4.1. Therapeutic indications

Oral treatment of superficial fungal (e.g. Candida) infections of the oropharynx in adults and paediatric patients 4 months and older.

4.2. Posology and method of administration

For oral administration.

The provided measuring device is equivalent to 122 mg for 5 ml.

For topical treatment of the oropharynx.

Infants: 4 – 24 months: 1.25 ml (¼ measuring spoon, of gel, applied four times a day after meals. Each dose should be divided into smaller portions and the gel should be applied to the affected area(s) with a clean finger. The gel should not be applied to the back of the throat due to possible choking. The gel should not be swallowed immediately but kept in the mouth as long as possible.

Adults and children 2 years of age and older: 2.5 ml (½ measuring spoon; of gel, applied four times a day after meals. The gel should not be swallowed immediately but kept in the mouth as long as possible/.

The treatment should be continued for at least a week after the symptoms have disappeared.

For oral candidosis, dental prostheses should be removed at night and brushed with the gel.

4.3. Contraindications

Hypersensitivity to the active substance(s), other imidazole derivatives or to any of the excipients listed in section 6.1.

In infants less than 4 months of age or in those whose swallowing reflex is not sufficiently developed (see section 4.4).

In patients with liver dysfunction.

Coadministration of the following drugs that are subject to metabolism by CYP3A4 or CYP2C9: (See Section 4.5 Interactions with Other Medicinal Products and Other Forms of Interaction)

- Substrates known to prolong the QT-interval e.g., astemizole, cisapride, dofetilide, mizolastine, pimozide, quinidine, sertindole and terfenadine

- Ergot alkaloids

- HMG-CoA reductase inhibitors such as simvastatin and lovastatin

- Triazolam and oral midazolam

- Warfarin

4.4. Special warnings and precautions for use

Miconazole is systemically absorbed and is known to inhibit CYP2C9 and CYP3A4 (see Section 5.2 Pharmacokinetic Properties) which can lead to prolonged effects of warfarin. Bleeding events, some with fatal outcomes have been reported with concurrent use of miconazole oral gel and warfarin (see Section 4.3 Contraindications, Section 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction and Section 4.8 Undesirable effects).

The label (outer carton and tube) will state: WARNING: Do not use if you are taking warfarin

If the concomitant use of Daktarin and an oral anticoagulant such as warfarin is planned, the anticoagulant effect must be carefully monitored and titrated (see section 4.5).

It is advisable to monitor miconazole and phenytoin levels, if these two drugs are used concomitantly.

In patients using certain oral hypoglycaemics such as sulphonylureas, an enhanced therapeutic effect leading to hypoglycaemia may occur during concomitant treatment with miconazole and appropriate measures must be considered (See Section 4.5 Interactions with Other Medicinal Products and Other Forms of Interaction).

It is important to take into consideration the variability of the maturation of the swallowing function in infants, especially when giving miconazole gel to infants between the ages of 4 – 6 months. The lower age limit should be increased to 5 – 6 months of age for infants who are pre-term, or infants exhibiting slow neuromuscular development.

Choking in infants and young children

Particularly in infants and young children (aged 4 months – 2 years), caution is required, to ensure that the gel does not obstruct the throat. Hence, the gel is not to be applied to the back of the throat. Each dose is to be divided into smaller portions and applied into the mouth with a clean finger. Observe the patient for possible choking. Also due to the risk of choking, the gel must not be applied to the nipple of a breast-feeding woman for administration to an infant.

Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during treatment with Daktarin Sugar Free 2% Oral Gel (see Adverse Reactions). If a reaction suggesting hypersensitivity or irritation should occur, the treatment should be discontinued.

Serious skin reactions (e.g. Toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported in patients receiving Daktarin Sugar Free 2% Oral Gel (see Adverse Reactions). It is recommended that patients be informed about the signs of serious skin reactions, and that use of Daktarin be discontinued at the first appearance of skin rash.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

This medicine contains 23 mg of alcohol (ethanol) in each 2.5 ml dose corresponding to 7.5 mg/g. The amount in each 2.5 ml dose is equivalent to less than 1 ml of beer or 1 ml of wine. The small amount of alcohol in this medicine will not have any noticeable effects.

This medicine contains benzyl benzoate which may cause allergic reactions.

This medicine contains 2.3 picograms of benzyl alcohol per gram. Benzyl alcohol may cause allergic reactions and mild local irritation. Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children. Do not give to your newborn baby (up to 4 weeks old), unless recommended by your doctor. Do not use for more than a week in young children (less than 3 years old), unless advised by your doctor or pharmacist. Ask your doctor or pharmacist for advice if you are pregnant or breast‑feeding. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”). Ask your doctor or pharmacist for advice if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

This medicine contains polysorbate which can cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

When using any concomitant medication consult the corresponding label for information on the route of metabolism. Miconazole can inhibit the metabolism of drugs metabolised by the CYP3A4 and CYP2C9 enzyme systems. This can result in an increase and/or prolongation of their effects, including adverse effects.

Oral miconazole is contraindicated with the coadministration of the following drugs that are subject to metabolism by CYP3A4 and CYP2C (See Section 4.3 Contraindications):

- Substrates known to prolong the QT-interval e.g., astemizole, cisapride, dofetilide, mizolastine, pimozide, quinidine, sertindole and terfenadine

- Ergot alkaloids

- HMG-CoA reductase inhibitors such as simvastatin and lovastatin

- Triazolam and oral midazolam

- Warfarin

When coadministered with oral miconazole the following drugs must be used with caution because of a possible increase or prolongation of the therapeutic outcome and/or adverse events. If necessary, reduce their dosage and, where appropriate, monitor plasma levels:

Drugs subject to metabolism by CYP2C9 (see Section 4.4 Special Warnings and Precautions for Use):

- Oral anticoagulants such as warfarin,

- Oral hypoglycaemics such as sulphonylureas

- Phenytoin

Other drugs subject to metabolism by CYP3A4;

- HIV Protease Inhibitors such as saquinavir;

- Certain antineoplastic agents such as vinca alkaloids, busulfan and docetaxel;

- Certain calcium channel blockers such as dihydropyridines and verapamil;

- Certain immunosuppressive agents: cyclosporin, tacrolimus, sirolimus (= rapamycin)

- Others: carbamazepine, cilostasol, disopyramide, buspirone, alfentanil, sildenafil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, trimetrexate, ebastine and reboxetine.

4.6. Fertility, pregnancy and lactation

Pregnancy

In animals, miconazole has shown no teratogenic effects but is foetotoxic at high oral doses. The significance of this to man is unknown. However, as with other imidazoles, Daktarin Sugar Free 2% Oral Gel should be avoided in pregnant women if possible. The potential hazards should be balanced against the possible benefits.

Breast-feeding

It is not known whether miconazole or its metabolites are excreted in human milk. Caution should be exercised when prescribing Daktarin Sugar Free 2% Oral Gel to nursing mothers.

4.7. Effects on ability to drive and use machines

Daktarin should not affect alertness or driving ability.

4.8. Undesirable effects

Description of selected adverse reactions

Increases in INR and bleeding events such as epistaxis, contusion, haematuria, melaena, haematemesis, haematoma and haemorrhages have been reported in patients treated with oral anticoagulants such as warfarin in association with miconazole oral gel (see sections 4.3, 4.4 and 4.5). Some events had fatal outcomes.

The safety of DAKTARIN Sugar free 2% Oral Gel was evaluated in 111 patients with oral candidiasis or oral mycoses who participated in 5 clinical trials. Of these 111 patients, 88 were adults with oral candidiasis or oral mycoses who participated in 1 randomised, active-controlled, double-blind clinical trial and 3 open-label clinical trials. The other 23 patients were paediatric patients with oral candidiasis who participated in 1 randomised, active-controlled, open-label clinical trial in paediatric patients (aged ≤1 month to 10.7 years). These patients took at least one dose of DAKTARIN Sugar free 2% Oral Gel and provided safety data.

Based on the pooled safety data from these 5 clinical trials (adult and paediatric), the most commonly reported (≥1% incidence) ADRs were nausea (6.3%), product taste abnormal (3.6%), vomiting (3.6%), oral discomfort (2.7%), regurgitation (1.8%), and dry mouth (1.8%). Dysgeusia was reported in 0.9% of patients.

Adult Patients

Based on the pooled safety data from the 4 clinical trials in adults, common ADRs reported included nausea (4.5%), product taste abnormal (4.5%), oral discomfort (3.4%), dry mouth (2.3%), dysgeusia (1.1%), and vomiting (1.1%).

Paediatric Patients

In the 1 paediatric clinical trial, the frequency of nausea (13.0%) and vomiting (13.0%) was very common, and regurgitation (8.7%) was common. As identified through post-marketing experience, choking may occur in infants and young children (See Section 4.3 Contraindications and Section 4.4 Special Warnings and Special Precautions). The frequency, type, and severity of other ADRs in children are expected to be similar to that in adults.

The frequency categories use the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Table A includes all identified ADRs, including those that that have been reported from post-marketing experience.

Table A: Adverse Drug Reactions in Patients Treated with DAKTARIN Sugar free 2% Oral Gel

System Organ Class

Adverse Drug Reactions

Frequency Category

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Not Known

Immune System Disorders

Anaphylactic reaction, Hypersensitivity

Nervous System Disorders

Dysgeusia

Respiratory, Thoracic and Mediastinal Disorders

Choking

Gastrointestinal Disorders

Dry mouth, Nausea, Oral discomfort, Vomiting, Regurgitation

Diarrhoea, Stomatitis, Tongue discolouration

Hepatobiliary Disorders

Hepatitis

Skin and Subcutaneous Tissue Disorders

Angioedema, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Urticaria, Rash. Acute generalised exanthematous pustulosis, Drug reaction with eosinophilia and systemic symptoms, Fixed drug eruption

General Disorders and Administration Site Conditions

Product taste abnormal

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms:

In the event of accidental overdose, vomiting and diarrhoea may occur.

Treatment:

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