FLUCONAZOLE 200 MG CAPSULES HARD

Active substance: FLUCONAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Fluconazole 200 mg capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule, hard contains 200 mg fluconazole.
Excipient: 202.24 mg lactose/hard capsule
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Capsules, hard
Size ‘0’ hard gelatin capsule filled with white to off-white powder and
imprinted with ‘E’ on white to off-white opaque cap and ‘98’ on white to offwhite opaque body with yellow ink.

4

CLINICAL PARTICULARS

4.1

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

- Treatment of
cryptococcal
meningitis.

Posology
Loading dose:
400 mg on Day
1

Duration of treatment
Usually at least 6 to 8
weeks.

In life threatening
Subsequent
infections the daily dose
dose: 200 mg to can be increased to 800 mg
400 mg daily

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

200 mg daily

Indefinitely at a daily dose
of 200 mg

risk of recurrence.

Coccidioidomycosis

200 mg to 400
mg

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

Invasive candidiasis

Loading dose:
800 mg on Day
1

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.

Subsequent
dose: 400 mg
daily

Treatment of
mucosal candidiasis

- Oropharyngeal
candidiasis

Loading dose:
200 mg to 400
mg on Day 1

7 to 21 days (until
oropharyngeal candidiasis
is in remission).

Subsequent
Longer periods may be
dose: 100 mg to used in patients with
200 mg daily
severely compromised
immune function
- Oesophageal
candidiasis

Loading dose:
200 mg to 400
mg on Day 1

14 to 30 days (until
oesophageal candidiasis is
in remission).

Longer periods may be
Subsequent
dose: 100 mg to used in patients with
severely compromised
200 mg daily
immune function
- Candiduria

200 mg to 400
mg daily

7 to 21 days. Longer
periods may be used in
patients with severely
compromised immune
function.

- Chronic atrophic
candidiasis

50 mg daily

14 days

- Chronic
mucocutaneous
candidiasis

50 mg to 100
mg daily

Up to 28 days. Longer
periods depending on both
the severity of infection or
underlying immune
compromisation and

infection
An indefinite period for
patients with chronic
immune suppression

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

An indefinite period for
patients with chronic
immune suppression

Genital candidiasis

- Acute vaginal
candidiasis

150 mg

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

Maintenance dose: 6
months.

150 mg once
weekly or 50
mg once daily

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

300 mg to 400
mg once
weekly

1 to 3 weeks

50 mg once
daily
150 mg once
weekly

2 to 4 weeks

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

Dermatomycosis

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

- tinea versicolor

- tinea unguium
(onychomycosis)

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

Prophylaxis of
candidal infections in
patients with
prolonged
neutropenia

200 mg to 400
mg

vary widely in individuals,
and by age. After
successful treatment of
long-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
Posology
Recommendations
- Mucosal candidiasis
Initial dose: 6 mg/kg
Initial dose may be used on the
Subsequent dose: 3 mg/kg daily first day to achieve steady state
levels more rapidly
- Invasive candidiasis
Dose: 6 to 12 mg/kg daily
Depending on the severity of the
- Cryptococcal meningitis
disease
- Maintenance therapy to
Dose: 6 mg/kg daily
Depending on the severity of the
prevent relapse of
disease
cryptococcal meningitis in
children with high risk of
recurrence
- Prophylaxis of Candida in Dose: 3 to 12 mg/kg daily
Depending on the extent and
immunocompromised
duration of the induced
patients
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



Co-administration of terfenadine is contra-indicated in patients receiving
fluconazole at multiple doses of 400 mg per day or higher based upon results of
a multiple dose interaction study.



4.4

Hypersensitivity to the active substance, to related azole substances, or to any of
the excipients (see section 6.1)..

Co-administration 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 contra-indicated
in patients receiving fluconazole (see sections 4.4 and 4.5).

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).
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 StevensJohnson 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).
This medicinal product contains 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 co-administered. A controlled study
found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four
times a day yielded a significant increase in cisapride plasma levels and prolongation
of QT 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 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
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).
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

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 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. Dose 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
medicinal products in systemic infection with A. fumigatus. The clinical significance of
results obtained in these studies is unknown.
Anticoagulants: In post-marketing experience, as with other azole antifungals,
bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena)
have been reported, in association with increases in prothrombin time in patients
receiving fluconazole concurrently with warfarin. During concomitant treatment with
fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably
due to an inhibition of the warfarin metabolism through CYP2C9. In patients
receiving coumarin-type anticoagulants concurrently with fluconazole the
prothrombin time should be carefully monitored.. Dose adjustment of warfarin may be
necessary.

Benzodiazepines (Short Acting) , i.e. midazolam, triazolam: Following oral
administration of midazolam, fluconazole resulted in substantial increases in
midazolam concentrations and psychomotor effects. Concomitant intake of
fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and
half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given
concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life
4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam
have been observed at concomitant treatment with fluconazole.. If concomitant
benzodiazepine therapy is necessary in patients being treated with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, 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 dihydropyridine calcium channel antagonists
(nifedipine, isradipine, amlodipine and felodipine) are metabolized by CYP3A4.
Fluconazole has the potential to increase the systemic exposure of the calcium
channel antagonists. Frequent monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and
celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%,
respectively. Half of the celecoxib dose may be necessary when combined with
fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole
results in an increase in serum bilirubin and serum creatinine. The combination may
be used while taking increased consideration to the risk of increased serum bilirubin
and serum creatinine.
Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole
interaction was reported. Furthermore, it was shown in healthy volunteers that
fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl
concentration may lead to respiratory depression. Patients should be monitored
closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl
may be necessary.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases
when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised
through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as
fluvastatin. If concomitant therapy is necessary, the patient should be observed for
symptoms of myopathy and rhabdomyolysis and creatinine kinase should be
monitored. HMG-CoA reductase inhibitors should be discontinued if a marked
increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or
suspected.
Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):
Ciclosporin: Fluconazole significantly increases the concentration and AUC of
ciclosporin. During concomitant treatment with fluconazole 200 mg daily and
ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This
combination may be used by reducing the dose of ciclosporin depending on
ciclosporin concentration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum
concentrations of everolimus through inhibition of CYP3A4.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by
inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This
combination may be used with a dose adjustment of sirolimus depending on the
effect/concentration measurements.
Tacrolimus: Fluconazole may increase the serum concentrations of orally
administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism
through CYP3A4 in the intestines. No significant pharmacokinetic changes have been
observed when tacrolimus is given intravenously. Increased tacrolimus levels have
been associated with nephrotoxicity. Dose of orally administered tacrolimus should
be decreased depending on tacrolimus concentration
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E31 74) which is responsible for most of the angiotensin Il-receptor antagonism which
occurs during treatment with losartan. Patients should have their blood pressure
monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone.
Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was
increased by 23% and 81%, respectively, when coadministered with fluconazole
compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of
the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and
82%, respectively, when fluconazole was coadministered with racemic ibuprofen
(400 mg) compared to administration of racemic ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the
systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen,
lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and
toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be
needed.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant
repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously,
caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With
coadministration, serum phenytoin concentration levels should be monitored in order
to avoid phenytoin toxicity.
Prednisone: There was a case report that a liver-transplanted patient treated with
prednisone developed acute adrenal cortex insufficiency when a three month therapy
with fluconazole was discontinued. The discontinuation of fluconazole presumably
caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone.
Patients on long-term treatment with fluconazole and prednisone should be carefully
monitored for adrenal cortex insufficiency when fluconazole is discontinued.
Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to
increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in
patients to whom fluconazole and rifabutin were coadministered. In combination
therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with
approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic
metabolism by CYP3A4 and inhibition of P- glycoprotein. Interaction with
saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment
of saquinavir may be necessary.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of
concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide,
glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and
appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Theophylline: In a placebo controlled interaction study, the administration of
fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma
clearance rate of theophylline. Patients who are receiving high dose theophylline or who
are otherwise at increased risk for theophylline toxicity should be observed for signs of
theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of
toxicity develop.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of
the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is
possibly due to an inhibitory effect on CYP3A4.
Vitamin A: Based on a case-report in one patient receiving combination therapy with
all-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.

τ

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approx. 45% decrease in oral zidovudine clearance. The halflife 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.

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

4.6

Pregnancy and lactation
Pregnancy
Data from several hundred pregnant women treated with standard doses (<200 mg/day)
of fluconazole, administered as a single or repeated dosage in the first trimester, show no
undesired effects in the foetus.
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.

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, < 1/10)
Uncommon: ( 1/1,000 < 1/100)
Rare ( 1/10,000 < 1/1,000)
Very rare (< 1/10,000, not known (cannot be estimated from the available data)
System Organ Common
Uncommon
Rare
Class









4.8

Anaemia

Blood and the
lymphatic
system
disorders

Anaphylaxis

Immune
system
disorders
Metabolism
and nutrition
disorders

Psychiatric
disorders
Nervous
system
disorders
Ear and
labyrinth
disorders
Cardiac
disorders

Gastrointestin
al disorders
Hepatobiliary
disorders

Agranulocytosis
, leukopenia,
thrombocytopen
ia, neutropenia

Decreased appetite

Hypercholestero
laemia,
hypertriglycerid
aemia,
hypokalemia

Somnolence, insomnia
Headache

Seizures, paraesthesia,
dizziness, taste perversion

Tremor

Vertigo

Torsade de
pointes (see
section 4.4), QT
prolongation
(see section 4.4)
Abdominal pain,
vomiting,
diarrhoea, nausea
Alanine
aminotransferase
increased (see
section 4.4),
aspartate
aminotransferase
increased (see
section 4.4),
blood alkaline
phosphatase
increased (see

Constipation, dyspepsia,
flatulence, dry mouth
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)

Skin and
subcutaneous
tissue
disorders

section 4.4)
Rash (see section
4.4)

Musculoskelet
al and
connective
tissue
disorders
General
disorders and
administration
site conditions

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

Myalgia

Fatigue, malaise, asthenia,
fever

Pediatric 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.

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 hemodialysis session decreases plasma levels
by approximately 50%.

5

PHARMACOLOGICAL PROPERTIES

5.1

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 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.
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)

Non-species
related
breakpoints

A S
Candid
a
albican
s
2/4

Candid
a
glabrat
a
IE

Candid
a krusei

Candida
parapsilosi
s

Candida
tropicali
s

Fluconazol
-2/4
2/4
2/4
e
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

Pharmacokinetic properties
Absorption:
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. The protein
binding is low (11-12%).
Fluconazole achieves good penetration in all body fluids studied. The levels of
fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal
meningitis, fluconazole levels in the CSF are approximately 80% the corresponding
plasma levels.
High skin concentration of fluconazole, above serum concentrations, are achieved in
the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates
in the stratum corneum. At a dose of 50 mg once daily, the concentration of
fluconazole after 12 days was 73 g/g and 7 days after cessation of treatment the
concentration was still 5.8 g/g. At the 150 mg once-a-week dose, the concentration
of fluconazole in stratum corneum on day 7 was 23.4 g/g and 7 days after the second
dose was still 7.1 g/g.

μ

μ

μ

μ

5.2

Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing
was 4.05 g/g in healthy and 1.8 g/g in diseased nails; and, fluconazole was still
measurable in nail samples 6 months after the end of therapy.

μ

μ

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 1 study were not interpretable due to changes in formulation partway 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 g/ml and occurred at 1.3
hours post-dose. The mean AUC was 76.4 ± 20.3 g 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.

μ

μ

5.3

Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered
sufficiently in excess of the human exposure indicating little relevance to clinical use.
Carcinogenesis
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated
orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 27 times the
recommended human dose). Male rats treated with 5 and 10 mg/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 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg
embryolethality in rats was increased and foetal abnormalities included wavy ribs,
cleft palate, and abnormal cranio-facial ossification.
The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and
prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg
intravenously. The disturbances in parturition were reflected by a slight increase in
the number of still-born pups and decrease of neonatal survival at these dose levels.
These effects on parturition are consistent with the species specific 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

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule content

Lactose monohydrate,
Maize starch,
Sodium lauril sulphate
Colloidal silica anhydrous
Magnesium stearate
Capsule shell
Titanium dioxide (E171)
Sodium lauril sulfate
Gelatin
Printing ink
Shellac
Propylene glycol
Yellow iron oxide (E172)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage condition.

6.5

Nature and contents of container
Clear PVC/PVDC-Aluminium blister
1, 2, 3, 4, 5, 6, 7, 10, 14, 20, 21, 28, 30, 50, 60, 90, 100 capsules
HDPE bottle with tamper-evident polypropylene closure
30 and 500 (clinical pack) capsules
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares, Odyssey Business Park
West End Road, South Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16363/0318

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/05/2011

10

DATE OF REVISION OF THE TEXT
21/02/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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