Melanorm F

Uses

For the treatment of fungal corneal ulcers/ keratitis.

Hydroquinone is used -

• For the gradual bleaching of hyperpigmented skin conditions such as chloasma, melasma, freckles, senile lentigines and other unwanted areas of melanin hyperpigmentation.
• To reduce hyperpigmentation caused by photosensitization associated with inflammation or with the use of certain cosmetics.

• For the treatment of acne vulgaris in which comedones, papules and pustules predominate.
• For the treatment of hyperpigmentation, roughness and fine wrinkling of photodamaged skin due to chronic sun exposure.
• For the treatment of Acute promyelocytic leukaemia

Melanorm F is also used to associated treatment for these conditions: Candida intertrigo, Candida pneumonia, Candida urinary tract infection, Candidemia, Candidiasis, Coccidioidomycosis, Esophageal Candidiasis, Fungal peritonitis caused by Candida, Infections, Fungal, Meningitis, Cryptococcal, Oropharyngeal Candidiasis, Peritoneal candidiasis, Pneumonia cryptococcal, Pruritus, Skin Irritation, Systemic Candida Infections caused by Candida, Vaginal Candidiasis, Disseminated CandidiasisAcne Vulgaris, Melasma, Skin hyperpigmentation, Moderate Melasma, Severe MelasmaAcne Vulgaris, Alopecia, Cornification and dystrophic skin disorders, FAB classification M3 Acute promyelocytic leukemia, Skin hyperpigmentation, Solar Lentigines, Facial fine wrinkling, Keratinization disorders of the feet, Keratinization disorders of the hand, Moderate Melasma, Mottled hyperpigmentation, Severe Melasma, Severe, recalcitrant Cystic acne, Tactile roughness of facial skin

How Melanorm F works

Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme normally works to convert lanosterol to ergosterol, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane.

Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing.

Hydroquinone reduces melanin pigment production through inhibition of the tyrosinase enzyme, which is involved in the initial step of the melanin pigment biosynthesis pathway. Hydroquinone takes several months to take effect.

Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. Although the exact mechanism of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced. Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. When Tretinoin is given systemically to APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

Dosage

Melanorm F dosage

Instill 1 drop to be instilled into the affected eye(s) 5 times daily.

Apply a thin film of Hydroquinone Cream to the effected area once daily, at least 30 minutes before bedtime. Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply Hydroquinone Cream to the hyperpigmented areas of melasma including about ½ inch of normal appearing skin surrounding eachlesion. Rub lightly and uniformly into the skin.

Therapy should be discontinued when control is achieved. During the day, use asunscreenof SPF 30, and wear protective clothing. Avoid sunlight exposure. Patients may use moisturizers and/or cosmetics during the day. Hydroquinone Cream is for topical use only. It is not for oral,ophthalmic, or intravaginal use.

Tretinoin cream: Tretinoin cream should be applied sparingly to the whole affected area once or twice daily. The skin should be thoroughly cleaned and dried before application. Patient should be advised that 6 to 8 weeks of treatment may be required before a therapeutic effect is observed. Moisturisers and cosmetics may be used during treatment with Cosmotrin cream but should not be applied to the skin at the same time. Astringent toiletries should be avoided.

Tretinoin gel: Tretinoin gel should be applied once or twice a day, before retiring, to the skin where lesions appear, using enough to cover the entire affected area lightly. The frequency of application can be adjusted to obtain maximum clinical efficacy with minimal erythema and scaling.

If Tretinoin gel is applied excessively, no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur. Should this occur accidentally or through over-enthusiastic use, application should be discontinued for few days.

Patience is needed in this treatment, since the therapeutic effects will not usually be observed until after 6-8 weeks of treatment. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen comedones and papules. Once the acne lesions have responded satisfactorily, it should be possible to maintain the improvement with less frequent applications.

Moisturizers and cosmetics may be used during treatment with Tretinoin gel but should not be applied to the skin at the same time. The skin should be thoroughly washed before application of Tretinoin gel. Astringent toiletries should be avoided.

Capsule: The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.

If after initiation of treatment of Tretinoin the presence of the translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to Tretinoin, alternative therapy appropriate for acute myelogenous leukemia should be considered.

Side Effects

This drug is generally well tolerated. Eosinophillia has been reported in some patients.

No systemic adverse reactions have been reported. Occasional hypersensitivity (localized contact dermatitis) may occur in which case the medication should be discontinued.

True allergic contact dermatitis is rare but a primary irritant dermatitis, manifesting itself as irritation, erythema, peeling and sensation of warmth, is common. Slight stinging is common as a mild reaction in many people but usually settles with continuous use and/or reduction in the frequency of application of the drug.

Toxicity

Acute oral toxicity (LD50): 1271 mg/kg (rat)

Overdose information

Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination. In cases of overdose, employ supportive treatment. Gastric lavage may be necessary. Other modalities such as forced diuresis or hemodialysis may also be used.

A note on liver toxicity

The FDA label warns that this drug carries a risk of hepatotoxicity. Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole. This group of patients has an increased risk of fatality when using fluconazole. In patients with existing liver dysfunction, use caution during fluconazole therapy. Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver. Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. Fluconazole induced hepatotoxicity is usually reversible.

Carcinogenesis, mutagenesis, and impairment of fertility

Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses equivalent to approximately 2-7 time the recommended human dose). Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation. The significance of these findings for humans is unknown.

Use in pregnancy

There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (27 Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy. Similar findings were observed in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly.

Use in nursing

Fluconazole is secreted in breastmilk at high concentrations. Exercise caution if this drug is used during nursing.

Precaution

Use of fluconazole may result in overgrowth of non-susceptible strains of candida other than Candida albicans

Hydroquinone is a skin bleaching agent which may produce unwanted cosmetic effects if not used as directed. The physician should be familiar with the contents of this insert before prescribing or dispensing this medication.

Test for skin sensitivity before using by applying a small amount to an unbroken patch of skin to check in 24 hours. Minor redness is not a contraindication, but where there is itching or vesicle formation or excessive inflammatory response, further treatment is not advised. If no bleaching or lightening effect is noted after 2 months of treatment, the medication should be discontinued.

Contact with the eyes and lips should be avoided. Hydroquinone should not be applied to cut or abraded skin.

Interaction

Fluconazole can alter pharmacokinetics of certain drugs undergoing hepatic metabolism.

Particular caution should be exercised in using preparations containing peeling agents (i.e. sulfur, resorcinol, benzoyl peroxide or salicylic acid). Use of topical preparations with high concentrations of alcohol, menthol, spices or lime- such as shaving lotions, astringents and perfume- should be avoided, especially during initial therapy.

Volume of Distribution

The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg.

Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections.[L6496] Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier[L6496]. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.

Elimination Route

The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached.

Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours.

Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole.

A note on the capsule and powder form and malabsorption syndromes

The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency.

1-31% (topical)

Half Life

The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.[L6496]. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.

0.5-2 hours

Clearance

This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h).

Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.

Elimination Route

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine.

A note on renal failure

The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.

Pregnancy & Breastfeeding use

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Fluconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Nursing mother should not be given as the drug is excreted in breast milk in concentration similar to plasma.

Pregnancy 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.

Lactation: It is not known whether topical hydroquinone is absorbed or excreted in human milk. Caution is advised when topical hydroquinone is used by a nursing mother.

Tretinoin is contraindicated in pregnancy or suspected pregnancy. The drug should be avoided by breast feeding mothers.

Contraindication

The drug is contraindicated in patients with hypersensitivity to azoles.

Hydroquinone is contraindicated to patients with prior history of hypersensitivity or allergic reaction to hydroquinone or other ingredients in the preparation.

Tretinoin is contraindicated in patients who are allergic to this drug. It is contraindicated in pregnancy or suspected pregnancy. It is also contraindicated in personal or familial history of cutaneous epithelioma.

Local irritation: The presence of cutaneous irritative signs (e.g. erythema, peeling, pruritus, sunburn, etc.) should prohibit initiation or recommencement of treatment with Tretinoin until the symptoms resolve. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with caution in patients with this condition.

Exposure to sunlight: Exposure to sunlight, including ultraviolet sun-lamps, should be avoided or minimised during the use of Tretinoin.

General precaution: Before application of Tretinoin, areas to be treated should be cleansed thoroughly. Abstain from washing the treated area frequently; twice daily is sufficient. Use of mild soap is recommended. Dry the skin without rubbing.

Avoid contact with eyes, eyelids, nostrils, mouth and mucous membranes. If contact in these areas occurs, careful washing with water is recommended.

Acute Overdose

There have been no systemic reactions from the use of topical hydroquinone. Some patients may experience a transient reddening of skin and mild burning sensation which does not preclude treatment.

Storage Condition

Keep out of the reach of children. Store in a cool, dry place, away from heat and direct light. Do not use more than 4 weeks after opening the bottle

Store between 20-25° C. Protect from light.

Store in a cool and dry place, away from light. Keep out of reach of children.

Innovators Monograph

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