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Active substance(s): FLUCONAZOLE
NAME OF THE MEDICINAL PRODUCT
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains fluconazole 150mg.
Excipient(s) of known effects: each hard capsule also contains 75 mg
For the full list of excipients, see section 6.1.
A hard gelatin size “1” capsule with a blue cap and blue body containing a white free
Azocan-P is indicated for the treatment of the following conditions:Vaginal candidiasis, acute or recurrent; or candidal balanitis associated with vaginal
Posology and method of administration
In Adults aged 16-60 years: Vaginal candidiasis or candidal balanitis –
150mg single oral dose.
Not recommended in children aged under 16 years.
Not recommended in patients aged over 60 years.
Fluconazole is excreted predominantly in the urine as unchanged drug.
No adjustments in single dose therapy are required.
Method of administration
For oral use.
Fluconazole should not be used in patients with known hypersensitivity to
fluconazole, to related azole compounds or to any of the excipients listed
in section 6.1.
Co-administration 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 (see sections 4.4 and 4.5).
Special warnings and precautions for use
Fluconazole should be administered with caution to patients with
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
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.
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. 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.
The coadministration of fluconazole at doses lower than 400 mg per day
with terfenadine should be carefully monitored (see sections 4.3 and 4.5).
In rare cases anaphylaxis has been reported (see section 4.3).
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 proarryhthmic conditions. Coadministration of other medicinal
products known to prolong the QT interval and which are metabolised via
the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and
Use with caution in patients with renal dysfunction ( see section 4.2)..
Ketoconazole is known to cause adrenal insufficiency, and this could also
although rarely seen be, applicable to fluconazole.
Adrenal insufficiency relating to concomitant treatment with Prednisone is
described in section 4.5 The effect of fluconazole on other medicinal
Fluconazole has been studied for treatment of tinea capitis in children. It
was shown not to be superior to griseofulvin and the overall success rate
was less than 20%. Therefore, Diflucan should not be used for tinea capitis.
The evidence for efficacy of fluconazole in the treatment of cryptococcosis
of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited,
which prevents dosing recommendations.
Deep endemic mycoses
The evidence for efficacy of fluconazole in the treatment of other forms of
endemic mycoses such as paracoccidioidomycosis, lymphocutaneous
sporotrichosis and histoplasmosis is limited, which prevents specific dosing
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 (see section
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4
inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated
patients who are concomitantly treated with medicinal products with a
narrow therapeutic window metabolised through CYP2C9, CYP2C19 and
CYP3A4, should be monitored (see section 4.5).
The coadministration of fluconazole at doses lower than 400 mg per day
with terfenadine should be carefully monitored (see sections 4.3 and 4.5).
The capsules contain lactose and should not be given to patients with rare
hereditary problems of galactose intolerance, the LAPP lactase deficiency
or glucose-galactose malabsorption.The product intended for pharmacy
availability without prescription will carry a leaflet which will advise the
patient: Do not use Azocan-P without first consulting your doctor:If you are under 16 or over 60 years of age.
If you are allergic to any of the ingredients in Azocan-P or other
antifungals and other thrush treatments.
If you are taking any medicine other than the contraceptive pill.
If you are taking the antihistamine terfenadine or the prescription
medicine cisapride, pimozide, quinidine and erythromycin.
If you have had thrush more than twice in the last six months.
If you have any disease or illness affecting your liver or kidneys or have
had unexplained jaundice.
If you suffer from heart disease including heart rhythm problems.
If you have abnormal levels of potassium, calcium or magnesium in your
If you develop severe skin reactions (itching, reddening of the skin or
If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do
adequate amounts of certain steroid hormones such as cortisol (chronic, or
fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain).
If you or your partner have had exposure to a sexually transmitted
If you are unsure about the cause of your symptoms.
If you are pregnant, suspect you might be pregnant or are breast
If you have any abnormal or irregular vaginal bleeding or a blood
If you have vulval or vaginal sores, ulcers or blisters.
If you are experiencing lower abdominal pain or burning on passing urine.
If your sexual partner does not have vaginal thrush.
If you have penile sores, ulcers or blisters.
If you have an abnormal penile discharge
If your penis has started to smell.
If you have pain on passing urine.
The product should never be used again if the patient experiences a rash
or anaphylaxis follows the use of the drug.
Recurrent use (men and women): Patients should be advised to consult their
physician if the symptoms have not been relieved within one week of
taking Azocan-P. A further capsule can be used if the candidal infection
returns after 7 days. However, if the candidal infection recurs more than
twice within six months, patients should be advised to consult their
4.5. Interactions with other medicinal products and other forms of
The following drug interactions relate to the use of multiple-dose
fluconazole, and the relevance to single-dose fluconazole 150mg has not
yet been established:
Concomitant use of the following other medicinal products is
Cisapride: There have been reports of cardiac events including torsade de
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 QTc interval. Concomitant treatment with fluconazole and
cisapride iscontraindicated (see section 4.3).
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 4.3). 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 4.3).
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
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 4.3).
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
Concomitant use of the following other medicinal products cannot be
Amiodarone: Concomitant administration of fluconazole with amiodarone
may increase QT prolongation. Therefore, caution should be taken when
both drugs are combined, notably with high dose fluconazole (800mg).
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 (see section 4.4).
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 20% shorter half-life of fluconazole. In
patients receiving concomitant rifampicin, an increase in the
fluconazole dose should be
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
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 4.3).
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. Dosage
adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of
amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may
be measured at initiation of the combination therapy and after one week.
Dosage of amitriptyline/nortriptyline should be adjusted, if necessary
Amphotericine 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 Aspergillus 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,
haematuria 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 coumarintype or indanedione anticoagulants concurrently with fluconazole the
prothrombin time should be carefully monitored. Dose adjustment of the
anticoagulant 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 dosage and the patients should be
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
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. Patient 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
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 Pglycoprotein. 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
Losartan: Fluconazole inhibits the metabolism of losartan to its active
metabolite (E-31 74) which is responsible for most of the angiotensin IIreceptor 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 of adjustment 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 dosage of NSAIDs may be needed.
Oral contraceptives: Two pharmacokinetic studies with combined oral
contraceptives have been performed using multiple doses of fluconazole.
There were no relevant effects on hormone level in a 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.
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
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 of saquinavir with
approximately 50%, Cmax with approximately 55%, due to inhibition of
saquinavir’s hepatic metabolism by CYP3A4 and inhibition of Pglycoprotein. Dosage adjustment of saquinavir may be necessary.
Sulphonylureas: Fluconazole has been shown to prolong the serum half-life
of concomitantly administered oral sulphonylureas (e.g., chlorpropamide,
glibenclamide, glipizide and tolbutamide) in healthy volunteers. Frequent
monitoring of blood glucose and appropriate reduction of sulfonylurea
dosage is recommended during coadministration.
Theophylline: In a placebo controlled interaction study, the administration of
fluconazole 200mg 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
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
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.
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. Dosage 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.
Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane
conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3fold and hydroxymethyl-ivacaftor (M1) exposure by 1.9-fold. A reduction of
the ivacaftor dose to 150 mg once daily is recommended for patients taking
concomitant moderate CYP3A inhibitors, such as fluconazole and
Fertility, pregnancy and lactation
There have been reports of multiple congenital 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 and
these events is unclear.
Studies in animals shown reproductive toxicity (see section 5.3).
Data from several hundred pregnant women treated with standard doses
(<200 mg/day) of fluconazole, administered as a single or repeated dose in
the first trimester, show no increased risk of undesirable effects in the
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-feedingFluconazole is found in human breast milk at lower
concentrations than those in plasma, Breast-feeding 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 did not affect the fertility of male or female rats (see section
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 (see
section 4.8) while taking Fluconazole and should be advised not to drive or
operate machines if any of these symptoms occur.
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
(≥1/1000, <1/100), rare (≥1/10000, <1/1000) and very rare
(>1/10000), not known (cannot be estimated from the available data):
System Order Class
Blood and the lymphatic
Immune system disorders Rare
Metabolism & nutrition Uncommon
Nervous system disorders Common
paraesthesia, taste perversion
Ear & labyrinth disorders Uncommon
Torsade de pointes (see section
4.4), QT Prolongation (see section
Gastrointestinal disorders Common
Skin & subcutaneous
Abdominal pain, diarrhoea,
Constipation dyspepsia, flatulence,
Increased (see section 4.4),
increased (see section 4.4),
blood alkaline phosphatase
increased (see section 4.4)
Cholestasis (see section 4.4),
jaundice (see section 4.4),
bilirubin Increased (see section
Hepatic failure (see section 4.4),
hepatocellular Necrosis (see
section 4.4), hepatitis,
hepatocellular damage (see section
Rash (see section 4.4)
Pruritus, urticaria (see section 4.4),
increased sweating, drug eruption*
(see section 4.4)
Toxic epidermal necrolysis (see
section 4.4), Stevens-Johnson
syndrome (see section 4.4), acute
section 4.4), dermatitis exfoliative,
angioedema, face oedema, alopecia
tissue & &
including Fixed Drug Eruption
Fatigue, malaise, asthenia, fever
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 Yellow card scheme at
There have been reports of overdosage with fluconazole and hallucination
and paranoid behaviour have been concomitantly reported
In the event of overdosage, supportive measures and symptomatic
treatment. (with gastric lavage if necessary) may be adequate.
As 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%.
Pharmacotherapeutic group: Antimycotics for systemic use – triazole
derivatives, ATC code: J02AC01
Mechanisam of action
Fluconazole, a member of the triazole class of antifungal agents. Its
primary mode of action is the inhibition of fungal cytochrome P-450mediated 14 alpha-lanosterol demethylation, an essential step in fungal
ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols
correlates with the subsequent loss of ergosterol in the fungal cell
membrane and may be responsible for the antifungal activity of
fluconazole. Fluconazole has been shown to be more selective for fungal
cytochrome P-450 enzymes than for various mammalian cytochrome P450 enzyme systems.
Fluconazole 50 mg daily given up to 28 days has been shown not to
effect testosterone plasma concentrations in males or steroid
concentration in females of child-bearing age. Fluconazole 200 mg 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.
Susceptibility in vitro:
In vitro, fluconazole displays antifungal activity against most clinically
common Candida species (including C. albicans, C. parapsilosis, C.
tropicalis). C. glabrata shows a wide range of susceptibility while C.
krusei is resistant to fluconazole.
Fluconazole also exhibits activity in vitro against Cryptococcus
neoformans and Cryptococcus. gattii as well as the endemic
moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma
capsulatum and Paracoccidioides brasiliensis.
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
Mechanisms 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
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 Testing-subcommittee 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
Species-related breakpoints (S≤/R>)
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
-- = 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
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 a loading dose (on day 1) of twice the
usual daily dose enables plasma levels to approximate to 90% steady state
level by day 2.
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%
of 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
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 (see section 4.5).
Fluconazole is also an inhibitor of the isozyme CYP2C19.
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 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, 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
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
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.
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
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 (supernumary ribs, renal pelvis dilation) and delays in ossification
were observed at 25 and 50mg/kg and higher doses. At doses ranging from
80mg/kg to 320mg/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 (see section 5.1).
Fluconazole showed no evidence of carcinogenic potential in mice and rats
treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day
(approximately 27 times the recommended human dose). Male rats treated
with 5 and 10mg/kg/day had an increased incidence of hepatocellular
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 1000µg/ml) showed no
evidence of chromosomal mutations.
List of excipients
Pregelatinised Maize Starch
Capsule shell composition:
Brilliant blue (E133)
Special precautions for storage
Do not store above 25°C.
Nature and contents of container
Aluminium and PVC/PVDC blister. Pack size: 1
Special precautions for disposal and
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.
MARKETING AUTHORISATION HOLDER
FDC International Ltd
Unit 6 Fulcrum 1,
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
16/11/2006 / 11/07/2011
DATE OF REVISION OF THE TEXT
Source: Medicines and Healthcare Products Regulatory Agency
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