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TRICAN
CAPSULES

DIFLUCAN
SUSPENSION

TRIFLUCAN I.V.
INJECTABLE SOLUTION FOR INFUSION

Composition
Trican Capsules
Each capsule contains

Active Ingredient
Fluconazole 50 mg, 100 mg, 150 mg, or 200 mg.

Other Ingredients
Lactose monohydrate starch, anhydrous colloidal silica, magnesium stearate and sodium lauryl sulfate.

Diflucan Suspension
Each 5 ml contains:

Active Ingredient
Fluconazole 50 mg or 200 mg

Other Ingredients
Sucrose (2.88 g per 50 mg dose in 50 mg/5 ml or 2.73 g per 200 mg dose in 200 mg/5 ml), natural orange
flavor, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, xanthan gum, colloidal silicon dioxide,
titanium dioxide.

Triflucan I.V. Injectable Solution for Infusion

Each ml contains:

Active Ingredient
Fluconazole 2 mg

Other Ingredients
Sodium chloride, water for injection.

Mechanism of Action
Pharmacotherapeutic group: Triazole derivatives, ATC code J02AC.

Fluconazole, a triazole antifungal agent, is a potent and selective inhibitor of fungal enzymes necessary for
the synthesis of ergosterol.

Pharmacodynamics
Both orally and intravenously administered fluconazole are active in a variety of animal fungal infection
models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp,
including systemic candidiasis and in immunocompromised animals; with Cryptococcus neoformans, including
intracranial infections; with Microsporum spp; and with Trichophyton spp.
Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with
Blastomyces dermatitidis; with Coccidioides immitis, including intracranial infection; and with Histoplasma
capsulatum in normal and immunosuppressed animals.

Israel, Diflucan Trican Triflucan, 07 August 2011 1

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often
inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal
therapy.

Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50 mg daily given up to
28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in
females of child-bearing age. Fluconazole 200 to 400 mg daily has no clinically significant effect on endogenous
steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate
that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Pharmacokinetics
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral
routes. After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability)
are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by
concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-
dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to
dose. Ninety percent steady-state levels are reached by day 4-5 with multiple once daily dosing.
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 (11-12%).
Fluconazole achieves good penetration into all body fluids studied. The levels of fluconazole in saliva and
sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the cerebrospinal
fluid (CSF) are approximately 80% of the corresponding plasma levels.
High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum,
epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once
daily, the concentration of fluconazole after 12 days was 73 g/g and 7 days after cessation of treatment the
concentration was still 5.8 g/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum
corneum on day 7 was 23.4 g/g and 7 days after the second dose was still 7.1 g/g.
Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 g/g in healthy and
1.8 g/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy.
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine
as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of
circulating metabolites.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis and
once daily dosing for all other indications.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes.
A study compared the saliva and plasma concentrations of a single fluconazole 100 mg dose administered in
an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing, or in a capsule. The
maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion,
and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after
ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in
saliva was significantly greater after the suspension compared to the capsule. There was no significant
difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.

Pharmacokinetics in Children
In children, the following pharmacokinetic data have been reported:

Age Studied Dose (mg/kg) Half-life (hours) AUC (mcg.h/ml)

11 days – 11 months Single-IV 3mg/kg 23 110.1
9 months- 13 years Single-Oral 2mg/kg 25.0 94.7
9 months- 13 years Single–Oral 8mg/kg 19.5 362.5
5 years – 15 years Multiple-IV 2mg/kg 17.4* 67.4*
5 years – 15 years Multiple-IV 4mg/kg 15.2* 139.1*
5 years – 15 years Multiple-IV 8mg/kg 17.6* 196.7*
Mean Age 7 years Multiple-Oral 3mg/kg 15.5 41.6

*Denotes final day

In premature newborns (gestational age around 28 weeks), intravenous administration of fluconazole of 6mg/kg
was given every third day for a maximum of five doses while the premature newborns remained in the intensive
care unit. The mean half-life (hour) was 74 (range 44-185) on day 1, which decreased with time to a mean of 53

Israel, Diflucan Trican Triflucan, 07 August 2011 2

(range 30-131) on day 7 and 47 (range 27-68) on day 13.

The area under the curve (mcg.h/ml) was 271 (range 173-385) on day 1, which increased with a mean of 490
(range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13.

The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1, which increased with time to a mean
of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral
dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/ml and
occurred at 1.3 hours post dose. The mean AUC was 7.64 ± 20.3 mcg ·h/ml, and the mean terminal half-life was
46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal
young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition,
creatinine clearance (74ml/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the
fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of
younger volunteers. Thus, the alteration of fluconazole disposition in elderly appears to be related to reduced
renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine
clearance compared with the predicted half-life - creatinine clearance curve derived from normal subjects and
subjects with varying degrees of renal insufficiency indicated that 21 to 22 subjects fell within the 95%
confidence limit of the predicted half-life - creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared
with normal young male volunteers are due to the decreased kindney function that is expected in the elderly.

Indications
Trican Capsules
Diflucan Suspension

Therapy may be instituted before the results of the cultures and other laboratory studies are known;
however, once these results become available, anti-infective therapy should be adjusted accordingly.

1. Cryptococcosis, including cryptococcal meningitis. Normal hosts and patients with AIDS, organ transplants or
other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to
prevent relapse of cryptococcal disease in patients with AIDS.
2. Systemic candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal
infection. These include infections of the peritoneum, endocardium, pulmonary and urinary tracts. Patients with
malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors
predisposing to candidal infections may be treated.
3. Mucosal candidiasis. These include oropharyngeal, esophageal, non-invasive bronchopulmonary infections,
candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and
patients with compromised immune function may be treated.
4. Vaginal candidiasis, acute or recurrent.
5. Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and candida infections
where topical therapy is considered inappropriate due to the site, severity or extent of the infection.

Triflucan I.V. Injectable Solution for Infusion

1. Cryptococcosis, as detailed above.
2. Systemic candidiasis, as detailed above.
3. Mucosal candidiasis, as detailed above.

Contraindications
Fluconazole should not be used in patients with known hypersensitivity to the drug, any of the inert ingredients
or to related triazole compounds.
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. Co-administration of other drugs
known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride,

Israel, Diflucan Trican Triflucan, 07 August 2011 3

astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving fluconazole (see
sections: Special Warnings and Drug Interactions).

Warnings
Fluconazole should be administered with caution to patients with liver 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 hepatotoxicity, no
obvious relationship total daily dose, duration of therapy, sex or age of patient has been observed.
Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients
who develop abnormal liver function tests during fluconazole therapy should be monitored for the development
of more severe hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with
liver disease develop that may be attributable to fluconazole.

In rare cases, as with other azoles, anaphylaxis has been reported.

In patients with renal function impairment, a reduction in dosage is recommended (See Dosage and
Administration). Serum creatinine concentration should be evaluated periodically.
Fluconazole should be administered with caution to patients with renal dysfunction (see also Dosage and
Administration).
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully
monitored (see Drug Interactions).

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.

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 metabolised through CYP2C9 and
CYP3A4 should be monitored (see section Drug Interactions).

Diflucan capsules contain lactose and should not be given to patients with rare hereditary problems of
galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Diflucan powder for oral suspension contains sucrose and should not be used in patients with hereditary
fructose, glucose/galactose malabsorption and sucrase-isomaltase deficiency.

Mutagenicity
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S.
typhimurium, and in the mouse lymphoma L5178Y system.
Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in
vitro (human lymphocytes exposed to fluconazole at 1000 g/ml) showed no evidence of chromosomal
mutations.

Carcinogenicity
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 2-7 times the recommended human dose). Male rats treated with
5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.

Teratogenic Effects
Pregnancy Category C:
Single 150 mg tablet use for Vaginal Candidiasis:
There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not
suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.

Pregnancy Category D:
All other indications:

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A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero
to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported
anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient
becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus.

Human Data
Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated
with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A
few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers
received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The
features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft
palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are
similar to those seen in animal studies.

Animal Data
Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10,
and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels
(approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg
(approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed.

In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain
was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg;
increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were
observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8
times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities
included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the
inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy,
organogenesis, and parturition

Impairment of 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
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 mg/kg (approximately 5-15 times the recommended human dose) and 40 mg/kg,
but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born
pups and decrease of neonatal survival at these dose levels.
The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by
high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
(see section Pharmacodynamics).

Use in Pregnancy
Data from several hundred pregnant women treated with doses <200 mg/day of fluconazole, administered as a
single or repeated dosage in the first trimester, show no undesired effects in the fetus
There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3
or more months with high dose (400 to 800 mg/day) fluconazole therapy for coccidioidomycosis. The
relationship between fluconazole use and these events is unclear. Adverse fetal effects have been seen in
animals only at high dose levels associated with maternal toxicity.
There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal
pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging
from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethality in rats was
increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of
lowered estrogen on pregnancy, organogenesis and parturition.

There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do
not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few
published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to
high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported
anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient
becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus.

Israel, Diflucan Trican Triflucan, 07 August 2011 5

Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal
infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.

Use in Breastfeeding
Fluconazole is found in human breast milk at concentrations similar to maternal plasma concentration. Caution
should be exercised when DIFLUCAN is administered to a nursing woman.

Use in Pediatrics
An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of
oropharyngeal candidiasis in children 6 months to 13 years of age.
The use of fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida
infections is supported by the efficacy shown for these indications in adults and by the results from several small
noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children have established a
dose proportionality between children and adults.
In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia,
the effectiveness of fluconazole was similar to that reported for the treatment of candidemia in adults. Of 17
subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had
a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but 2 of these
patients relapsed at 10 and 18 days, respectively, following cessation of therapy.
The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 4 of 5 children
treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis.
There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in
children.
The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years who
received doses ranging from 1 - 15 mg/kg body weight/day for 1 - 1,616 days.
Efficacy of fluconazole has not been established in infants less than 6 months of age. A small number of
patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.

Effects on Ability to Drive and Use Machines

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures
may occur.

Undesirable Effects
Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal
and hematological function test results and hepatic abnormalities (see section Warnings) have been observed
during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment
is uncertain.

The following undesirable effects have been observed and reported during treatment with fluconazole with the
following frequencies: 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), not known (cannot be estimated form the available data).

System Organ Class Frequency Undesirable effects

Blood and the lymphatic system Rare Agranulocytosis, leukopenia, neutropenia,
disorders thrombocytopenia
Immune system disorders Rare Anaphylaxis, angioedema
Metabolism and nutrition disorders Rare Hypertriglyceredemia, hypercholesterolemia,
Hypokalemia
Psychiatric disorders Uncommon Insomnia, somnolence
Nervous system disorders Common Headache
Uncommon Seizures, dizziness, paraesthesia, taste perversion
Rare Tremor
Ear and labyrinth disorders Uncommon Vertigo

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 Cardiac disorders Rare Torsade de pointes, QT prolongation
Gastrointestinal disorders Common Abdominal pain, diarrhea, nausea, vomiting
Uncommon Dyspepsia, flatulence, dry mouth
Hepato-biliary disorders Common Alanine aminotransferase increased, aspartate
aminotransferase increased, blood alkaline
phosphatase increased
Uncommon Cholestasis, jaundice, bilirubin increased
Rare Hepatic toxicity, including rare cases of fatalities,
Hepatic failure, hepatocellular necrosis, hepatitis,
hepatocellular damage
Skin and subcutaneous tissue Common Rash
disorders Uncommon Pruritus, urticaria, increased sweating, drug
eruption
Rare Toxic epidermal necrolysis, Stevens-Johnson
syndrome, acute generalised exanthematous-
pustulosis, dermatitis exfoliative, face edema,
alopecia
Musculoskeletal, connective tissue Uncommon Myalgia
and bone disorders
General disorders and Uncommon Fatigue, malaise, asthenia, fever
administration site conditions

Pediatric Population

The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical
trials are comparable to those seen in adults.

Precautions
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
severe cutaneous reactions to many drugs. In patients with serious underlying disease (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome.
If a rash develops in a patient treated for a superficial fungal infection which is considered attributable to
fluconazole, further therapy with this agent should be discontinued.
If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and
fluconazole discontinued if bullous lesions or erythema multiforme develop.
There have been reports of cases of superinfection with candida species other than C. Albicans, which are
often inherently not susceptible to fluconazole (e.g. Candida Krusei). Such cases may require alternative
antifungal therapy.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities
of hepatic, renal, hematological and other biochemical function tests have been observed during treatment with
fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

Diflucan Suspension
Each 5 ml of Diflucan Suspension 50 mg/5ml and Diflucan Suspension 200mg/5ml contains about 2.88 g and
2.73 g sucrose, respectively. Therefore caution should be exercised when administering this product to
diabetics.

Drug Interactions
Concomitant use of the following other medicinal products is contraindicated:

Cisapride: There have been reports of cardiac events including Torsade de Pointes in patients to whom fluconazole
and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and
cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of

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QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section
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 (see section
Contraindications). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine
should be carefully monitored.

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 section
Contraindications).

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
section Contraindications).

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may
result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare
occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see
section Contraindications)

Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death.
Coadministration of fluconazole and erythromycin is contraindicated (see section Contraindications).

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on fluconazole

Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to

healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this
magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant
diuretics.

Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a
20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose
should be considered.

The effect 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 metabolized 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 (See section Contraindications).

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ 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.

Israel, Diflucan Trican Triflucan, 07 August 2011 8

 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.

Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin
administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events
(bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with
increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in
patients receiving coumarin-type anticoagulants should be carefully moniored. Dose adjustment of warfarin may be
necessary.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of
a single 1200 mg oral dose of azitromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as
well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic
interaction between fluconazole and azithromycin.

Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial
increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more
pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If
concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration
should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases
t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum

carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage
adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium Channel Blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil
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.

Oral 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.

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.

Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed
using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study,
while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively.
Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined
oral contraceptive.

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.

Israel, Diflucan Trican Triflucan, 07 August 2011 9

 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 be
observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA
reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible
for most of the angiotensin Il-receptor antagonism which 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: The Cmax and AUC of flurbiprofen were increased by 23% and 81%,
respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly,
the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%,
respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration
of racemic ibuprofen alone.
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.

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 for theophylline toxicity should be observed for
signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately if signs of
toxicity develop.

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 with approximately 50%, Cmax with approximately
55% and decreases clearance of saquinavir with approximately 50% 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.

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.

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.

Israel, Diflucan Trican Triflucan, 07 August 2011 10

 Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-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.

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an
approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by
approximately 128% 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.

Vorizonazole: (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400
mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h
for 4 days) to 6 healthy male subjects resulted in an increase in C, and AUC, of voriconazole by an average of
57% (90% C1: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8
healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or
diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not
recommended

Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or
following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole
absorption occurs .

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted,
but such interactions may occur.

Dosage and Administration

Note: in the dosing instructions below, the daily dose of fluconazole is the same for oral (tablets and
suspension) and intravenous administration since oral absorption is rapid and almost complete.
The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Most cases of
vaginal candidiasis respond to single dose therapy.
Therapy for those types of infections requiring multiple dose treatment should be continued until clinical
parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of
treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually
require maintenance therapy to prevent relapse.

Administration of Triflucan I.V. Injectable Solution for Infusion

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.

Triflucan injection is intended for intravenous infusion only.

Fluconazole may be administered by intravenous infusion at a rate not exceeding 10 ml/min, the route
being dependant on the clinical state of the patient.
On transferring from the intravenous to the oral route or vice versa, there is no need to change the daily dose.
Triflucan is formulated in 0.9% sodium chloride solution, each 200 mg (100 ml bottle) containing 15 mmol each
of Na+ and Cl-. Because fluconazole is available as a dilute saline solution, in patients requiring sodium or fluid
restriction, consideration should be given to the rate of fluid administration.

Use In Adults
Cryptococcal Meningitis and Cryptococcal Infections at Other Sites. The usual dose is 400 mg on the first day
followed by 200 to 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical
and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis.
For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full
course of primary therapy, Diflucan may be administered indefinitely at a daily dose of 200 mg.

Candidemia, Disseminated Candidiasis and Other Invasive Candidal Infections.

The usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response, the
dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response.

Israel, Diflucan Trican Triflucan, 07 August 2011 11

Mucosal Candidiasis
- Oropharyngeal Candidiasis.
The usual dose is 50 to 100 mg once daily for 7-14 days. If necessary, treatment can be continued for
longer periods in patients with severely compromised immune function. For atrophic oral candidiasis associated
with dentures, the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic
measures to the denture.

- Other Candidal Infections of Mucosa (Except Vaginal Candidiasis), e.g. Esophagitis, Non-Invasive
Bronchopulmonary Infections,Candiduria, Mucocutaneous Candidiasis, etc.
The usual effective dose is 50 to 100 mg daily, given for 14-30 days.
For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the patient receives a
full course of primary therapy, fluconazole may be administered at a 150 mg once weekly dose.

Vaginal Candidiasis.
Fluconazole 150 mg should be administered as a single oral dose.
To reduce the incidence of recurrent vaginal candidiasis, a 150 mg once monthly dose may be used. The duration
of therapy should be individualized, but ranges from 4-12 months. Some patients may require more frequent dosing.

For Candida balanitis, fluconazole 150 mg should be administered as a single oral dose.

Prevention Of Candidiasis
The recommended fluconazole dosage is 50 to 400 mg once daily, based on the patient’s risk for developing fungal
infection. For patients at high risk of systemic infection, e.g., patients who are anticipated to have profound or
prolonged neutropenia, the recommended daily dose is 400 mg once daily. Fluconazole administration should start
several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises
above 1000 cells per mm3.

Dermal Infections
-Tinea Pedis, Corporis, Cruris and Candida Infections
The recommended dosage is 150 mg once weekly or 50 mg once daily. Duration of treatment is normally 2 to
4 weeks but tinea pedis may require treatment for up to 6 weeks.

-Tinea Versicolor
The recommended dose is 300 mg once weekly for 2 weeks; a third weekly dose of 300 mg may be needed in
some patients, whereas, in some patients, a single dose of 300 to 400 mg may be sufficient. An alternate dosing
regimen is 50 mg once daily for 2 to 4 weeks.

-Tinea Unguium
The recommended dosage is 150 mg once weekly. Treatment should be continued until infected nail is
replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally requires 3 to 6 months and 6
to 12 months, respectively. However, growth rates may vary widely in individuals, and by age. After successful
treatment of long-term chronic infections, nails occasionally remain disfigured.

Use In Elderly
Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For
patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be
adjusted as described below.

Use In Renal Impairment

Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single dose therapy
are necessary. In patients (including children) with impaired renal function who will receive multiple doses of
fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose
(according to indication) should be based on the following table:

Percent of
Creatinine clearance (ml/min) Recommended Dose
____________________________________________________________

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>50 100%

≤ 50 (no dialysis) 50%

Regular dialysis. 100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis
days, patients should receive a reduced dose according to their creatinine clearance

Use In Children
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response.
The maximum adult daily dosage should not be exceeded in children. Fluconazole is administered as a single
dose each day.
The recommended dosage of fluconazole for mucosal candidiasis is 3mg/kg daily. A loading dose of 6 mg/kg
may be used on the first day to achieve steady state levels more rapidly.
For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6 to 12
mg/kg daily, depending on the severity of the disease.
For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of
fluconazole is 6 mg/kg once daily.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence
of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 to 12 mg/kg daily,
depending on the extent and duration of the induced neutropenia (see Use In Adults ). (For children with impaired
renal function, see Use In Renal Impairment).

Use In Children 4 weeks of age and younger.

Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children
should be used but administered every 72 hours. During weeks 3 and 4 of life, the same dose should be given
every 48 hours.

Overdosage
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behaviour.
In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary)
may be adequate.
There have been reports of overdosage with fluconazole and in one case, a 42 year-old patient infected with
human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly
ingesting 8200 mg of fluconazole. The patient was admitted to the hospital, and his condition resolved within 48
hours.
Fluconazole is largely excreted in the urine; forced diuresis would probably increase the elimination rate. A 3-
hour hemodialysis session decreases plasma levels by approximately 50%.

Pharmaceutical Precautions
Triflucan I.V. Injectable Solution for Infusion
Triflucan intravenous infusion is compatible with the following fluids:
1. 0.9% Sodium Chloride Injection.
2. 20% Dextrose Injection.
3. Hartmann's Solution ( lactic acid 0.24% v/v-equivalent to sodium lactate 0.32% w/v, sodium chloride 0.6%
w/v, potassium chloride 0.04% w/v, calcium chloride dihydrate 0.027% w/v, water for injection).
4. Ringer's Solution (sodium chloride 8.6 g, potassium chloride 0.3 g, calcium chloride dihydrate 0.33 g , water
for injection to 1000 ml).
5. Sodium bicarbonate 4.2%.
6. Potassium chloride in dextrose.
7. Aminofusin

Fluconazole may be infused through an existing line with one of the above listed fluids. Although no specific
incompatibilites have been noted, mixing with any other drug prior to infusion is not recommended.

Diflucan Suspension

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 The powder for oral suspension is reconstituted by tapping the bottle to loosen powder, adding 24 ml of water;
and shaken well to produce 35 ml of suspension. Any unused portion of the suspension must be discarded after
14 days. Protect from freezing

Special Precautions for Storage

Store below 30˚C.

Instructions for Use/Handling

Capsules and tablets should be swallowed whole.
Shake suspension immediately prior to use.

Presentation
Trican Capsules 50 mg, 100 mg, and 200 mg: 7 capsules
Trican Capsules 150 mg : 1 capsule.
Dilfucan Suspension : Powder for the preparation of 35 ml suspension.
Triflucan I.V. Injectable Solution for I.V. Infusion : Vials of 50 ml.

Manufacturer
Pfizer France

For
Pfizer Pharmaceuticals Israel Ltd.
9 Shenkar St.
Hertzliya Pituach 46725

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