miconazole
DAKTARIN
Oral Gel
PRODUCT INFORMATION
[
Miconazole, 1-(2(2,4-dichlorophenyl)-2-(2,4-dichlorophenyl)methoxy]ethyl)-1H-imidazole, is a synthetic 1- phenethyl-imidazole derivative. It is white, microcrystalline powder, practically insoluble in water and slightly soluble in polyethoxylated castor oil (Cremophor EL) (1%) and ethanol (10%).
CAS-22916-47-8 C18H14Cl4N2O MW: 416.14 DAKTARIN Oral Gel contains miconazole base 2% - white homogenous gel with orange taste. It also contains glycerol, purified - water, pregelatinised potato starch, ethanol, polysorbate 20, saccharin sodium, cocoa flavour, orange flavour.
Miconazole has shown fungistatic activity, in vitro, against a number of fungi.
Miconazole appears to act on the fungal cell wall membranes inducing permeability changes, which alter the ionic macromolecular composition of the affected cells by the inhibition of the ergosterol biosynthesis in fungi. The result is fungal cell necrosis.
DAKTARIN Oral Gel has a low bioavailability in man (25-30%) compared with intravenous administration because of the limited absorption of miconazole from the gastrointestinal 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.
1 DAKTARINGL(060210)API.doc
Absorbed miconazole is bound to plasma proteins (88.2%), primarily to serum albumin and red blood cells (10.6%).
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.
DAKTARIN Oral Gel is indicated for the treatment of clinically significant oral candidiasis.
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-administration of the following drugs that are subject to metabolism by CYP3A4 (see
Interactions with other drugs):
Substrates known to prolong the QT-interval e.g. 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.
No known cardiac or renal complications have been reported after oral administration of miconazole. Administration of DAKTARIN Oral Gel has been shown to induce mild side effects (see "Adverse Reactions") but no haematological or biochemical abnormalities have been reported. Prolonged use of miconazole may result in superinfection from non-susceptible organisms. If superinfection occurs, the sensitivity of the organism should be determined to decide the most appropriate therapy. If the concomitant use of DAKTARIN and anticoagulants such as warfarin is envisaged, the anticoagulant effect should be carefully monitored and titrated. 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 with other drugs)
DAKTARIN Oral Gel may be used in children and infants over the age of 6 months suffering from oral candidiasis. Caution is required when administering DAKTARIN Oral Gel to infants and younger children, to ensure the throat does not become obstructed by the gel (see Dosage and Administration).
Category A. Although there is no evidence that miconazole is embryotoxic or teratogenic in animals, potential hazards of prescribing DAKTARIN Oral Gel during pregnancy should always be weighed against the expected therapeutic benefits.
There is no information whether miconazole or its metabolites are excreted in breast milk. Therefore, miconazole is not recommended for nursing mothers unless its use is considered essential or alternative- feeding arrangements can be made for the baby.
DAKTARIN does not affect the alertness. However, it may affect the ability to focus the eyes. Patients should be warned not to drive or operate machinery if affected.
Effect of DAKTARIN Oral Gel on other drugs
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.
Coumarin-like drugs: Miconazole can increase the oral anticoagulant effect of coumarin derivatives such as warfarin. If co-administered with DAKTARIN, the dosage of such drugs should be reduced if necessary.
Miconazole slows the metabolism of cyclosporine, tacrolimus and sirolimus (also known as rapamycin). The dosage of these drugs may need to be reduced in patients using DAKTARIN Oral Gel.
The metabolism of terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, dofetilide, quinidine, pimozide, bepridil, halofantrine, sertindole and CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin may be inhibited by miconazole. These drugs, therefore, should not be used by patients receiving DAKTARIN Oral Gel.
Antagonism between miconazole and amphotericin B has been reported in vitro and in vivo. In this study miconazole and amphotericin combination were 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 administered 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 probably 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.
Oral hypoglycaemics such as sulfonylureas (CYP2C9), phenytoin (CYP2C9), carbamazepine, cilostasol, disopyramide, buspirone, alfentanil, sildenafil, alprazolam, brotizolam, intravenous midazolam, rifabutin, methylprednisolone trimetrexate, ebastine and reboxetine. 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.
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 group are presented in Table 1. Patients were examined daily and 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 | ||
|---|---|---|
| System/Organ Class Adverse Drug Reaction | DAKTARIN oral gel (n=23) % | Nystatin suspension (n=24) % |
| Overall adverse reactions Gastrointestinal Disorder Nausea Regurgitation of food Vomiting | 34.8 3 (13%) 2 (8.7%) 3 (13%) | 8.3 1 (4.3%) 1 (4.3%) --- |
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 with 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.
General disorders
Very rare Malaise, chills and difficulty in accommodation.
Half (1/2) a measuring spoon * of gel four times a day.
One quarter (1/4) of a measuring spoon * of gel four times a day is recommended. * 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 dropped on the tongue and kept in the 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 prostheses, it is recommended that in addition to application to the mouth, DAKTARIN Oral Gel be applied directly to the dentures in the evening, left on overnight, and washed off before the dentures are put back in the morning. Generally treatment should be continued until all clinical and mycological laboratory tests no longer indicate that active fungal infection is present. It is recommended that treatment should continue for at least a week after the symptoms have disappeared.
In the event of accidental dosage, vomiting and diarrhoea may occur. Accidental ingestion of large quantities of Daktarin may have clinically relevant implications for patients concomitantly using medication metabolised by cytochrome P450 subsystems 3A4 and/or 2C9 (see Interactions with other drugs). Treatment of overdose is symptomatic and supportive. A specific antidote is not available. For the latest treatment advice, contact the Poisons Information Centre on 131126 in Australia or 0800 764 766 in New Zealand.
DAKTARIN Oral Gel supplied in 15 g and 40 g tubes each with a measuring spoon.
DAKTARIN Oral Gel should be stored below 30oC.
Johnson & Johnson Pacific 45 Jones Street Ultimo NSW 2007 Australia
Date of TGA approval: 08 March 2006 Amended November 2007