Justeen Pharmaceauticals Limited

MYCORON PLUS CREAM

Antifungal, Antibacterial & Anti Inflammatory

• QUALITATIVE AND QUANTITATIVE COMPOSITION

  
  Clotrimazole U.S.P.: 1.0 w/w
  Betamethasone Dipropionate U.S.P: 0.05 w/w
  Neomycin sulfate U.S.P: 0.5 w/w
  Preservative:
  Chlorocresol U.S.P. NF: 0.1 w/w
  Cream base: q.s.
  

• PHARMACEUTICAL FORM

  Cream.
  For Topical use.

• CLINICAL PARTICULARS

  Therapeutic indications

  It is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in patients 17 years and older.

  Posology and method of administration

  Apply a thin film of Cream, into the affected skin areas twice a day for one week. Do not use more than 45 grams per week. Do not use with occlusive dressings. If a patient shows no clinical improvement after 1 week of treatment with Cream, the diagnosis should be reviewed. Do not use longer than 2 weeks.

  Contraindications

  Hypersensitivity to any component of this medication.

  Special warnings and precautions for use

  The Cream can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Cushing's syndrome and hyperglycemia may also occur due to the systemic effect of corticosteroids while on treatment.

  Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressing, altered skin barrier, liver failure, and young age. Because of the potential for systemic corticosteroid effects, patients may need to be periodically evaluated for HPA axis suppression. This may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

  Interaction with other medicinal products and other forms of interaction

  Clotrimazole:
  Laboratory tests have suggested that, when used together, this product may cause damage to latex contraceptives. Consequently the effectiveness of such contraceptives may be reduced. Patients should be advised to use alternative precautions for at least five days after using this product.

  Betamethasone Dipropionate:
  None stated.

  Neomycin sulphate:
  Neomycin may impair absorption of other drugs including phenoxymethylpenicillin, digoxin, methotrexate and some vitamins. Aminoglyccsides exhibit synergistic activity with a number of beta lactams, but aminoglycoside activity was reported to be diminished in a few patients with severe renal impairment.

  Care should be taken when considering the use of neomycin concurrently with drugs with a potential to cause nephrotoxicity (including other aminoglycosidea, some of the cephalosporins, amphotericin, ciclosporin, capreomycin, polymixins, platinum compounds, telcoplanin and vancomycin) or ototoxicity (including loop diuretics, capreomycin, teicoplanin, vancomycin and possibly platinum compounds). The effect of non-depolarising muscle relaxants may be enhanced by aminoglycosides.

  Care is required if other drugs with a neuromuscular blocking action, including botulinum toxic, are given concomitantly. Care is required when patients being treated with aminoglycosides are to receive a general anaesthetic or opioids in order to avoid the possible neuromuscular side-effects provoking severe respiratory depression.

  The effect of the parasympathomimetic drugs neostigmine and pyridostigmine, may be antagonised by aminoglycosides. The hypoglycaemic effect of acarbose may be enhanced by neomycin and the severity of gastrointestinal side effects increased. Aminoglycosides may increase the risk of hypocalcaemia in patients receiving bisphosphonates.

  Experience in anticoagulant clinics suggests that INR (International Normalised Ratio) may be altered by antibacterials such as neomycin given for local action on the gut. The efficacy of oral contraceptives may be reduced with broad spectrum antibiotics. Oral typhoid vaccine is inactivated by concomitant antibiotic administration.

  Pregnancy and Lactation

  Pregnancy
  There are no adequate and well-controlled studies with Clotrimazole Betamethasone Dipropionate and neomycin sulphate cream, in pregnant women. Therefore, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

  There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. Studies in pregnant rats with intravaginal doses up to 100 mg/kg (I5 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure.

  No increase in foetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation Days 6 to 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights), and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore foetuses were not evaluated in this group.

  Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or foetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above. 50 mg/kg clotrimazole was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks.

  Oral clotrimazole doses of 25, 50, 100 and 200 mg/kg/day (2 to 15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18 to 55 times the maximum human dose).Betarnethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. This dose is approximately one-fifth the maximum human dose.

  The abnormalities observed included umbilical hernias, cephalocele, and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals.

  Nursing Mothers
  Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

  It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Clotrimazole Betamethasone Dipropionate and neomycin sulphate cream is administered to a nursing woman.

  Undesirable effects

  CIotrimazole
  Immune system disorders: allergic reaction (syncope, hypotension, dyspnea, urticaria). Skin and subcutaneous tissue disorders: blisters, discomfort, pain, oedema, erythema, irritation. peeling/exfoliation, pruritus, rash, stinging/burning.

  Betamethasone Dipropionate
  It is generally well tolerated and side-effects are rare. The systemic absorption of betamethasone dipropionate may be increased if extensive body surface areas or skin folds are treated for prolonged periods or with excessive amounts of steroids. Suitable precautions should be taken in these circumstances, particularly with infants and children. The following local adverse reactions that have been reported with the use of Diprosone include: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation. perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, striae and miliaria. Continuous application without interruption may result in local atrophy of the skin, striae and superficial vascular dilation, particularly on the face.

  Neomycin sulfate
  Nausea, vomiting, diarrhoea, increased salivation, stomatitis, nephrotoxicity, ototoxicity, rise in serum levels of hepatic enzymes and bilirubin, blood dyscrasias, haemolytic anaemia, confusion, paraesthesia, disorientation, nystagmus, hypersensitivity reactions including dermatitis, pruritus, drug fever and anaphylaxis. Cross-sensitivity with other aminoglycosides may occur.

  Malabsorption syndrome With steatorrhoea and diarrhoea, which can be severe, may be caused by prolonged oral therapy. Superinfection may occur, especially with prolonged oral treatment. Electrolyte disturbances (notably hypomagnesaemia but also hypocalcaemia and hypokalaemia) have occurred with other aminoglycosides. Generally it well tolerated. Despite this, patients should report all side effects they notice to their physician.

  
  

  Possible side effects include:

  • Irritation
  • Itching
  • Peeling
  • Redness
  • Inflammation
  • Stinging sensations
  • Burning sensations
  Seek immediate medical attention if you experience any of the following.
  • Edema
  • Pigmentation changes
  • Atrophy
  • Growth changes
  • Stretch marks
  • Cushing's syndrome
  • Symptoms of allergic or hypersensitive reaction (such as difficulty breathing or swallowing, chest pains, skin rash, hives, or swelling)

  Overdose

  Clotrimazole
  

  • No risk of acute intoxication is seen as it is unlikely to occur following a single dermal application of an overdose (application over a large area under conditions favourable to absorption) or inadvertent oral ingestion. There is no specific antidote.
  • However, in the event of accidental oral ingestion, gastric lavage is rarely required and should be considered only if a life-threatening amount of Clotrimazole has been ingested within the preceding hour or if clinical symptoms of overdose become apparent (e.g. dizziness, nausea or vomiting). Gastric lavage should be carried out only if the airway can be protected adequately.

  Betamethasone Dipropionate
  

  • Excessive prolonged use of topical corticosteroids can suppress pituitary-adrenal functions resulting in secondary adrenal insufficiency which is usually reversible. In such cases appropriate symptomatic treatment is indicated. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, reduce the frequency of application, or to substitute a less potent steroid.
  • The steroid content of each tube is so low as to have little or no toxic effect in the unlikely event of accidental oral ingestion.
  Neomycin sulphate:
  • In overdose, exacerbation of the adverse events reported for neomycin (nausea, diarrhoea nephrotoxicity, ototoxicity etc.) is expected.
  • Monitor renal and auditory function. If these are impaired, haemodialysis is indicated.
  • Prolonged assisted ventilation may also be required.

• PHARMACOLOGICAL PROPERTIES

  Pharmacodynamic properties

  Clotrimazole
  Clotrimazole acts against fungi by inhibiting ergosterol synthesis. Inhibition of ergosterol synthesis leads to structural and functional impairment of the fungal cytoplasmic membrane. Clotrimazole has a broad antimycotic spectrum of action in vitro and in vivo, which includes dermafophytes, yeasts, moulds, etc. Under appropriate test conditions, the MIC values for these types of fungi are in the region of less than 0.062-8.0 ?g/ml substrate. The mode of action of clotrimazole is primarily fungistatic or fungicidal depending on the concentration of clotrimazole at the site of infection. In vitro activity is limited to proliferating fungal elements; fungal spores are only slightly sensitive. In addition to its antimycotic action, clotrimazole also acts on gram-positive microorganisms (Streptococci / Staphylococci / Gardnerella vaginalis), and gram-negative microorganisms (Bacteroides). In vitro clotrimazole inhibits the multiplication of Corynebacteria and gram-positive cocci - with the exception of Enterococci - in concentrations of 0.5-10 ?g/ml substrate. Primarily resistant variants of sensitive fungal species are very rare; the development of secondary resistance by sensitive fungi has so far only been observed in very isolated cases under therapeutic conditions.

  Betamethasone Dipropionate
  Betamethasone is a glucocorticoid exhibiting the general properties of corticosteroids. In pharmacological doses, corticosteroids are used primarily for their anti-inflammatory and/or immune suppressive effects. Topical corticosteroids such as betamethasone dipropionate are effective in the treatment of a range of dermatoses because of their anti-inflammatory, anti-pruritic and vasoconstrictive actions. However, while the physiologic, pharmacologic and clinical effects of the corticosteroids are well known, the exact mechanisms of their action in each disease are uncertain.

  Neomycin sulphate
  Neomycin is an aminoglycoside antibiotic. Neomycin acts by binding to polysomes, inhibiting protein synthesis and generating errors in the transcription of the genetic code.

  Pharmacokinetic properties

  Clotrimazole
  Phannacokinetic investigations after dermal application have shown that clotrimazole is minimally absorbed from the intact or inflamed skin into the human blood circulation. The resulting peak serum concentrations of clotrimazole were below the detection limit of 0.00 I mcg/ml, suggesting that clotrimazole applied topically is unlikely to lead to measurable systemic effects or side effects.

  Betamethasone Dipropionate
  The extent of percutaneous absorption of topical corticosteroids is determined by many factors including vehicle, integrity of the epidermal barrier & the use of occlusive dressings. Topical corticosteroids can be absorbed through intact, normal skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins iv varying degrees, are metabolised primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted in the bile.

  Neomycin sulphate
  The absorption of neomycin from the alimentary tract is poor: Only 3% of an oral dose is absorbed, neomycin is rapidly excreted by the kidneys in the unchanged form. The plasma half-life in healthy adults is approximately 2-3 hours. Oral doses of 3g produce peak plasma concentrations of up to 4 ?g/ml.

• PHARMACEUTICAL PARTICULARS

  Special precaution for storage

  Store in a cool n dry place and avoid exposure to heat. Store below 30?C. Keep out of reach of children.