SUMMARY PRODUCT CHARACTERISTIC (SPC)
FLUCONAZOLE
150 MG CAPSULES
1. NAME OF THE MEDICINAL PRODUCT
Fluconazole
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule of Fluconazole contains:
active ingredient: fluconazole - 150 mg;
inactive ingredients: lactose monohydrate, ethylcellulose
Composition of each hard gelatin capsule:
Cap and body : Brilliant Blue FCF (E133, C.I number 42090) (BLUE Nº1), Sunset Yellow FCF
(E110, C.I number 15985) (YELLOW Nº6) , Quinoline Yellow WS (E104, C.I number 47005)
(YELLOW Nº10), Titannium Dioxide (Е 171, C.I number 77891), Propylene Glycol (E1520),
MethylParaben (E218), PropylParaben (E216) , SLS (Е487), Acetic Acid (E260), Colloidal Silicon
Dioxide (Е551), Gelatin q.s.p.
3. PHARMACEUTICAL FORM
Capsules
4. CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Fluconazole is a triazole antifungal used for treatment of vaginal candidiasis and candidal balanitis.
4.2 POSOLOGY AND METHOD OF ADMINISTRATION
Fluconazole is given by mouth.
In adult
Fluconazole, 150 mg by mouth as a single dose may be used for vaginal candidiasis or candidal
balanitis.
In children
Despite extensive data supporting the use of Fluconazole in children there are limited data
available on the use of Fluconazole for genital candidiasis in children below 16 years. Use at
present is not recommended unless antifungal treatment is imperative and no suitable alternative
agent exists.
Elderly patients do not require correction dosing regimen.
4.3 CONTRAINDICATIONS
Fluconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient
in the respective formulation.
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 medicinal products known to prolong the QT interval and which are
metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide,
quinidine and erythromycin are contraindicated in patients receiving fluconazole.
The use of fluconazole with astemizole, cisapride, pimozide, quinidine and erythromycin are
should therefore be avoided.
Pregnancy, breast-feeding.
Children up to age 16 years.
Acute porphyria.
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Renal system
Fluconazole should be administered with caution to patients with renal dysfunction .
Hepatobiliary system
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 to total daily dose, duration of therapy, sex or age of patient
has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of
therapy.
Patients who develop abnormal liver function tests during fluconazole therapy must be monitored
closely for the development of more serious hepatic injury.
The patient should be informed of suggestive symptoms of serious hepatic effect (important
asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be
immediately discontinued and the patient should consult a physician.
Cardiovascular system
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 torsades 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 treatment that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions. Coadministration of other medicinal products known to prolong the QT interval and
which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated .
Halofantrine
Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a
substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not
recommended .
Dermatological reactions
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 medicinal products. If a rash, which is
considered attributable to fluconazole, develops in a patient treated for a superficial fungal
infection, further therapy with this medicinal product 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.
Hypersensitivity
In rare cases anaphylaxis has been reported .
Cytochrome P450
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an
inhibitor of CYP2C19. Fluconazole treated patients who are concomitantly treated with medicinal
products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and
CYP3A4, should be monitored .
Terfenadine
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be
carefully monitored.
Excipients
Capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
Capsules contain dye «Sunset Yellow» FCF (E110) , which may cause allergic reactions.
4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 co-administered. . 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 QTc interval. Co-administration of cisapride is
contra-indicated in patients receiving fluconazole.
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 200mg daily dose of fluconazole failed to
demonstrate a prolongation in QTc interval. Another study at a 400mg and 800mg daily dose of
fluconazole demonstrated that fluconazole taken in doses of 400mg per day or greater significantly
increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole
at doses of 400mg or greater with terfenadine is contra-indicated. The co-administration of
fluconazole at doses lower than 400mg 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.
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.
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 oftorsades de pointes. Coadministration of fluconazole
and quinidine is contraindicated.
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.
Concomitant use of the following other medicinal products canot be:
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase
the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden
heart death. This combination should be avoided.
Concomitant use of the following other medicinal products lead to precautions and dose
adjustments:
The effect of other medicinal products on fluconazole
Rifampicin: Concomitant administration of fluconazole and rifampicin has resulted in a 25%
decrease in the AVC and 20% shorter half-life of fluconazole. In patients receiving concomitant
rifampicin, an increase in the fluconazole dose should be considered.
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.
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.
Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20
µg/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of
CYP3A4. Dose adjustment of alfentanil may be 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 medicinal products in systemic infection with A. fumigatus.
The clinical significance of results obtained in these studies is unknown.
Anticoagulants: 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. During concomitant treatment with fluconazole and warfarin the prothrombin time was
prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9.
In patients receiving coumarin-type anticoagulants concurrently with fluconazole the prothrombin
time should be carefully monitored. Dose adjustment of warfarin may be necessary.
Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of
midazolam, fluconazole resulted in substantial increases in midazolam concentrations and
psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally
increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg
daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life
4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been
observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is
necessary in patients being treated with fluconazole, consideration should be given to decreasing the
benzodiazepine dose, and the patients should be appropriately monitored.
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.
Dose 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.
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 fentanyl intoxication due to possible fentanyl fluconazole interaction
was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the
elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory
depression. Patients should be monitored closely for the potential risk of respiratory depression.
Dosage adjustment of fentanyl may be necessary.
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.
Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):
Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During
concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 
1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of
ciclosporin depending on ciclosporin concentration.
Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum
concentrations of everolimus through inhibition of CYP3A4.
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
dose 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. Dose of orally administered
tacrolimus should be decreased depending on tacrolimus concentration.
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. Dose adjustment of
methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was 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] was 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 dose of NSAIDs may be needed.
Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated
administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of
the phenytoin AUC24 by 75% and Cmin by 128%. 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: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC
of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and
rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be
taken into consideration.
Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and
55% respectively, due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition
of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more
marked. Dose adjustment of saquinavir may be necessary.
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
dose is recommended during coadministration.
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 rate of theophylline. Patients
who are receiving high dose theophylline or who are otherwise at increased risk for theophylline
toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy
should be modified 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 all-transretinoid 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.
Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration 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 8 healthy male subjects resulted in an increase in Cmax and AUC of
voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%),
respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would
eliminate this effect have not been established. Monitoring for voriconazole associated adverse
events is recommended if voriconazole is used sequentially after fluconazole.
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. Dose reduction of zidovudine may be considered.
Azithromycin: An open-label, randomized, three-way crossover 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. There was no significant pharmacokinetic interaction between fluconazole and
azithromycin.
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.
4.6 FERTILITY, PREGNANCY AND BREAST FEEDING
Pregnancy
An observational study has suggested an increased risk of spontaneous abortion in women treated
with fluconazole during the first trimester.
There have been reports of multiple congential abnormalities (including brachycephalia, ears
dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose
mothers were being treated for at least three or more months with high dose (400 - 800 mg daily) of
fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is
unclear.
Studies in animals have shown reproductive toxicity.
Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless
clearly necessary.
Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except
for potentially life-threatening infections.
Breast-feeding
Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breastfeeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breastfeeding is not recommended after repeated use or after high dose fluconazole.
Fertility
Fluconazole did not affect the fertility of male or female rats
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
No studies have been performed on the effects of Fluconazole on the ability to drive or use
machines.
Patients should be warned about the potential for dizziness or seizures while taking Fluconazole and
should be advised not to drive or operate machines if any of these symptoms occur.
4.8 UNDESIRABLE EFFECTS
The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea,
nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood
alkaline phosphatase increased and rash.
The following adverse reactions 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 from the available data).
System Organ
Class
Common Uncommon Rare Not known
Blood and the
lymphatic system
disorders
Anaemia Agranulocytosis,
leukopenia,
thrombocytopenia,
neutropenia
Immune system
disorders
Anaphylaxis
Metabolism and
nutrition disorders
Decreased appetite Hypercholesterolaemia,
hypertriglyceridaemia,
hypokalemia
Psychiatric
disorders
Somnolence,
insomnia
Nervous system
disorders
Headache Seizures,
paraesthesia,
dizziness, taste
perversion
Tremor
Ear and labyrinth
disorders
Vertigo
Cardiac disorders Torsade de pointes, QT
prolongation
Gastrointestinal
disorders
Abdominal pain,
vomiting, diarrhoea,
nausea
Constipation
dyspepsia,
flatulence, dry
mouth
Hepatobiliary
disorders
Alanine
aminotransferase
increased, aspartate
aminotransferase
increased, blood
alkaline phosphatase
increased
Cholestasis,
jaundice, bilirubin
increased
Hepatic failure,
hepatocellular necrosis,
hepatitis,
hepatocellular damage
Skin and
subcutaneous tissue
disorders
Rash Drug eruption,
urticaria, pruritus,
increased sweating
Toxic epidermal
necrolysis, StevensJohnson syndrome,
acute generalised
Drug reaction with
eosinophilia and
systemic symptoms
(DRESS- syndrome)
Paediatric population
The pattern and incidence of adverse reactions and laboratory abnormalities recorded during
paediatric clinical trials, excluding the genital candidiasis indication, are comparable to those seen
in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at
www.mhra.gov.uk/yellowcard.
4.9 OVERDOSAGE
There have been reports of overdose with Fluconazole and hallucination and paranoid behaviour
have been concomitantly reported.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
necessary) may be adequate.
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%.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC classification
Antifungal; J02AC01
Mechanism of action
Fluconazole usually is fungistatic in action. Fluconazole and other triazole-derivative antifungal
agents appear to have a mechanism of action similar to that of the imidazole-derivative antifungal
agents. Like imidazoles, fluconazole presumably exerts its antifungal activity by altering cellular
membranes resulting in increased membrane permeability, leakage of essential elements, and
impaired uptake of precursor molecules. Although the exact mechanism of action of fluconazole
and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-αdesmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g.,
lanosterol) and decreased concentrations of ergosterol. It appears that this may occur because a
nitrogen atom (N-4) in the triazole molecule binds to the heme iron of cytochrome P-450 14-αdesmethylase in susceptible fungi. Unlike some imidazoles that suppress ATP concentrations in
intact cells and spheroplasts of C. albicans, fluconazole does not appear to have an appreciable
effect on ATP concentrations in the organism. It is unclear whether this effect is related to the in
vivo antifungal effects of the drugs. Fluconazole generally is fungistatic against Candida albicans
when the organism is in either the stationary or early logarithmic phase of growth.
exanthematouspustulosis, dermatitis
exfoliative,
angioedema, face
oedema, alopecia
Musculoskeletal
and connective
tissue disorders
Myalgia
General disorders
and administration
site conditions
Fatigue, malaise,
asthenia, fever
Susceptibility in vitro
Fluconazole is a triazole antifungal drug which in sensitive fungi inhibits cytochrome P450-
dependent enzymes, resulting in impairment of ergosterol synthesis in fungal cell membranes. It is
active against Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus
neoformans, Epidermophyton spp., Histoplasma capsulatum, Microsporum spp., and Trichophyton
spp.
Resistance has developed in some Candida spp. following long-term prophylaxis with fluconazole,
and cross-resistance with other azoles has been reported.
Microbiological interactions. A synergistic antifungal effect was seen in vitro with terbinafine and
fluconazole against strains of Candida albicans.
PK/PD relationship
In animal studies, there is a correlation between MIC values and efficacy against experimental
mycoses due to Candidaspp. In clinical studies, there is an almost 1:1 linear relationship between
the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between
the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent
candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher
fluconazole MIC.
Mechanism(s) of resistance
Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal
strains which have developed one or more of these resistance mechanisms are known to exhibit
high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in
vivo and clinically.
There have been reports 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.
Breakpoints (according to EUCAST)
Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and
clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testingsubcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole
for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been
divided into non-species related breakpoints; which have been determined mainly on the basis of
PK/PD data and are independent of MIC distributions of specific species, and species related
breakpoints for those species most frequently associated with human infection. These breakpoints
are given in the table below:
Antifungal Species-related breakpoints (S≤/R>) Non-species related
breakpointsA S≤/R>
Candida
albicans
Candida
glabrata
Candida
krusei
Candida
parapsilosis
Candida
tropicalis
Fluconazole 2/4 IE -- 2/4 2/4 2/4
S = Susceptible, R = Resistant
A = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and
are independent of MIC distributions of specific species. They are for use only for organisms that
do not have specific breakpoints.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the
medicinal product.
IE = There is insufficient evidence that the species in question is a good target for therapy with the
medicinal product
5.2 Pharmacokinetic properties
Absorption
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. Plasma concentrations are proportional to dose.
Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing.
Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to
approximate to 90% steady-state levels by day 2.
Distribution
The apparent volume of distribution approximates to total body water. Plasma protein binding is
low (11-12%).
Fluconazole achieves good penetration in 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
CSF are approximately 80% the corresponding plasma levels.
High skin concentration 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 µg/g and 7 days
after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose,
the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the
second dose was still 7.1 µg/g.
Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g
in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6
months after the end of therapy.
Biotransformation
Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a
changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and
CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19.
Excretion
Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion
is renal, with approximately 80% of the administered dose appearing in the urine as unchanged
medicinal product. 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, once daily and once weekly dosing for other indications.
Pharmacokinetics in renal impairment
In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98
hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and
to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of
fluconazole is eliminated from blood.
Pharmacokinetics in children
Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose
studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not
interpretable due to changes in formulation pathway through the study. Additional data were
available from a compassionate use study.
After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years,
an AUC of about 38 µg•h/ml was found per 1 mg/kg dose units. The average fluconazole plasma
elimination half-life varied between 15 and 18 hours and the distribution volume was approximately
880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately
24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination
half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The
distribution volume in this age group was about 950 ml/kg.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature
newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was
0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven 
patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole
were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1
which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day
13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and 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 and 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 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µg·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. Coadministation of diuretics did
not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of
medicinal product recovered unchanged in urine (0-24 h, 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 the elderly appears to be related to reduced renal
function characteristics of this group.
5.3 PRECLINICAL SAFETY DATA
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of
the human exposure indicating little relevance to clinical use.
Carcinogenesis
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.
Mutagenesis
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4
strains of Salmonella 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 µg/ml) showed no evidence of
chromosomal mutations.
Reproductive toxicity
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.
There were no foetal effects at 5 or 10 mg/kg; increases in foetal 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 to 320 mg/kg embryolethality in rats was
increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial
ossification.
The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of
parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. 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. These effects on parturition 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.
6. PHARMACEUTICAL PARTICULARS
6.1 SHELF LIFE
3 years.
6.1 STORAGE CONDITIONS 
Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from
light.
6.3 PRESENTATION
1 blister packet with 10 capsules in the cardboard box.
6.4.IDENTIFICATION
Appearance of capsule: the capsules have a yellow body and a yellow cap
Appearance of granules: white or off white with tints of pink granules
6.5 MANUFACTURER
“ARPIMED” LLC
Bldg. 19, mcr 2-nd, Abovyan, Kotayki Marz, Republic of Armenia
Tel.: (374) 222 21703
Fax: (374) 222 21924
6.6 MARKETING AUTHORIZATION HOLDER
“ARPIMED” LLC
Bldg. 19, mcr 2-nd, Abovyan, Kotayki Marz, Republic of Armenia
Tel.: (374) 222 21703 Fax: (374) 222 21924