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FLUCONAZOLE 200MG HARD CAPSULES

Active substance(s): FLUCONAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Fluconazole 200mg Hard Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 200mg of fluconazole.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Capsules, hard
Fluconazole 200mg Capsules are white capsules.

4

4.1

CLINICAL PARTICULARS

Therapeutic indications
Fluconazole is indicated in the following fungal infections (see section 5.1).
Fluconazole is indicated in adults for the treatment of:










Cryptococcal meningitis (see section 4.4).
Coccidioidomycosis (see section 4.4).
Invasive candidiasis.
Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria
and chronic mucocutaneous candidiasis.
Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical
treatment are insufficient.
Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate.
Candidal balanitis when local therapy is not appropriate.
Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea
versicolor and dermal candida infections when systemic therapy is indicated.
Tinea unguinium (onychomycosis) when other agents are not considered
appropriate.

Fluconazole is indicated in adults for the prophylaxis of:
• Relapse of cryptococcal meningitis in patients with high risk of recurrence.

• Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV
who are at high risk of experiencing relapse.
• To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a
year).
• Prophylaxis of candidal infections in patients with prolonged neutropenia (such as
patients with haematological malignancies receiving chemotherapy or patients
receiving Hematopoietic Stem Cell Transplantation (see section 5.1)).
Fluconazole is indicated in term newborn infants, infants, toddlers, children, and
adolescents aged from 0 to 17 years old:
Fluconazole is used for the treatment of mucosal candidiasis (oropharyngeal,
oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of
candidal infections in immunocompromised patients. Fluconazole can be used as
maintenance therapy to prevent relapse of cryptococcal meningitis in children with
high risk of reoccurrence (see section 4.4).
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.
Consideration should be given to official guidance on the appropriate use of
antifungals.

4.2

Posology and method of administration
Posology
The dose should be based on the nature and severity of the fungal infection.
Treatment of infections requiring multiple dosing 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.
Adults
Indications
Cryptococcosis

Posology

- Treatment of
cryptococcal
meningitis.

Loading dose:
400mg on Day 1
Subsequent dose:
200mg to 400 mg
daily

- Maintenance
therapy to
prevent relapse
of cryptococcal
meningitis in
patients with
high risk of
recurrence.

200 mg daily

Duration of
treatment
Usually at least 6
to 8 weeks.
In life threatening
infections the daily
dose can be
increased to
800 mg
Indefinitely at a
daily dose of
200 mg

Coccidioidomycosis

200 mg to 400 mg

Invasive candidiasis

Loading dose:
800 mg on Day 1
Subsequent dose:
400 mg daily

Treatment of
mucosal candidiasis

- Oropharyngeal
candidiasis

Loading dose:
200 mg to 400 mg
on Day 1
Subsequent dose:
100 mg to 200 mg
daily

- Oesophageal
candidiasis

Loading dose:
200 mg to 400 mg
on Day 1
Subsequent dose:
100 mg to 200 mg
daily

- Candiduria

200 mg to 400 mg
daily

- Chronic atrophic
candidiasis
- Chronic
mucocutaneous
candidiasis

50 mg daily
50 mg to 100 mg
daily

11 months up to 24
months or longer
depending on the
patient. 800 mg
daily may be
considered for
some infections
and especially for
meningeal disease
In general, the
recommended
duration of therapy
for candidemia is
for 2 weeks after
first negative
blood culture
result and
resolution of signs
and symptoms
attributable to
candidemia.
7 to 21 days (until
oropharyngeal
candidiasis is in
remission).
Longer periods
may be used in
patients with
severely
compromised
immune function
14 to 30 days
(until oesophageal
candidiasis is in
remission).
Longer periods
may be used in
patients with
severely
compromised
immune function
7 to 21 days.
Longer periods
may be used in
patients with
severely
compromised
immune function
14 days
Up to 28 days.
Longer periods
depending on both
the severity of

Prevention of
relapse of mucosal
candidiasis in
patients infected
with HIV who are at
high risk of
experiencing relapse

- Oropharyngeal
candidiasis

100 mg to 200 mg
daily or 200 mg
3 times per week

- Oesophageal
candidiasis

100 mg to 200 mg
daily or 200 mg
3 times per week

Genital candidiasis

- Acute vaginal
candidiasis
- Candidal
balanitis
- Treatment and
prophylaxis of
recurrent vaginal
candidiasis (4 or
more episodes a
year).

150 mg

Dermatomycosis

- tinea pedis,
- tinea corporis,
- tinea cruris,
- candida
infections
- tinea versicolor

- tinea unguium
(onychomycosis)

infection or
underlying
immune
compromisation
and infection
An indefinite
period for patients
with chronic
immune
suppression
An indefinite
period for patients
with chronic
immune
suppression
Single dose

150 mg every third
day for a total of 3
doses (day 1,4,
and 7) followed by
150 mg once
weekly
maintenance dose
150 mg once
weekly or 50 mg
once daily

Maintenance dose:
6 months

300 mg to 400 mg
once weekly
50 mg once daily
150 mg once
weekly

1 to 3 weeks

2 to 4 weeks, tinea
pedis may require
treatment for up to
6 weeks

2 to 4 weeks
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-

Prophylaxis of
candidal infections
in patients with
prolonged
neutropenia

200 mg to 400 mg

term chronic
infections, nails
occasionally
remain disfigured.
Treatment should
start several days
before the
anticipated onset
of neutropenia and
continue for 7 days
after recovery
from neutropenia
after the neutrophil
count rises above
1000 cells per
mm3.

Special populations
Elderly
Dosage should be adjusted based on the renal function (see “Renal impairment”).
Renal impairment
No adjustments in single dose therapy are necessary. In patients (including paediatric
population) with impaired renal function who will receive multiple doses of
fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the
recommended daily dose for the indication. After this initial loading dose, the daily
dose (according to indication) should be based on the following table:
Creatinine clearance (ml/min)
> 50
≤ 50 (no dialysis)
Regular dialysis

Percent of recommended dose
100%
50%
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.
Hepatic impairment
Limited data are available in patients with hepatic impairment, therefore fluconazole
should be administered with caution to patients with liver dysfunction (see sections
4.4 and 4.8).
Paediatric population
A maximum dose of 400 mg daily should not be exceeded in paediatric population.
As with similar infections in adults, the duration of treatment is based on the clinical
and mycological response. Fluconazole is administered as a single daily dose.
For paediatric patients with impaired renal function, see dosing in “Renal
impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric
population with renal insufficiency (for “Term newborn infants” who often exhibit
primarily renal immaturity please see below).

Infants, toddlers and children (from 28 days to 11 years old):
Indication
- Mucosal candidiasis

Posology
Initial dose: 6 mg/kg
Subsequent dose:
3 mg/kg daily

- Invasive candidiasis
- Cryptococcal meningitis
- Maintenance therapy to
prevent relapse of
cryptococcal meningitis
in children with high
risk of recurrence
- Prophylaxis of Candida
in immunocompromised
patients

Dose: 6 to 12 mg/kg
daily
Dose: 6 mg/kg daily

Dose: 3 to 12 mg/kg
daily

Recommendations
Initial dose may be used on
the first day to achieve
steady state levels more
rapidly
Depending on the severity
of the disease
Depending on the severity
of the disease

Depending on the extent
and duration of the induced
neutropenia (see Adults
posology)

Adolescents (from 12 to 17 years old):
Depending on the weight and pubertal development, the prescriber would need to
assess which posology (adults or children) is the most appropriate. Clinical data
indicate that children have a higher fluconazole clearance than observed for adults. A
dose of 100, 200 and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in
children to obtain a comparable systemic exposure.
Safety and efficacy for genital candidiasis indication in paediatric population has not
been established. Current available safety data for other paediatric indications are
described in section 4.8. If treatment for genital candidiasis is imperative in
adolescents (from 12 to 17 years old), the posology should be the same as adults
posology.
Term newborn infants (0 to 27 days):
Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support
this posology in term newborn infants (see section 5.2).
Age group
Term newborn infants (0
to 14 days)

Term newborn infants
(from 15 to 27 days)

Posology
The same mg/kg dose as
for infants, toddlers and
children should be given
every 72 hours
The same mg/kg dose as
for infants, toddlers and
children should be given
every 48 hours

Recommendations
A maximum dose of
12 mg/kg every 72 hours
should not be exceeded
A maximum dose of
12 mg/kg every 48 hours
should not be exceeded

Method of administration
Fluconazole may be administered either orally or by intravenous infusion, the route
being dependent 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.
The capsules should be swallowed whole and independent of food intake.

4.3

Contraindications
Hypersensitivity to the active substance, to related azole substances, or to any
of the excipients listed in section 6.1.
Coadministration of terfenadine is contraindicated in patients receiving
fluconazole at multiple doses of 400mg 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).

4.4

Special warnings and precautions for use
Tinea capitis
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, fluconazole should not be used for tinea capitis.
Cryptococcosis
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
recommendations.
Renal system
Fluconazole should be administered with caution to patients with renal
dysfunction (see section 4.2).
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 (see sections 4.3 and 4.5).
Adrenal insufficiency
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.
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 (see section 4.5).
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 (see section 4.3).
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 (see section 4.5).
Terfenadine
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).
Excipients
Fluconazole Hard 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.

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 torsades 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 QTc interval. Concomitant treatment with
fluconazole and cisapride is contraindicated (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 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 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 torsades 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 torsades de pointes. Coadministration of fluconazole and
pimozide is contraindicated (see section 4.3).

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).
Amiodarone: Concomitant administration of fluconazole with amiodarone
may result in inhibition of amiodarone metabolism. Use of amiodarone has
been associated with QT prolongation. Co-administration of fluconazole and
amiodarone 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 section 4.3).
Concomitant use of the following other medicinal products cannot be
recommended:
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 concentration of fluconazole by 40%.
An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.1
1

Mesure R. Protocol 245. An open placebo-controlled crossover study to
determine any effect of concomitant diuretic treatment on fluconazole
pharmacokinetics in healthy volunteers
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.
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. Fluconazole is also an inhibitor of the
isozyme CYP2C19. In addition to the observed/documented interactions
mentioned below, there is a risk of increased plasma concentration of other
compounds metabolised by CYP2C9 and CYP3A4 coadministered 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 AUC10
increased 2-fold, probably through inhibition of CYP3A4. Dose 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. Dose of
amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin
B in infected normal and immunosuppressed mice showed the following
results: a small additive antifungal effect in systemic infection with C.
albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two 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, 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 coumarin-type 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 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 metabolised 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 Pglycoprotein. 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 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.
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 (400mg) 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 metabolised 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.
Sulphonylureas: Fluconazole has been shown to prolong the serum half-life of
concomitantly administered oral sulphonylureas (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 200mg 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-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 AUCT 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, randomised, 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 50mg fluconazole study,
while at 200mg 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 lactation
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 congenital abnormalities (including
brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and
radio-humeral synostosis) in infants whose mothers were treated for at least
three or more months with high doses (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 (see section 5.3).
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. Breast-feeding may be maintained after a single use of a standard
dose 200 mg fluconazole or less. Breast-feeding is not recommended after
repeated use or after high dose fluconazole.
Fertility
Fluconazole did not affect the fertility of male or female rats (see section 5.3).
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 (see section
4.8) 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
Blood and the
lymphatic system
disorders
Immune system
disorders
Metabolism and
nutrition
disorders
Psychiatric
disorders
Nervous system
disorders

Ear and labyrinth

Common

Headache

Uncommon

Rare

Anaemia

Agranulocytosis,
leukopenia,
thrombocytopenia,
neutropenia
Anaphylaxis

Decreased appetite

Hypercholesterolaemia,
hypertriglyceridaemia,
hypokalaemia

Somnolence,
insomnia
Seizures,
paraesthesia,
dizziness, taste
perversion
Vertigo

Tremor

disorders
Cardiac disorders

Torsades de pointes (see
section 4.4), QT
prolongation (see section
4.4)

Gastrointestinal
disorders

Abdominal pain,
vomiting,
diarrhoea, nausea

Constipation,
dyspepsia,
flatulence, dry
mouth

Hepatobiliary
disorders

Alanine
aminotransferase
increased (see
section 4.4),
aspartate
aminotransferase
increased (see
section 4.4), blood
alkaline
phosphatase
increased (see
section 4.4)
Rash (see section
4.4)

Cholestasis (see
section 4.4),
jaundice (see
section 4.4),
bilirubin increased
(see section 4.4)

Hepatic failure (see
section 4.4),
hepatocellular necrosis
(see section 4.4),
hepatitis (see section
4.4), hepatocellular
damage (see section 4.4).

Drug eruption* (see
section 4.4), urticaria
(see section 4.4),
pruritus, increased
sweating

Toxic epidermal
necrolysis (see section
4.4), Stevens-Johnson
syndrome (see section
4.4), acute generalised
exanthematouspustulosis (see section
4.4), dermatitis
exfoliative, angioedema,
face oedema, alopecia

Skin and
subcutaneous
tissue disorders

Musculoskeletal
and connective
tissue disorders
General disorders
and
administration
site conditions

Myalgia

Fatigue, malaise,
asthenia, fever

* including Fixed Drug Eruption

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

Overdose
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

5.1

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties
ATC classification
Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC
code: J02AC01.
Mode of action
Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition
of fungal cytochrome P-450-mediated 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 P-450 enzyme systems.
Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone
plasma concentrations in males or steroid concentration in females of child-bearing
age. Fluconazole 200mg to 400mg 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 50mg 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.

PK/PD relationship
In animal studies, there is a correlation between MIC values and efficacy against
experimental mycoses due to Candida spp. 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 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 nonspecies 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 Candida
Candida Candida
Candida
albicans glabrata
krusei
parapsilosis
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
The pharmacokinetic properties of fluconazole are similar following administration
by the intravenous or oral route.
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 50mg 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 (see section 4.5). 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 halflife 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. Coadministration 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 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 adenomas.
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 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 oestrogenlowering property produced by high doses of fluconazole. Such a hormone change
has not been observed in women treated with fluconazole (see section 5.1).

6

6.1

PHARMACEUTICAL PARTICULARS

List of excipients
Lactose monohydrate
Microcrystalline cellulose
Pregelatinised maize starch
Colloidal anhydrous silica
Magnesium stearate
Sodium lauryl sulphate
Capsule shells
Titanium dioxide E171
Gelatin.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
36 months.

6.4

Special precautions for storage

No special precautions for storage.

6.5

Nature and contents of container
PVC / Aluminium blisters containing 7 capsules.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd
Ash Road North
Wrexham
LL13 9UF
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL29831/0305

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/08/2004 / 24/11/2009

10

DATE OF REVISION OF THE TEXT
09/06/2017

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