Flakenil

Uses

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.

6% Salicylic Acid: This topical preparations treat the following common scaly conditions:

• Chronic atopic dermatitis
• Lichen simplex
• Psoriasis
• Seborrhoeic dermatitis
• Ichthiosis

12% Salicylic Acid: This topical preparations treat the following common scaly conditions:

• Warts (small excessive growths of skin caused by a type of virus. Warts often occur on the fingers or on the back of the hands).
• Verruca (occurs only on the sole of the feet and can be painful. It often looks like a small white ring of skin with a black dot in the centre).
• Corns and Calluses (are hard, thick pads of skin caused by pressure and friction. They usually occur on the feet due to poorly fitting shoes and can occur on the hands).

Flakenil is also used to associated treatment for these conditions: Bacterial 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, Actinic Keratosis (AK), Alopecia Areata (AA), Atopic Dermatitis (AD), Blackheads, Chronic Eczema, Chronic cutaneous lupus erythematosus, Corns, Dandruff, Dermatitis, Contact, Dermatitis, Eczematous, Dermatitis, Eczematous of the scalp, Discoid Lupus Erythematosus (DLE), Foot Callus, Fungal skin infection, Furuncle, Hand Eczema, Hyperkeratosis, Hyperkeratosis follicularis et parafollicularis, Infections, Fungal, Infections, Fungal of the Skin Folds, Infections, Fungal of the face, Infections, Fungal of the feet, Infections, Fungal of the hand, Keratosis Palmaris et Plantaris, Lichen, Lichen Plano-Pilaris, Lichen Planus (LP), Lichen simplex chronicus, Molluscum Contagiosum, Musculoskeletal Pain, Neurodermatitis, Palmo-Plantar Pustulosis, Plantar Warts, Pruritus, Psoriasis, Psoriasis Vulgaris (Plaque Psoriasis), Psoriasis of the scalp, Rash, Ringworm of the Skin, Ringworm of the scalp, Seborrheic Dermatitis, Seborrhoeic Dermatitis of the Scalp, Skin Infections, Bacterial, Verrucous Psoriasis, Warts, Calluses, Corticosteroid-responsive dermatoses, Keratinization disorders, Scaling, Scaling of skin, Scalp seborrhea, Superficial Fungal skin infection, Keratolysis

How Flakenil works

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.

Salicylic acid directly irreversibly inhibits COX-1 and COX-2 to decrease conversion of arachidonic acid to precursors of prostaglandins and thromboxanes. Salicylate's use in rheumatic diseases is due to it's analgesic and anti-inflammatory activity. Salicylic acid is a key ingredient in many skin-care products for the treatment of acne, psoriasis, calluses, corns, keratosis pilaris, and warts. Salicylic acid allows cells of the epidermis to more readily slough off. Because of its effect on skin cells, salicylic acid is used in several shampoos used to treat dandruff. Salicylic acid is also used as an active ingredient in gels which remove verrucas (plantar warts). Salicylic acid competitively inhibits oxidation of uridine-5-diphosphoglucose (UDPG) with nicotinamide adenosine dinucleotide (NAD) and noncompetitively with UDPG. It also competitively inhibits the transferring of the glucuronyl group of uridine-5-phosphoglucuronic acid (UDPGA) to a phenolic acceptor. Inhibition of mucopoly saccharide synthesis is likely responsible for the slowing of wound healing with salicylates.

Dosage

Flakenil dosage

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.

Topical/Cutaneous (Adult)-

Hyperkeratotic and scaling skin conditions: As 1.8-3% preparation: Apply to affected area of the skin and/or scalp 1-4 times daily.

Acne: As 0.5-2% preparation: Apply thinly to affected area 1-3 times daily, reduce to once daily or every other day if dryness or peeling occur.

Warts and calluses:

• As 12-40% plaster: Fit over the wart/callus for 48 hr, repeat process 48 hrly as needed until wart/callus is removed (up to 12 wk for warts or up to 14 days for calluses).
• As 5-17% preparation in collodion-like vehicle: Apply a small amount to sufficiently cover wart/callus and allow to dry. Repeat 1-2 times daily until wart/callus is removed (up to 12 wk for warts or up to 14 days for calluses).
• As 15% preparation in karaya gum-glycol plaster vehicle: Smoothen warts with emery board and place a drop of warm water prior to application. Apply the plaster in the evening and leave in place for at least 8 hr to be removed in the morning. Repeat process 24 hrly, if necessary up to 12 wk.

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

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

An allergic reaction (shortness of breath, closing of the throat, swelling of the lips, face or tongue or hives) or severe skin irritation.

Toxicity

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.

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

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

For external use only. Avoid contact with eyes and other mucous membranes.

Interaction

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.

Do not use other topical preparations on the treated area unless otherwise directed by your healthcare provider. They may interfere with treatment or increase skin irritation.

Volume of Distribution

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 volume of distribution is about 170 mL/kg of body weight.

Elimination Route

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.

Half Life

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

Clearance

Ketoconazole has an estimated clearance of 8.66 L/h.

Elimination Route

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

About 10% is excreted unchanged in the urine.

Pregnancy & Breastfeeding use

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.

Pregnancy Category C. If used by nursing mothers, it should not be used on the chest area to avoid accidental contamination of the child.

Contraindication

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).

It should not be used in any patient known to be sensitive to Salicylic Acid or any other listed ingredients.

Special Warning

Renal Impairment: Oral: No dosage adjustment needed.

Hepatic Impairment: Oral: Contraindicated.

Salicylic Acid is used in children over 2 years.

Acute Overdose

An overdose of Salicylic Acid topical is unlikely to occur. If you do suspect an overdose or if the medication has been ingested, call a poison control center or emergency room for advice.

Storage Condition

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

Store at a temperature below 25° C.

Innovators Monograph

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