar for all groups. The mean incidence of resorption was 1.2, 1, 0.5 and 0.6 per dam for the 20, 100 and 200 mg/kg groups and control group, respectively. Average litter size in the treated group did not differ significantly from that of the controls. No fetal abnormalities were detected in any of the groups.

Rats

Pregnant rats were divided into 3 groups of 29-31 animals each and given daily doses of 20, 100 or 200 mg/kg sodium fusidate by gavage from the 3rd to the 15th day of gestation. Another group of 59 pregnant rats, serving as controls, received just water by gavage. On the 21st day of pregnancy, half the dams were sacrificed. The remaining dams were allowed to go to term.

Litter size and sex distribution of the fetuses and young of the dosed animals were comparable to the controls with no dose-related differences. Birth weights and weight gain over a 4-month period were comparable for all groups. No fetal deformities were observed in any group.

Rabbits

Eighteen pregnant rabbits were treated orally with 125 mg sodium fusidate in tablet form once per day from the 6th to the 18th day of pregnancy. Eleven pregnant animals, serving as controls, received a placebo tablet each day. On the 30th day of pregnancy 9 treated animals and 3 controls were sacrificed. The remaining animals were allowed to go to term.

Sex distribution of fetuses and young, fetal and birth weights and weight gain were normal and similar for both groups. Three dead fetuses were found in each of 2 treated animals and in 1 control animal. Average litter size was lower in the treated group (4.8 young per litter) than in the control group (7.6 young per litter). Macroscopic examination of the young failed to reveal any teratogenic or other abnormalities.

Skin Tolerance Studies

Daily application of FUCIDIN (sodium fusidate) ointment to the ears of rabbits for a period of one month evolved neither general intolerance, local irritation to the eye, change in capillary permeability of the treated region, nor sensitization to the irritant effects of locally applied chloroform.