Data Sheet

DAKTARIN^®

miconazole 2% Oral Gel

Presentation

A white, homogenous, orange-flavoured oral gel containing miconazole 20 mg/g. The other ingredients are glycerol, purified water, pregelatinised potato starch, ethanol, polysorbate 20, sodium saccharin, orange flavour, and cocoa flavour.

Uses

Actions

Miconazole possesses an antifungal activity against the common dermatophytes and yeasts as well as an antibacterial activity against certain gram-positive bacilli and cocci. Its activity is based on the inhibition of the ergosterol biosynthesis in fungi and the change in the composition of the lipid components in the membrane, resulting in fungal cell necrosis.

Pharmacokinetics

Absorption

The oral bioavailability is low (25-30%) because there is little absorption of miconazole from the intestinal tract.

Miconazole is systemically absorbed after administration as the oral gel. Administration of 60 mg dose of DAKTARIN Oral Gel results in peak plasma concentrations of 31-49 ng/mL, occurring approximately two hours post-dose.

Distribution

Absorbed miconazole is bound to plasma proteins (88.2%), primarily to serum albumin and red blood cells (10.6%).

Metabolism and Elimination

The absorbed portion of DAKTARIN Oral Gel is largely metabolized; less than 1% of the administered dose is excreted unchanged in the urine. The terminal plasma half-life is 20-25 hours in most patients. The elimination half-life of miconazole is similar in any renally impaired patient. Plasma concentrations of miconazole are moderately reduced (approximately 50%) during hemodialysis.

Indications

DAKTARIN oral gel is indicated for the treatment of clinically significant oral and gastrointestinal candidiasis.

Dosage and Administration

Infants: For infants 6-24 months, one quarter (1/4) of a measuring spoon* of gel four times daily, or 20 mg/kg/day is recommended.

Children (2years of age and older) and Adults: Half (1/2) a measuring spoon* of gel four times daily.

*A measuring spoon (5 mL) is provided with the gel. One spoonful contains approximately 124 mg of miconazole. All spoonful dose volumes should be administered with this spoon.

DAKTARIN oral gel should be placed on the tongue and kept in mouth for as long as possible before swallowing. When treating infants and younger children it is recommended that the measured dose of gel be given in several portions in the front of the mouth. Avoid dosing to the back of the throat to prevent obstruction. With oral thrush in elderly patients where a contributing cause is the dental prosthesis it is recommended that DAKTARIN oral gel be applied directly to the dentures in the evening and left on overnight. The treatment should be continued for at least one week after the symptoms have disappeared and generally until all clinical and mycological laboratory tests no longer indicate that active fungal infection is present.

Contraindications

DAKTARIN Oral Gel is contraindicated in the following situations:

• In patients with a known hypersensitivity to miconazole or to any of the other ingredients of the gel.
• In infants less than 6 months of age or in those whose swallowing reflex is not yet sufficiently developed.
• In patients with liver dysfunction.
• Co-administrating of the following drugs that are subject to metabolism by CYP3A4 (see Interactions):
  • Substrates known to prolong the QT-interval eg. Astemizole, bepridil, cisapride, dofetilide, halofantrine, mizolastine, pimozide, quinidine, sertindole and terfenadine.
  • Ergot alkaloids.
  • HMG-CoA reductase inhibitors such as simvastatin and lovastatin.
  • Triazolam and oral midazolam.

Warnings and Precautions

If the concomitant use of DAKTARIN oral gel and anticoagulants such as warfarin is envisaged, the anticoagulant effect should be carefully monitored and titrated. (see Interactions)

It is advisable to monitor miconazole and phenytoin levels, if they are used concomitantly.

In patients using certain oral hypoglycaemic such as sulfonylureas, an enhanced therapeutic effect leading to hypoglycaemia may occur during concomitant treatment with miconazole and appropriate measures should be considered (see Interactions).

Pregnancy and Lactation

Although there is no evidence that miconazole is embryotoxic or teratogenic in animals, potential hazards of prescribing these medicines during pregnancy should always be weighed against the expected therapeutic benefits.

There are no data available on the excretion of miconazole in human milk; therefore caution should be exercised when breastfeeding women are using DAKTARIN.

Effects on ability to drive and use machines

DAKTARIN does not affect alertness or driving ability.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation; single and repeated dose toxicity, genotoxicity and toxicity to reproduction.

Adverse Effects

In a randomized, active-controlled, open-labelled trial of 47 paediatric patients, 0-10.7 years of age with oral candidiasis due to various predisposing conditions, efficacy and safety of DAKTARIN Oral Gel were compared to nystatin suspension. The adverse drug reactions reported for ≥ 1% of patients in either treatment was continued for 3 days after symptoms had disappeared.

Table 1: Adverse Drug Reactions Reported for ≥ 1% of Patients in Either Treatment Group in a Randomized, Active-controlled, Open-label Clinical Trial of DAKTARIN

Note: A dash indicates that adverse reaction was not reported by patients in the specified treatment group.

Postmarketing Experience

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience DAKTARIN Oral Gel are presented below. The adverse drug reactions are presented by system/organ class, and are ranked by frequency, using the following convention:

Very common ≥10%;
Common ≥1% to <10%;
Uncommon ≥0.1% to <1%;
Rare ≥0.01% to <0.1%;
Very Rare <0.01%.

The frequency provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare:  Allergic conditions, including angioneurotic oedema and anaphylactic reactions.

Respiratory, thoracic and mediastinal disorders

Vary rare:  Choking (see Contraindications).

Gastrointestinal system disorders

Very rare:  Nausea, vomiting and diarrhoea, anorexia.

Hepatobiliary disorders

Very rare: Hepatitis.

Skin and subcutaneous disorders

Very rare: Lyell syndrome (Toxic Epidermal Necrolysis), Stevens Johnson syndrome, urticaria, rash.

Interactions

• Miconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A4 and 2C9 enzyme systems. This can result in an increase and/or prolongation of the effects, including adverse effects of these drugs.
• Miconazole may increase the anticoagulant effect of coumarin derivatives (e.g. warfarin). Patients taking coumarin anticoagulants who are given DAKTARIN oral gel should be monitored for anticoagulant effect and the dosage of the coumarin derivative adjusted, if necessary.
• Similarly miconazole can potentiate the effect of oral hypoglycaemics such as sulfonylureas, so that a reduction of their dosage may be needed. Miconazole slows the metabolism of phenytoin and cyclosporine, tacrolimus and sirolimus. The dosage of these medicines may need to be reduced in patients using DAKTARIN oral gel.
• The metabolism of terfenadine, astemizole, triazolam, oral midazolam, quinidine, pimozide, bepridil, halofantrine, sertindole and CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin and cisapride may be inhibited by miconazole. These medicines should, therefore, not be used by patients receiving DAKTARIN Oral Gel. (see Contraindications).
• Antagonism between miconazole and amphotericin B has been reported in vitro and in vivo. In studies miconazole and amphotericin combination were also shown to be antagonistic in antifungal activity against Candida albicans.
• HIV protease inhibitors (such as saquinavir): In vitro inhibition of the metabolism of saquinavir has been demonstrated. Therefore, the dosage may need to be reduced in patients receiving DAKTARIN oral gel. However, clinically relevant interactions between oral miconazole and, indinavir and ritonavir, are not expected.
• Antineoplastic agents: Miconazole, when adminstered orally, may inhibit the metabolism of vinca alkaloids, busulfan and docetaxel resulting in elevation of plasma concentration. Dosage adjustment may be required in these instances.
• CYP3A4-metabolised calcium channel blockers (such as dihydropyridines and verapamil): There is the potential for increased plasma concentrations of these drugs when administered concomitantly with oral miconazole. Dosage adjustments may be required in these instances.
• Carbamazepine, cilostasol, disopyramide, buspirone, alfentanil, sildenafil, alprazolam, intravenous midazolam, rifabutin, methylprednisolone and trimetrexate: Miconazole, when administered orally, may alter the metabolism of these drugs resulting in elevation of plasma concentration. Dosage adjustment may be required in these instances.
• Ergot alkaloids.

Overdosage

Treatment

Treatment is symptomatic and supportive. A specific antidote is not available.

In the event of accidental ingestion of large quantities of DAKTARIN Oral Gel, an appropriate method of gastric emptying may be used, if considered necessary (see Interactions)

Pharmaceutical Precautions

Store below 30°C.

Medicine Classification

Restricted Medicine

Package Quantities

DAKTARIN Oral Gel is supplied in 40 g tubes with a measuring spoon.

Name and Address

Janssen-Cilag Pty Ltd, PO Box 9222, Newmarket, Auckland, New Zealand

Tel: (09) 524 5012

Fax: (09) 523 1646

Date of Preparation

08 July 2005