INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DAKTARIN® I.V. Solution

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

DAKTARIN^® I.V. Solution

COMPOSITION:
A solution of 10 mg/mL of miconazole in cremophor and water with 0,05% m/v methylparaben and 0,005% m/v propylparaben as preservatives.

PHARMACOLOGICAL CLASSIFICATION:
A 20.2.2 Antimicrobial (Chemotherapeutic) agents. Fungicides.

PHARMACOLOGICAL ACTION:
Miconazole is a synthetic 1-phenethylimidazole derivative. In vitro, low concentrations of miconazole are fungistatic against all Phycomycetes, Ascomycetes and Adelomycetes tested (e.g. Saprolegnia, Candida, Cryptococcus, Aspergillus, Phialophora, Sporotrichum), and fungicidal against Trichophyton mentagrophytes, Trichophyton rubrum, Epidermophyton floccosum. Trichophyton interdigitale and Microsporum canis.
Concentration in the cerebrospinal fluid in one-tenth of the blood concentration of miconazole after intravenous administration and miconazole is hardly excreted at all in the urine.

INDICATIONS:
DAKTARIN I.V. solution is indicated for the treatment of systemic fungal infections caused by Candida spp, Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma spp, Coccidioides immitis, Paracoccidioides brasiliensis.
The results obtained in Aspergillus infections depend on the sensitivity of the strain.

CONTRA-INDICATION:
DAKTARIN I.V. solution is contra-indicated in those patients who have shown hypersensitivity to miconazole.

WARNINGS:
Rapid infusion of DAKTARIN I.V. solution may produce cardiovascular complications, such as tachycardia and arrhythmia. Clinical experience indicates that these are transient and respond to lidocaine.
Infusions of DAKTARIN I.V. solution over periods of 15 minutes or more are well tolerated even by those patients with pre-existing cardiovascular disorders and with cardiovascular reactions to other antifungal agents. During intravenous use liver function must be carefully monitored since histological changes occur in the liver of animals at a dose of 35 mg/kg and this dosage has already been exceeded in administration to man.

DOSAGE AND DIRECTIONS FOR USE:

–	Intravenous Infusion: DAKTARIN I.V. solution should be diluted in physiological saline solution, or alternatively in dextrose 5% and administered by intravenous infusion over a period of 30 to 60 minutes.
–	Adults The doses may vary form 200 mg to 600 mg per single infusion but should not exceed 600 mg. The total daily dosage recommended is 600 to 1800 mg although this may be increased to 3600 mg daily in more severe cases. The recommended amount of fluid per infusion –preferably physiological saline, administered by I.V. catheter –is 200 mL including the DAKTARIN I.V. solution.
–	Children A daily dose of 15 to 20 mg/kg body mass is recommended with maximum of 15 mg/kg body mass per infusion.
–	Other uses: Intrathecally (undiluted) –2 mL daily.
	Treatment should continue until cultures show a negative result.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects encountered with DAKTARIN I.V. solution are phlebitis, pruritis, nausea and vomiting, febrile reactions, rash, drowsiness, diarrhoea, anorexia and flushes. Using a subclavian catheter or changing the site of infusion every 48 to 72 hours reduces the incidence and severity of phlebitis. Nausea and vomiting can be prevented by administering an antihistamine or antiemetic agent prior to infusion, by reducing the dose, by slowing the rate of infusion and by avoiding administration at meal times. Febrile reactions may be due to drug hypersensitivity or to lysis of the fungal organism.
Hyperlipaemia and rouleaux formation on blood smears, which may occur, are reversible upon discontinuation of treatment.
DAKTARIN I.V. solution should not be administered by direct intravenous injection but only by infusion.
Avoid combination with other antifungal drugs, such as amphotericin B as these agents in combination mutually reduce antifungal activity. The infusion of DAKTARIN I.V. solution in large amounts of fluids may produce a decrease in haemoglobin, haematocrit and serum sodium.
Miconazole treatment may result in microsomal enzyme induction. In patients who depend on critically dosed drugs, such as anti-coagulants or hypoglycemic drugs, the effects of these drugs should be carefully titrated during miconazole treatment. Reductions of the doses of these concomitant drugs may be indicated.

PRECAUTIONS:
Reproduction studies in rats and rabbits have revealed no evidence of impaired fertility or harm of the foetus due to miconazole. There is, however, no data on the use of the medicine in pregnant women and thus DAKTARIN I.V. solution should be used in pregnant women only when in the physician's opinion the benefits outweigh the risk.
Haematological and biochemical controls are recommended since the infusion of large amounts of fluids may produce a decrease in haemoglobin, haematocrit and serum sodium, in addition, hyperlipidaemia and aggregation of erythrocytes or rouleaux formation may be impaired. These effects are reversible on discontinuation of treatment but are usually not an indication that treatment should be discontinued. The possibility of bone marrow depression cannot be excluded.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
At too high doses, loss of appetite, nausea and vomiting may occur. In such instances, the daily dose should be reduced to a level where these side-effects no longer occur.
Patients should be carefully monitored for ventricular tachyarrhythmias an d for possible bone marrow depression and hepatic toxicity. If arrhythmias occur, the drug of choice would be lidocaine and possible the infusion of calcium.

IDENTIFICATION:
DAKTARIN I.V. solution is a clear, slightly yellow, opalescent solution.

PRESENTATION:
DAKTARIN I.V. solution is supplied in 20 mL glass ampoules in packs of 5.

STORAGE INSTRUCTIONS:
Store below 25°C, but do not freeze or refrigerate.
Keep out of reach of children.

REGISTRATION NUMBER:
L/20.2.2/179 (Act 101/1965)

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Cilag A division of
Janssen Pharmaceutica (Pty) Ltd.,
(Reg. No. 80/11122/07)
15th Road, Halfway House 1685

© JANSSEN PHARMACEUTICAA (Pty) Ltd

DATE OF PUBLICATION:
27 March, 1980.

                        Code No.: 022097
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