Covate Mixi

Uses

Clobetasol Propionate is used for:

• Initial control of all forms of hyperacute eczema in all age groups
• Chronic hyperkeratotic eczema of the hands and feet and patches of chronic lichen simplex
• Chronic hyperkeratotic psoriasis of any area of the body
• Severe acute photosensitivity
• Hypertrophic lichen planus
• Localized bullous disorders
• Keloid scarring
• Pretibial myxoedema
• Vitiligo
• Suppression of reaction after cryotherapy
• Scalp Solution is used for the topical therapy of recalcitrant corticosteroid-responsive dermatoses of the scalp, including recalcitrant cases of psoriasis and seborrheic dermatitis.

Treatment of superficial and deep mycoses:

• Infections of the skin, hair and nails by dermatophytes and/or yeasts (dermatomycosis, onychomycosis, perionyxis, pityriasis versicolor, chronic mucocutaneous candidiasis etc.) especially when topical treatment is difficult or not very effective, owing to involvement of large skin surfaces or to lesions affecting deeper dermal layers, nails and hairs
• Yeast infection of the mouth (oral thrush, perleche) and the gastrointestinal tract
• Vaginal candidiasis, especially chronic recurrent cases or cases responding poorly to topcial treatment
• Systemic mycotic infections such as systemic candidiasis, paracoccidioidomycosis, histoplasmosis, coccidioidomycosis etc.

Maintenance treatment to prevent recurrence in systemic mycotic infections and in chronic mucocutaneous candidiasis.Prophylactic treatment to prevent mycotic infection in patients with reduced host defenses, e.g., patients with cancer, organ transplant and burns.

Neomycin is an aminoglycoside antibiotic agent used orally and topically to treat a wide variety of infections in the body.

Oral neomycin sulfate is indicated as an adjunctive therapy in hepatic coma (portal-system encephalopathy) by reducing ammonia-forming bacteria in the intestinal tract. It is strongly recommended that oral neomycin is only used in infections that are proven or strongly suspected to be caused by susceptible bacteria to reduce the risk of the development of drug-resistant bacteria.

Neomycin, in combination with polymyxin B sulfates and hydrocortisone in otic suspensions, is used in the treatment of superficial bacterial infections of the external auditory canal caused by organisms susceptible to the antibiotics. This otic formulation is also used in the treatment of infections of mastoidectomy and fenestration cavities caused by organisms susceptible to the antibiotics.

The ophthalmic solution containing neomycin in combination with polymyxin B sulfates and dexamethasone is used to treat steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where bacterial infection or a risk of bacterial infection exists.

Tolnaftate is used to treat skin infections such as athlete's foot, jock itch, and ringworm. It is an antifungal that works by preventing the growth of fungus.

Covate Mixi is also used to associated treatment for these conditions: Alopecia, Severe Plaque psoriasis, Corticosteroid responsive, Inflammatory Dermatosis, Corticosteroid responsive, pruritic Dermatosis, Moderate Plaque psoriasis, Moderate Scalp Psoriasis, Severe Scalp PsoriasisBacterial Vaginosis (BV), Blastomycosis, Candidiasis, Systemic, Chromomycosis, Chronic Mucocutaneous Candidiasis (CMC), Coccidioidomycosis, Dandruff, Endogenous Cushing's Syndrome, Histoplasmosis, Infections, Fungal, Paracoccidioidomycosis, Seborrheic Dermatitis, Tinea Corporis caused by Epidermophyton floccosumin, Tinea Corporis caused by Trichophyton mentagrophytes, Tinea Corporis caused by Trichophyton rubrum, Tinea Cruris caused by Epidermophyton floccosumin, Tinea Cruris caused by Trichophyton mentagrophytes, Tinea Cruris caused by Trichophyton rubrum, Tinea Pedis caused by Epidermophyton floccosumin, Tinea Pedis caused by Trichophyton mentagrophytes, Tinea Pedis caused by Trichophyton rubrum, Vaginal Candidiasis, Vulvovaginal Candidiasis, Cutaneous candidiasis, Recalcitrant Dermatophytosis, Tinea versicolor caused by Malassezia infectionAcne pustular, Allergic Contact Dermatitis, Allergy Skin, Atopic Dermatitis (AD), Atopic Dermatitis (AD) of the external ear canal, Bacterial diarrhoea, Burns, Carbuncle, Cradle Cap, Dermatitis, Dermatitis, Contact, Dermatitis, Eczematous, Diarrhoea, Discoid Lupus Erythematosus (DLE), Ear infection bacterial, Ear infection bacterial caused by susceptible bacteria, Gastrointestinal Infections, Hepatic coma, Hidradenitis Suppurativa (HS), Hot Water Burns (Scalds), Impetigo, Impetigo contagious, Infantile Eczema, Infected Wounds, Infected skin ulcer, Infection of the outer ear caused by susceptible bacteria, Infectious diarrhea, Inflammatory Reaction caused by Acne, Intertrigo, Itching caused by Infection, Lichen Planus (LP), Localized Infection caused by susceptible bacteria, Nail infection, Neurodermatitis, Otitis Externa, Postoperative Wound Infection, Psoriasis Vulgaris (Plaque Psoriasis), Pustular Dermatosis, Radiodermatitis, Secondarily Infected Eczema, Secondary Bacterial Infection, Skin Burns, Skin Infections, Skin Infections, Bacterial, Skin Irritation, Skin Ulcer, Solar erythema, Abrasions, Blistering caused by Staphylococcus, Erythematous eruptions, Intertriginous erythema of the anogenital, Ocular bacterial infections caused by susceptible bacteria, Resistant to other corticosteroids Dermatosis, Susceptible Bacterial InfectionsDermatophytosis, Pityriasis versicolor, Ringworm, Tinea Corporis, Tinea Cruris, Tinea Pedis

How Covate Mixi works

The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.

Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.

Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.

Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed.

Like other aminoglycoside antibiotic drugs, neomycin inhibits bacterial ribosomes by binding to the 30S ribosomal subunit of susceptible bacteria and disrupting the translational machinery of bacterial protein synthesis. Bacterial translation is normally initiated by the mRNA binding to the 30S ribosomal subunit and subsequent binding with 50S subunit for elongation.

Tolnaftate is a topical fungicide. Though its exact mechanism unknown, it is believed to prevent ergosterol biosynthesis by inhibiting squalene epoxidase. It has also been reported to distort the hyphae and to stunt mycelial growth in susceptible organisms.

Dosage

Covate Mixi dosage

Nyclobate Cream & Ointment

Adults and children over 1 year:

• Apply sparingly to cover the affected area, and gently rub into the skin. Frequency of application is 2 to 3 times daily according to the severity of the condition. The total dose applied should not exceed 50 g weekly.

• Treatment should not be continued for more than 7 days without medical supervision. If a longer course is necessary, it is recommended that treatment should not be continued for more than 4 weeks without the patient\\\'s condition being reviewed.

• Repeated short courses of Clobetasol may be used to control exacerbations

Children below 1 year: Under 1 year this preparation is not recommended

Nyclobate Scalp Application

• It should be applied to the affected scalp areas twice daily, once in morning and once at night.

• Total dosage should not exceed 50 ml per week.

• As with other highly active topical steroid preparations, therapy should be discontinued when control is achieved

Children: Under 1 year this preparation is not recommended.

Nyclobate Shampoo

• It should be applied to the dry (not wet) scalp once a day to the affected areas only.

• It should be massaged gently into the lesions and left in place for 15 minutes before lathering and rinsing.

• Treatment should be limited to 4 consecutive weeks.

• Total dosage of shampoo should not exceed 50 g per week.

• Under 18 years this preparation is not recommended.

Oral-

Fungal infections:

• Adult: 200 mg once daily; may increase to 400 mg once daily if clinical response is insufficient. Continue treatment until symptoms have cleared and cultures have become negative.
• Child: ≥2 yr 3.3-6.6 mg/kg once daily. Treatment duration: 1-2 wk for candidiasis; at least 4 wk in recalcitrant dermatophyte infections and up to 6 mth for other systemic mycoses.
• Elderly: No dosage adjustment needed.

Topical (Adult)-

Pityriasis versicolor, Skin fungal infections:

• As 2% cream: Apply 1-2 times daily to cover affected and surrounding area until at least a few days after disappearance of symptoms.
• As 2% shampoo: Apply on scalp once daily for up to 5 days. For prophylaxis: As 2% shampoo, use once daily for a max of 3 days before exposure to sunlight.

Seborrhoeic dermatitis:

• As 2% foam: Apply to the affected area bid for 4 wk.
• As 1 or 2% shampoo: Apply on the scalp twice wkly for 2-4 wk. For prophylaxis: As 2% shampoo, use once every 1-2 wk.

Use this medication on the skin only. Clean and thoroughly dry the area to be treated. Apply this medication to the affected skin, usually twice a day or as directed on the product package or by your doctor. Dosage and length of treatment depends on the type of infection being treated.

Some forms of tolnaftate (e.g., powder) need to be shaken before applying. Check your product package to see if your form of this medication needs to be shaken. Apply enough medication to cover the affected area and some of the surrounding skin. After applying this medication, wash your hands. Do not wrap, cover, or bandage the area unless directed to do so by your doctor.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day.

Continue to use this medication until the full prescribed amount is finished, even if symptoms disappear after starting tolnaftate. Stopping the medication too early may allow the fungus to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition persists after 2 weeks of treatment for jock itch, after 4 weeks of treatment for athlete's foot or ringworm, or if your condition worsens at any time.

Duration of Treatment

• Pityriasis versicolor: 1 to 6 weeks
• Dermatomycoses: 2 to 8 weeks
• Onychomycoses: 1 to 12 months
• Mycoses of hair and scalp: 1 to 2 months
• Chronic mucocutaneous candidiasis : 1 to 12 months
• Oral mycoses: 5 to 10 days
• Systemic candidiasis: 1 to 2 months
• Paracoccidioidomycosis,histoplasmosis
• and other systemic mycosis: 1 month to 2 years

Side Effects

Generally Clobetasol Propionate is well tolerated. However, few side effects after prolonged and intensive treatment may cause local atrophic changes in the skin such as Burning, itching, irritation, dry skin eczema.

Ketoconazole is very well tolerated. Nausea and itching may occasionally occur. In some patients, an idosyncratic liver reaction may occur (incidence 1 : 10,000).

Irritation of the treated skin may occur. If this effect persists or worsens, notify your doctor or pharmacist promptly.

If your doctor has directed you to use this medication, remember that he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Toxicity

Data regarding acute overdoses of glucocorticoids are rare. Overdoses of clobetasol propionate can lead to reversible HPA axis suppression and glucocorticoid insufficiency. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency.[A188405] Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment.[A188405]

Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice. In case of overdose, gastric lavage with activated charcoal may be used if within one hour of ketoconazole ingestion otherwise provide supportive care. If the patient shows signs of adrenal insufficiency, administer 100 mg hydrocortisone once together with saline and glucose infusion and monitor the patient closely. Blood pressure and fluid and electrolyte balance should be monitored over the next few days.

The oral LD₅₀ of neomycin sulfate in mouse is > 8 g/kg. The subcutaneous LD₅₀ is 200 mg/kg in rat and 190 mg/kg in mouse. The intraperitoneal LD₅₀ in mouse is 305 mg/kg. The oral Lowest published toxic dose (TDLo) in woman is 12600 mg/kg/7D.

Because of low absorption, acute overdosage from oral neomycin is not likely to occur. However, prolonged administration of neomycin should be avoided because of the possibility of some systemic absorption and the risk of neurotoxicity, ototoxicity, and/or nephrotoxicity. Hemodialysis will remove neomycin from the blood. While nephrotoxicity and ototoxicity have been reported in otherwise patients without compromised renal function, the risk for developing these toxicities is increased in patients with renal impairment. Like other aminoglycosides, neomycin may cause fetal harm and total irreversible bilateral congenital deafness when administered in pregnant women.

Oral rat LD50: 891 mg/kg. Inhalation rat LC50: > 900 mg/m3/1hr. Irritation: skin rabbit: 500 mg/24H mild. Eye rabbit: 100 mg severe. Investigated a mutagen and reproductive effector.

Precaution

Do not swallow. For external use only.

Predisposition to adrenocortical insufficiency. Admin with acidic drink in patients with achlorhydria. Pregnancy and lactation.

Before using tolnaftate, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system problems (e.g., organ transplant, HIV disease), diabetes.

This medication should be used only if clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Interaction

No hazardous interactions have been reported with use of Clobetasol Propionate.

Reduced absorption with antimuscarinics, antacids, H2-blockers, PPIs and sucralfate. Reduced plasma concentrations with rifampicin, isoniazid, efavirenz, nevirapine, phenytoin. May also reduce concentrations of isoniazid and rifampicin. May reduce efficacy of oral contraceptives. May increase serum levels of CYP3A4 substrates e.g. digoxin, oral anticoagulants, sildenafil, tacrolimus.

There are no known significant interactions.

Volume of Distribution

Data regarding the volume of distribution of clobetasole propionate are not readily available.

Ketoconazole has an estimated volume of distribution of 25.41 L or 0.36 L/kg. It distributes widely among the tissues, reaching effective concentrations in the skin, tendons, tears, and saliva. Distribution to vaginal tissue produces concentrations 2.4 times lower than plasma. Penetration into the CNS, bone, and seminal fluid are minimal. Ketoconazole has been found to enter the breast milk and cross the placenta in animal studies.

The small fraction of absorbed neomycin is rapidly distributed in the tissues. The amount of systemically absorbed neomycin is reported to increase cumulatively with each repeated dose administered until a steady state is reached.

Elimination Route

Twice daily application of clobetasol foam leads to a C_max of 59±36pg/mL with a T_max of 5 hours. Clobetasol cream showed an increase in clobetasol concentrations from 50.7±96.0pg/mL to 56.3±104.7pg/mL.

Ketoconazole requires an acidic environment to become soluble in water. At pH values above 3 it becomes increasingly insoluble with about 10% entering solution in 1 h. At pH less than 3 dissolution is 85% complete in 5 min and entirely complete within 30 min. A single 200 mg oral dose produces a Cmax of 2.5-3 mcg/mL with a Tmax of 1-4 h. Administering ketoconazole with food consistently increases Cmax and delays Tmax but literature is contradictory regarding the effect on AUC, which may experience a small decrease. A bioavailablity of 76% has been reported for ketoconazole.

Neomycin is poorly absorbed from the gastrointestinal tract. Gastrointestinal absorption of the drug may be increased if inflammatory or ulcerative gastrointestinal disease is present.

Half Life

Data regarding the half life of clobetasol propionate are not readily available.

Ketoconazole experiences biphasic elimination with the first phase having a half-life of 2 hours and a terminal half life of 8 hours.

There is limited information on the half-life of neomycin.

Clearance

Data regarding the clearance of clobetasol propionate are not readily available.

Ketoconazole has an estimated clearance of 8.66 L/h.

There is limited information on the clearance rate of neomycin.

Elimination Route

Corticosteroids are eliminated predominantly in the urine.

Only 2-4% of the ketoconazole dose is eliminated unchanged in the urine. Over 95% is eliminated through hepatic metabolism.

The small absorbed fraction of neomycin is excreted by the kidney. The unabsorbed portion of the drug is excreted unchanged in the feces.

Pregnancy & Breastfeeding use

The safe use of Clobetasol Propionate during pregnancy & lactation has not been established.

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Tolnaftate topical has not been formally assigned to a pregnancy category by the FDA. Animal studies have not been reported. There are no controlled data in human pregnancy. Tolnaftate topical is only recommended for use during pregnancy when benefit outweighs risk. There are no data on the excretion of tolnaftate topical into human milk.

Contraindication

Contraindicated in Cutaneous infections such as impetigo, tinea corporis and herpes simplex, Infestations such as scabies, Acne vulgaris, Hypersensitivity, Rosacea, Gravitational ulceration, Perioral dermatitis, Children under 1 year

Hypersensitivity; preexisting liver disease. Concurrent use with CYP3A4 substrates e.g. HMG-CoA reductase inhibitors (e.g. lovastatin, simvastatin), midazolam, triazolam, cisapride, dofetilide, eplerenone, nisoldipine, pimozide, quinidine, terfenadine, astemizole, ergot alkaloids (e.g. ergotamine, dihydroergotamine).

Hypersensitivity. Nail and scalp infections. Do not apply this medication in the eyes, nose, mouth, or vagina.

Special Warning

Use in Paediatrics: The drug may be used in paediatrics patients in appropriate dosage, but large quantities for prolonged period should be avoided. It is contraindicated in children less than one year.

Renal Impairment: Oral: No dosage adjustment needed.

Hepatic Impairment: Oral: Contraindicated.

Acute Overdose

Acute overdosage is very unlikely to occur. However, in the case of chronic overdose or misuse the features of hypercortisolism may appear.

Storage Condition

Do not store above 30 0 C. Keep away from light and out of the reach of children. Do not freeze.

Store between 15-25° C. Protect from moisture and light.

Store at 15-30° C.

Innovators Monograph

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