Canesoral duo approved pi _22feb2011_

CANESORAL DUO – Product Information
CANESORAL DUO
A combination pack containing the following medicines:

CANESORAL Fluconazole Capsule 150 mg CANESTEN Clotrimazole Cream 10 mg/g PRODUCT INFORMATION
NAME OF THE MEDICINE
CANESORAL
Active ingredient: Fluconazole Chemical name: 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol Structural formula:
CANESTEN Clotrimazole Cream
Active ingredient: Clotrimazole Chemical name: 1-(o-chloro-α,α-diphenylbenzyl)Imidazole Structural formula: CANESORAL DUO – Product Information

DESCRIPTION
FLUCONAZOLE
Fluconazole is a white to off-white crystalline powder, which is sparingly soluble in water and saline.
Each CANESORAL fluconazole capsule contains fluconazole 150 mg as the active ingredient.
Other ingredients: gelatin, lactose, maize starch, silicon dioxide, magnesium stearate, sodium lauryl sulfate,
titanium dioxide, TekPrint SW-9008 black printing ink, TekPrint SW-9009 black printing ink.
CLOTRIMAZOLE
Clotrimazole is a colourless, crystalline, weakly alkaline substance, melting point 141°- 145°C, soluble in acetone, chloroform and ethanol and practically insoluble in water. It forms stable salts with both organic and inorganic acids. It is not photosensitive but is slightly hygroscopic, and may be hydrolysed in acid media. CANESTEN clotrimazole cream contains 10 mg/g (1%) of clotrimazole in a vanishing cream base. Other ingredients: sorbitan monostearate, polysorbate 60, cetyl palmitate, cetostearyl alcohol, octyldodecanol, benzyl alcohol and purified water. PHARMACOLOGY
FLUCONAZOLE
Pharmacodynamics
Fluconazole is a member of the bis-triazole class of antifungal agents. Fluconazole is a highly selective
inhibitor of fungal cytochrome P450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is
much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the
accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of
fluconazole. Fluconazole 50 mg daily given up to 28 days has been shown not to affect corticosteroid levels
or adrenocorticotrophic hormone (ACTH) stimulated response in healthy female volunteers. Plasma
oestradiol levels and urinary free cortisol levels were decreased with little effect on plasma testosterone
levels. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not
affect its metabolism.
Pharmacokinetics and Metabolism
Adults: The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is
over 90% compared with intravenous administration. In fasted normal volunteers, peak plasma
concentrations occur between 1 and 2 hours post dose with a terminal plasma elimination half-life of
approximately 30 hours (range 20 to 50 hours). Plasma concentrations are proportional to dose and steady-
state levels are reached within 5-10 days with oral doses of 50-400 mg once daily. Steady-state levels are
approximately 2.5 times the levels achieved with single doses. Administration of loading dose (on day 1) of
twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The
apparent volume of distribution approximates to total body water. Plasma protein binding is low (11 to
12%).
Fluconazole has been found to achieve good penetration into all tissues and body fluids studied. See table
below.
CANESORAL DUO – Product Information
Tissue or Fluid
Tissue (Fluid) : Plasma
Concentration#
# Relative to concurrent concentrations in plasma in subjects with normal renal function
+ Independent of degree of meningeal inflammation
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the
urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The
pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse
relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to
be reduced in patients with impaired renal function (see Dosage and Administration). A 3-hour
haemodialysis session reduces plasma concentration by about 50%.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis.
Children: There are differences in the pharmacokinetics of fluconazole between adults and children, with
children, after the neonatal period, generally having a faster elimination rate and larger volume of
distribution than adults.
Microbiology
Fluconazole administered orally or intravenously was active in a variety of animal models of fungal
infections using standard laboratory strains of fungi.
Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida species. Activity has
been demonstrated in vivo in normal and immunocompromised animals against infections with Candida spp.,
including systemic candidiasis, and in normal animals with Cryptococcus neoformans, including intracranial
infections. One case of cross-resistance of Candida to fluconazole in a patient [not infected with human
immunodeficiency virus (HIV)] previously treated with ketoconazole has been reported. The efficacy of
fluconazole in vivo is greater than would be apparent from in vitro testing against the above mentioned fungi.
Concurrent administration of fluconazole and amphotericin B in infected normal and immunocompromised
mice showed antagonism of the two drugs in systemic infection with Aspergillus fumigatus. The clinical
significance of results obtained in these studies is unknown.

CLOTRIMAZOLE
Microbiology
Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity.
Clotrimazole acts against fungi by inhibiting ergosterol synthesis. Inhibition of ergosterol synthesis leads to
structural and functional impairment of the cytoplasmic membrane.
Pharmacodynamics
Clotrimazole has a broad antimycotic spectrum of action in vitro and in vivo, which includes dermatophytes, yeasts, moulds etc. Under appropriate test conditions, the MIC values for these types of fungi are in the region of less than 0.062-4 (-8) µg/mL substrate. The mode of action of clotrimazole is fungistatic or fungicidal depending on the concentration of clotrimazole at the site of infection. In-vitro activity is limited to proliferating fungal CANESORAL DUO – Product Information

elements; fungal spores are only slightly sensitive.
In addition to its antimycotic action, clotrimazole also acts on Trichomonas vaginalis, gram-positive micro
organisms (Streptococci / Staphylococci), and gram-negative micro organisms (Bacteroides / Gardnerella
vaginalis).
In vitro clotrimazole inhibits the multiplication of Corynebacteria and gram-positive cocci – with the
exception of Enterococci – in concentrations of 0.5-10 µg/mL substrate and exerts a trichomonacidal action
at 100 µg/mL.
Primarily resistant variants of sensitive fungal species are very rare; the development of secondary resistance
by sensitive has so far only been observed in very isolated cases under therapeutic conditions.
Pharmacokinetics
Pharmacokinetic investigations after dermal application have shown that only a small amount of clotrimazole (<2 % of the dose) is absorbed. The resulting peak plasma concentrations of the active ingredient are <10ng/ml (i.e. below the detection limit) and do not lead to measurable systemic effects or side effects. INDICATIONS
CANESORAL DUO is indicated for the treatment of vaginal and vulvovaginal candidiasis. CONTRAINDICATIONS
CANESORAL DUO is contraindicated in patients with known sensitivity to fluconazole, clotrimazole, to
related azole compounds or to any of its excipients.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400
mg per day or higher based upon results of a multiple dose interaction study.
Coadministration of other drugs known to prolong the QT interval and which are metabolised via the enzyme
CYP3A4 such as cisapride, astemizole, pimozide and quinidine is contraindicated in patients receiving
fluconazole (see Precautions – Interactions with Other Medicines).
PRECAUTIONS
Anaphylaxis
Anaphylaxis has been reported in rare instances.
Hepatic Impairment
Fluconazole should be administered with caution to patients with livery dysfunction. Fluconazole has been
associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious
underlying medical conditions. In cases of fluconazole-associated hepatoxicity, no obvious relationship to
total daily dose, duration of therapy, sex or age of the patient has been observed.
Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the
development of more severe hepatic injury. CANESORAL DUO should be discontinued if clinical signs
and symptoms consistent with liver disease develop that may be attributable to fluconazole (see Adverse
Effects).
Renal Impairment
CANESORAL DUO – Product Information

Fluconazole should be administered with caution to patients with renal dysfunction.
Elderly Patients with Renal Impairment
Dosage should be adjusted for elderly patients with renal impairment (see Dosage and Administration).
Skin and Subcutaneous Tissue Disorders
Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic
epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development
of serious cutaneous reactions to many drugs. If rash which is attributable to fluconazole develops in a
patient treated for a superficial fungal infection, CANESORAL should be discontinued. If patients with
invasive/systemic fungal infections develop rashes, they should be monitored closely and CANESORAL
discontinued if bullous lesions or erythema multiforme develop (see Adverse Effects).
QT Interval Prolongation
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the
electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation
and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with
multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant
medications that may have been contributory. Fluconazole should be administered with caution to patients
with these potentially proarrhythmic conditions (see Adverse Effects).
If evidence of local intolerance develops when using the cream, consider withdrawal of the medicine and
institution of appropriate therapy.
Use of CANESTEN clotrimazole cream may reduce the effectiveness and safety of latex products, such as
condoms and diaphragms. This effect is temporary and occurs only during treatment.
CANESTEN clotrimazole cream is not intended for ophthalmic use.
CYP2C9 and CYP3A4 Interactions
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients
who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9
and CYP3A4 should be monitored (see Precautions – Interactions with Other Medicines).
Effect on Fertility
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or
20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly
delayed at 20 mg/kg given orally. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia
and prolongation of parturition were observed in a few dams at 20 and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of stillborn pups and decrease of
neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species
specific oestrogen lowering property produced by high doses of fluconazole. Such a hormone change has
not been observed in women treated with fluconazole (see Pharmacology – Pharmacodynamics).
CANESTEN clotrimazole cream has shown no observed carcinogenicity or mutagenicity in animal studies.
Use in Pregnancy (Category D)
There are no adequate and well controlled studies of fluconazole use in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for three or more months with high dose fluconazole therapy (400 to 800 mg/day) for coccidiomycosis. The relationship between fluconazole use and these events is unclear. Adverse foetal effects have been seen in animals only at high dose levels associated with maternal toxicity. These findings are not considered relevant to fluconazole used at therapeutic doses. Use in pregnancy should be avoided except in patients with severe or potentially CANESORAL DUO – Product Information

life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the
possible risk to the foetus. Controlled clinical studies for CANESTEN clotrimazole cream in pregnant
women do not exist, however epidemiological investigations give no indication that harmful effects on the
mother and child should be anticipated when used during pregnancy.
Australian Categorisation Definition of Category D: Drugs which have caused, are suspected to have caused
or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage.
These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for
further details.
Use in Lactation
Fluconazole has been found in human breast milk at concentrations similar to those in plasma. Although
systemic absorption of clotrimazole following topical or vaginal administration is low, caution should be
exercised when clotrimazole is administered to nursing mothers as there is no information on whether or not
clotrimazole is excreted in breast milk. Hence, the use of CANESORAL DUO in breastfeeding women is not
recommended.
Carcinogenicity and Mutagenicity
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at
doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with
5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of
Salmonella typhimurium and in the mouse lymphoma system. Cytogenetic studies in vivo and in vitro
showed no evidence of chromosomal mutations.
Interactions with Other Medicines
Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP 2C and to a lesser extent
the CYP 3A isoforms. Co-administration of fluconazole with some other drugs metabolised primarily by
these P450 isoforms may result in altered plasma concentrations of these drugs that could change therapeutic
effects and/or adverse event profiles.
Clinically or potentially significant drug interactions have been observed between fluconazole and the
following agents: short acting benzodiazepines, cisapride, coumarin-type anticoagulants, cyclosporin,
hydrochlorothiazide, oral hypoglycaemics, phenytoin, rifampicin, rifabutin, tacrolimus and theophylline.
These are described in greater detail below.
The relevance of the following drug interactions to single-dose fluconazole is unknown. Patients on other
medications should be advised to consult their doctor or pharmacist before starting CANESORAL.
Effects of other medicinal products on fluconazole:

The exposure to fluconazole is significantly increased by the concomitant administration of the following
agent:
Hydrochlorothiazide: Concomitant oral administration of fluconazole 100 mg and hydrochlorothiazide
50 mg for 10 days in normal volunteers resulted in an increase of 41% in Cmax and an increase of 43% in
AUC of fluconazole, compared to fluconazole given alone. Overall the plasma concentrations of fluconazole
were approximately 3.26 to 6.52 µmol/L higher with concomitant diuretic. These changes are attributable to
a mean net reduction of approximately 20% in renal clearance of fluconazole.
The exposure to fluconazole is significantly decreased by the concomitant administration of the following
agent:
Rifampicin: Administration of a single oral dose of fluconazole 200 mg after chronic rifampicin
administration resulted in a 25% decrease in AUC and a 20% shorter half-life of fluconazole in normal
CANESORAL DUO – Product Information

volunteers. Depending on clinical circumstances, an increase of the dose of fluconazole should be
considered when it is administered with rifampicin.
Minor or no significant pharmacokinetic interactions that require no dosage adjustment:
Gastrointestinal Drugs: In fasted normal volunteers, absorption of orally administered fluconazole does not
appear to be affected by agents that increase gastric pH. Single dose administration of fluconazole (100 mg)
with cimetidine (400 mg) resulted in a 13% reduction in AUC and a 21% reduction in Cmax of fluconazole.
Administration of an antacid containing aluminium and magnesium hydroxides immediately prior to a single
dose of fluconazole (100 mg) had no effect on the absorption or elimination of fluconazole.
Effects of fluconazole on other medicinal products:

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of
CYP3A4. In addition to the observed/documented interactions mentioned below, there is a risk of increased
plasma concentration of other compounds metabolised by CYP2C9 and CYP3A4 co-administered with
fluconazole. Therefore caution should be exercised when using these combinations and the patients should
be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation
of fluconazole treatment due to the long half-life of fluconazole.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T1/2
of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is
fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one
week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in systemic
infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and
antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results
obtained in these studies is unknown.
Concomitant use of the following agents with fluconazole is contraindicated:
Cisapride: Fluconazole 200 mg daily increased the AUC and Cmax of cisapride (20 mg four times daily) both
after a single dose (AUC increased 101% and Cmax increased 91%) and multiple doses (AUC increased 192%
and Cmax increased 154%). A significant prolongation in QTc interval was recorded. Cardiac events
including torsades de pointes have been reported in patients receiving fluconazole and cisapride
concomitantly. In most of these cases, the patients appear to have been predisposed to arrhythmias or had
serious underlying illness. The co-administration of fluconazole and cisapride is contraindicated (see
Contraindications).
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the
QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have
been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in
QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that
fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine
when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine
is contraindicated. The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine
should be carefully monitored (see Contraindications).
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of
astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare
occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated (see
Contraindications).
CANESORAL DUO – Product Information

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide
may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is
contraindicated (see Contraindications).
Concomitant use of the following other medicinal products cannot be recommended:
Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This
combination should be avoided.

Interaction of fluconazole with the following agents may result in increased exposure to these drugs. Careful
monitoring and/or dosage adjustment should be considered:
Benzodiazepines (short acting): Studies in human subjects have reported changes in midazolam
pharmacokinetics and clinical effects that are dependent on dosage and route of administration. Single doses
of fluconazole 150 mg resulted in modest increases in midazolam concentrations and psychomotor effects
following oral administration of 10 mg that may not be clinically significant. At doses used to treat systemic
mycoses, fluconazole resulted in substantial increase in midazolam concentrations and psychomotor effects
following oral administration of 7.5 mg, but only modest increases that are not likely to be clinically
significant following intravenous infusion of midazolam 0.05 mg/kg. This effect on midazolam appears to
be more pronounced following oral administration of fluconazole than with fluconazole administered
intravenously. There have been reports of sleepiness and disturbed consciousness in patients taking
fluconazole for systemic mycoses and triazolam. However, in most of these cases the patients had serious
underlying illnesses and/or concomitant therapies that could have contributed to the reported events and a
true fluconazole-triazolam interaction has not been established. If concomitant benzodiazepine therapy is
necessary in patients being treated with fluconazole, consideration should be given to decreasing the
benzodiazepine dosage and monitoring the patient’s response. Fluconazole increases the AUC of triazolam
(single dose) by approximately 50% Cmax with 20-32% and increases the half life by 25-50% due to the
inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine,
amlodipine and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the
systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is
recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the
celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be
necessary when combined with fluconazole.

Cyclosporin: Fluconazole significantly increases the concentration and AUC of cyclosporin. This
combination may be used by reducing the dosage of cyclosporin depending on cyclosporin concentration.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in
serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to
the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that
the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve
healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated
fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on
CYP3A4.
HMG-CoA Reductase Inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is
coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and
simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should
CANESORAL DUO – Product Information

be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is
responsible for most of the angiotensin II-receptor antagonism that occurs during treatment with losartan.
Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of
methadone may be necessary.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Although not specifically studied, fluconazole has the
potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g.
naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related
to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Oral Hypoglycaemic Agents: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycaemic agents tolbutamide, glipizide and glibenclamide were examined in three placebo-controlled
crossover studies in normal volunteers. All subjects received the sulfonylurea alone and following treatment
with fluconazole 100 mg as a single daily oral dose for 7 days. Fluconazole administration resulted in
significant increases in Cmax and AUC of the sulfonylurea. Several subjects in these three studies
experienced symptoms consistent with hypoglycaemia. In the glibenclamide study, several volunteers
required oral glucose treatment. As fluconazole is a potent inhibitor CYP 2C8 and CYP 2C9, it may also
interact with other sulfonylureas (eg. glimepiride and gliclazide) and the thiazolidinediones (eg. pioglitazone
and rosiglitazone), which are metabolised by these enzymes. When fluconazole and sulfonylureas or
thiazolidinediones are coadministered, blood glucose concentrations should be monitored carefully and the
dose of the sulphonylurea adjusted accordingly.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum
phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute
adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The
discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased
metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be
carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been
reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving
rifabutin and fluconazole concomitantly should be carefully monitored.

Saquinavir: Fluconazole increases the AUC of saquinavir and decreases clearance of saquinavir due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage
adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the
metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage
adjustment of sirolimus depending on the effect/concentration measurements.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered
oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers.
Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended
during coadministration.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5
times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant
pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus
levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be
decreased depending on tacrolimus concentration.
CANESORAL DUO – Product Information

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14
days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving
high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be observed
for signs of theophylline toxicity while receiving fluconazole and therapy modified appropriately if signs of
toxicity develop.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids
(e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on
CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with alltrans-retinoid acid
(an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of
pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination
may be used but the incidence of CNS related undesirable effects should be borne in mind.
Warfarin: A single dose of warfarin 15 mg given to normal volunteers, following 14 days of orally
administered fluconazole 200 mg resulted in a 12% increase in the prothrombin time response (area under
the prothrombin time-time curve). One in 13 subjects experienced a two-fold increase in prothrombin time
response. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis,
gastrointestinal bleeding, haematuria and melaena) have been reported in association with increases in
prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of
prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended.
Zidovudine: Fluconazole increases Cmax and AUC of zidovudine, respectively, due to decrease in oral
zidovudine clearance. The half-life of zidovudine was likewise prolonged following combination therapy
with fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Carbamazepine: Azole antifungals may raise carbamazepine plasma concentrations. Since high plasma
concentrations of carbamazepine and/or carbamazepine-10, 11-epoxy may result in adverse effects (e.g.
dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or
plasma concentrations monitored when used concomitantly with fluconazole.
Minor or no significant pharmacokinetic interactions that require no dosage adjustment:
Oral Contraceptives: Oral contraceptives were administered as a single dose both before and after oral
administration of fluconazole 50 mg once daily for 10 days in 10 healthy women. There was no significant
difference in ethinyloestradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The
mean increase in ethinyloestradiol AUC was 6% (range: -47 to 108%) and levonorgestrel AUC increased
17% (range: -33 to 141%).
In a second study, twenty-five normal females received daily doses of 200 mg fluconazole or placebo for
two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole
during one cycle and placebo during the other. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyloestradiol were administered on the final treatment day (day 10) of both cycles.
Following administration of 200 mg of fluconazole, the mean percentage increase in AUC for levonorgestrel
compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyloestradiol
compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly
different from placebo.
In a third study 21 healthy women received 300 mg weekly doses of fluconazole and single doses of
ethinyloestradiol 35 microgram and norethindrone 0.5 mg. AUC of ethinyloestradiol was increased by 24%
(range: 3 to 59%) and AUC of norethindrone was increased by 13% (range: -5 to 36%).
Multiple doses of fluconazole may increase exposure to hormone levels in women taking oral contraceptives
and are unlikely to result in decreased efficacy of the oral contraceptive.
CANESORAL DUO – Product Information

Two-way interactions:

Minor or no significant pharmacokinetic interactions that require no dosage adjustment:
Azithromycin: An open-label, randomised, three-way cross study in 18 healthy subjects assessed the effect
of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of
fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. The estimated
ratio of the mean AUC of fluconazole coadministered with azithromycin to fluconazole administered alone
was 101%. The estimated ratio of the mean AUC of azithromycin coadministered with fluconazole to
azithromycin administered alone was 107%. The estimated ratio of the mean Cmax of fluconazole
coadministered with azithromycin to fluconazole administered alone was 104%. The estimated ratio of the
mean Cmax of azithromycin coadministered with fluconazole to azithromycin administered alone was 82%.
Guidance on the Clinical Management of Drug Interactions
Contraindications
Dose adjustments of
Dose adjustment
No dose adjustment of
fluconazole
and/or monitoring of
fluconazole or other
other drugs
Rifabutin5 Tacrolimus5 Theophylline5 Warfarin6 Zidovudine5 1. Fluconazole blood levels increased
2. Fluconazole blood levels decreased
3. Carefully monitor blood glucose levels
4. Carefully monitor plasma drug levels
5. Carefully monitor patients for signs of toxicity or adverse events
6. Carefully monitor patient’s prothrombin time
There have been no reported drug interactions with CANESTEN clotrimazole cream.
Effects on driving and using machinery
When driving vehicles or operating machinery it should be taken into account that occasionally dizziness or seizures may occur. ADVERSE EFFECTS
Fluconazole and clotrimazole are generally well tolerated. Common adverse events (>1% and <10%) observed during vaginal candidiasis clinical trials and associated with fluconazole. Nervous System Disorders: Headache Gastrointestinal Disorders: Nausea, abdominal pain, diarrhoea, dyspepsia Hepatobiliary Disorders: Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased CANESORAL DUO – Product Information

Uncommon adverse events (>0.1% and <1%) observed during vaginal candidiasis clinical trials associated
with fluconazole.
Eye Disorders: Abnormal vision

Skin and Subcutaneous Tissue Disorders: Pruritus, genital pruritus, rash, erythematous rash, dry skin,
abnormal skin odour, urticaria
Nervous System Disorders: Dizziness, vertigo, hyperkinesia, hypertonia, taste perversion, visual field defect
Gastrointestinal: Constipation, dry mouth, flatulence, vomiting, loose stools

Infections and Infestations: Pharyngitis, herpes simplex
Metabolism and Nutrition Disorders:Anorexia
Psychiatric Disorders: Insomnia, nervousness
Reproductive System and Breast Disorders: Intermenstrual bleeding, dysmenorrhoea, leucorrhoea,
menorrhagia, uterine spasm, vaginal disorder, female sexual dysfunction
Vascular Disorders: Flushing, hot flushes

Hepatobiliary Disorders: Cholestasis, jaundice, bilirubin increased

Renal and Urinary Disorders: Polyuria, renal pain
General Disorders and Administration Site Conditions: Fatigue, hot flushes, malaise, back pain, herpes
simplex, pain, rigors, thirst, asthenia, fever
Musculoskeletal and Connective Tissue Disorders: Back pain, myalgia
Rare adverse events (>0.01% and <0.1%) observed during vaginal candidiasis clinical trials associated with
fluconazole.
Hepatobiliary Disorders: Hepatic toxicity, including rare cases of fatalities. Hepatic failure, hepatocellular
necrosis, hepatitis, hepatocellular damage
Cardiac Disorders: Torsade de pointes, QT prolongation
Post-Marketing Experience
Cardiac Disorders: Torsade de pointes (see Precautions)
Gastrointestinal Disorders: Dyspepsia, vomiting
Hepatobiliary Disorders: Hepatocellular necrosis
Immune System Disorders: Anaphylaxis (including face oedema, angioedema and pruritus)
Investigations: QT prolongation (see Precautions)
Metabolism and Nutrition Disorders: Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia
Nervous System Disorders: Dizziness
CANESTEN clotrimazole cream is generally well tolerated after local application. The following have been
reported infrequently: erythema, stinging, blistering, peeling, oedema, pruritus, urticaria and general
CANESORAL DUO – Product Information
DOSAGE AND ADMINISTRATION
Apply gently to the irritated area – for OVERDOSAGE
The minimal lethal human dose has been not established. There have been reports of overdosage with
fluconazole, and in one case a 42-year-old patient infected with HIV developed hallucinations and exhibited
paranoid behaviour after reportedly ingesting 8,200 mg of fluconazole. The patient was admitted to hospital,
and his condition resolved within 48 hours.
Signs and symptoms are likely to be an extension of those under Adverse Effects.
There is no specific antidote. Treatment is symptomatic and supportive, including respiratory and
cardiovascular function. Monitor for hypokalaemia and elevated liver enzymes; and obtain a full blood
count to monitor for possible thrombocytopenia and agranulocytosis.
Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination
rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%.
There have been no reports of over dosage with CANESTEN clotrimazole cream.
Contact the Poisons Information Centre on 131 126 for advice on the management of an overdose.
PRESENTATION AND STORAGE CONDITIONS
A size 1, white opaque body and white opaque cap, hard gelatin capsule, printed with “FC 150” and “G” on both body and cap in black ink. CANESORAL is available in blister packs of 1 capsule. Store below 25°C. CANESTEN clotrimazole cream is presented in a tube containing 10 mg clotrimazole per gram of cream (1%). NAME AND ADDRESS OF THE SPONSOR
Bayer Australia Limited
ABN 22 000 318 714
Consumer Care Business Group
875 Pacific Highway
Pymble NSW 2073
POISON SCHEDULE OF THE MEDICINE
CANESORAL DUO – Product Information

DATE OF APPROVAL
Approved by the Therapeutic Goods Administration on: 22 February 2011

Source: http://www.canesten.com.au/static/files/Canesoral_Duo_PI_22Feb2011.pdf