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FLUCONAZOLE 150 MG CAPSULE

Active substance(s): FLUCONAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Fluconazole 150 mg Capsule

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 150 mg of the active ingredient fluconazole.
Excipient:
Lactose: 111.96 mg (per capsule).
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Size 1 hard gelatin capsules, blue opaque cap and body: marked with
the code ‘FCZ 150’.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Vaginal candidiasis, acute or recurrent. Candidal balanitis associated with vaginal
candidiasis.

4.2

Posology and method of administration
For oral use.
Use in adults
Candidal vaginitis or balanitis: 150 mg single oral dose.

Use in children
Not recommended in children under 16 years.

Use in the elderly
Not recommended in patients aged over 60 years.

Use in patients with impaired renal function
Fluconazole is excreted predominantly in the urine as unchanged drug. No
adjustments in single dose therapy are required.
Method of Administration
Fluconazole capsules should be swallowed whole and may be taken without regard to
meals.

4.3

Contraindications
Patients with known hypersensitivity to fluconazole or to related triazole
anti-fungal agents or to any other ingredient in the formulation.
Patients who are taking cisapride, terfenadine or astemizole (see sections
4.4 and 4.5).
Patients with congenital or documented acquired QT prolongation.
Patients who are taking other medicaments that prolong the QT interval
such as antiarrhythmics of classes IA and III.
Patients with electrolyte disturbance, particularly hypokalaemia and
hypomagnesaemia.
Patients with clinically relevant bradycardia, cardiac arrythmia or severe
cardiac insufficiency.

4.4

Special warnings and precautions for use
The product is intended for pharmacy availability without prescription and
will include a leaflet which will advise the patient:
Do not use this Fluconazole 150 mg Capsule without first asking your
pharmacist or doctor if:


You are under 16 or over 60 years of age.



You are or have you ever been told that you are allergic to fluconazole
or to other drugs of the same type (called triazoles) that are used to
treat fungal infections.



You are allergic to any of the other ingredients in these capsules?



You are taking cisapride, terfenadine or astemizole. Fluconazole must
not be taken by people who are taking one of these medicines because
there is a risk of a serious rhythm disturbance of the heart.



You take medicine(s) to control your heart rate or rhythm. These drugs
include quinidine, amiodarone, sotalol, disopyramide, but there are
many others so check with your doctor or pharmacist before you take
fluconazole.



You have a very slow heart rate or a serious heart rhythm disturbance
or heart failure. Also, have you ever been told that you have a long QT
interval (a type of heart rhythm disturbance that is found on ECG’s).



You suffer from low levels of potassium or magnesium in your blood.



You have a serious ongoing illness, such as cancer, or severe problems
with your body, liver or kidneys. Fluconazole is particularly likely to
cause changes in blood test results in such people.



You have AIDS. You can still take fluconazole but be aware that
people who have AIDS are more likely to develop very severe skin
reactions to fluconazole.



You developed problems with your liver while taking fluconazole
previously. If so, you should not take fluconazole to treat vaginal
thrush.




Women Only:
You are pregnant or trying to become pregnant or are breast feeding
(see below).
You have any abnormal or irregular vaginal bleeding or a blood stained
discharge.




You have vulval or vaginal sores, ulcers or blisters.
You are experiencing lower abdominal pain or burning on passing urine.







Men Only:
Your sexual partner does not have vaginal thrush.
You have penile sores, ulcers or blisters.
You have an abnormal penile discharge (leakage)
Your penis has started to smell.
You have pain passing urine.

The product should never be used again if the patient experiences a rash or
anaphylaxis following use of the drug.
Recurrent use (men and women): Patients should be advised to consult
their physician if the symptoms have not been relieved within one week of
taking a Fluconazole 150 mg Capsule. Fluconazole 150 mg Capsules can be
used if the candidal infection returns after 7 days. However, if the candidal
infection recurs more than twice within six months, patients should be advised
to consult their physician.
In some patients, particularly those with serious underlying diseases such as
AIDS and cancer, abnormalities in haematological, hepatic, renal and other
biochemical function test results have been observed during multiple-dose
treatment with fluconazole but the clinical significance and relationship to
treatment is uncertain.
In cases of hepatotoxicity, no obvious relationship to total daily dose of
fluconazole, duration of therapy, sex or age of the patient has been observed;
the abnormalities have usually been reversible on discontinuation of
fluconazole therapy. However, fluconazole should not be given to patients
who developed clinical signs or symptoms consistent with liver disease during
previous treatment with fluconazole.
Patients have rarely developed exfoliative cutaneous reactions, such as
Stevens-Johnson syndrome and toxic epidermal necrolysis, during or after
treatment with fluconazole. AIDS patients are more prone to the development
of severe cutaneous reactions to many medicinal products.
Patients who developed a rash that was considered attributable to fluconazole
during previous therapy should not receive fluconazole again, even as single
dose therapy.
Lactose intolerance: the 150 mg capsules contain approximately 112 mg of
lactose. This amount is not thought likely to cause symptoms in patients with
lactose intolerance.

4.5

Interaction with other medicinal products and other forms of interaction
The following combinations are contra-indicated:
Cisapride (CYP3A4 substrate): There have been reports about cardiac cases including
torsades de pointes in patients receiving fluconazole concomitantly with cisapride.
Concomitant treatment with fluconazole and cisapride is contra-indicated.
Terfenadine (CYP3A4 substrate): Due to the occurrence of serious cardiac
dysrhythmias secondary to prolongation of the QTc-interval in patients receiving
azole antifungal drugs concomitantly with terfenadine, interaction studies have been
performed. One study with 200mg fluconazole daily did not show any prolongation
of the QTc-interval. Another study with 400mg and 800mg fluconazole daily showed
that fluconazole 400mg or more daily significantly increases the plasma level of

terfenadine when taken concomitantly. There have been spontaneous case-reports of
palpitations, tachycardia, dizziness and chest pain in patients taking concomitant
fluconazole and terfenadine. Concomitant treatment with terfenadine and fluconazole
is contra-indicated.
Astemizole (CYP3A4 substrate): Astemizole overdoses have led to prolonged QT
interval and severe ventricular arrhythmia, torsades de pointes and cardiac arrest.
Concomitant treatment with fluconazole and astemizole is contra-indicated due to the
potential for serious, potentially fatal, cardiac effects.
Effect of fluconazole on the metabolism of other medicinal products:
Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a
moderate inhibitor of CYP3A4. Besides the observed/documented interactions listed
below there is a risk of increased plasma concentrations of other medicinal products
metabolised by CYP2C9 or CYP3A4 (e.g. ergot-alkaloids, quinidine) when coadministered with fluconazole. Therefore, care should always be taken when using
these combinations and the patients should be carefully monitored. The enzymeinhibiting effect of fluconazole may persist for 4-5 days after end of fluconazole
treatment due to the long fluconazole half-life.
Alfentanil (CYP3A4 substrate): Concomitant intake of fluconazole 400 mg and
alfentanil 20 pg/kg intravenously in healthy volunteers increased the alfentanil AUC10
approximately 2-fold and decreased the clearance by 55%, probably through
inhibition of CYP3A4. Adjustment of the alfentanil dose may be required.
Amitriptyline: Several case reports have described the development of increased
amitriptyline concentrations and signs of tricyclic toxicity when amitriptyline was
used in combination with fluconazole. Co-administration of fluconazole with
nortriptyline, the active metabolite of amitriptyline, has been reported to result in
increased nortriptyline levels. Due to the risk of amitriptyline toxicity, consideration
should be given to monitoring amitriptyline levels and making dose adjustments as
may be necessary.
Anticoagulants (CYP2C9 substrate): Concomitant intake of fluconazole during
warfarin treatment may prolong the prothrombin time up to 2-fold. This is likely to be
due to an inhibition of warfarin metabolism via CYP2C9. As for other azoles there
have been reports of bleeding (bruises, nose bleeding, gastrointestinal bleeding, blood
in the urine and faeces) in connection with an increase of prothrombin time in patients
concomitantly treated with warfarin. Prothrombin times must be closely monitored in
patients on treatment with coumarin derivatives.
Benzodiazepines (CYP3A4 substrate): Concomitant intake of fluconazole 400 mg
and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7- fold
and 2.2-fold, respectively, and also the psychomotor effects. Fluconazole 100 mg
daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC
and half-life 2.5-fold and 1.8-fold, respectively. Potentiated and prolonged effects of
triazolam have been observed during concomitant treatment with concomitantly with

fluconazole, a reduction of the benzodiazepine dose should be considered and the
patients should be closely monitored.
Calcium channel antagonists (CYP3A4 substrates): Some dihydropyridine calcium
channel antagonists (including nifedipine, isradipine, nicardipine, amlodipine, and
felodipine) are metabolised via CYP3A4. Literature reports have documented
substantial peripheral oedema and/or elevated calcium
antagonist serum concentrations during concurrent use of itraconazole and felodipine,
isradipine, or nifedipine. An interaction might occur also with fluconazole.
Celecoxib (CYP2C9 substrate): In a clinical study, concomitant treatment with
fluconazole 200 mg daily and celecoxib 200 mg resulted in a 68% and 134% increase
in celecoxib Cmax and AUC, respectively. The interaction is believed to be due to
inhibition of cytochrome P450 2C9 metabolism of celecoxib. Halving the Celecoxib
dose is recommended in patients concurrently treated with fluconazole.
Ciclosporin (CYP3A4 substrate): Clinically significant interactions with ciclosporin
have been shown at fluconazole doses of 200 mg and higher. In a pharmacokinetic
study with renal transplant patients receiving fluconazole 200 mg daily and
ciclosporin 2.7 mg/kg/day, there was an 1.8-fold increase in ciclosporin AUC and a
55% decrease in clearance. However, in another study, multiple dosing with
fluconazole 100 mg daily did not influence cyclosporin concentrations in patients
after bone marrow transplants. Plasma concentrations of ciclosporin should be
monitored during treatment with fluconazole.
Didanosine: Although co-administration of didanosine and fluconazole appears to
have little effect on the pharmacokinetics or efficacy of didanosine, the response to
fluconazole should be monitored. It may be advantageous to administer fluconazole
at some time prior to didanosine.
HMG-CoA reductase inhibitors (CYP2C9 or CYP3A4 substrates): The risk of
myopathy is increased when fluconazole is administered concurrently with HMG
CoA reductase inhibitors that are metabolised via CYP3A4, such as atorvastatin and
simvastatin, or via CYP2C9, such as fluvastatin. Up to 200% individual increases in
the area under the curve (AUC) of fluvastatin may occur as a result of the interaction
between fluvastatin and fluconazole. Caution is warranted if concurrent
administration of fluconazole and HMG-CoA reductase inhibitors is deemed
necessary. The combination may require a dose reduction of the HMG CoA reductase
inhibitors. Patients should be monitored for signs and symptoms of myopathy or
rhabdomyolysis (muscle pain, tenderness or wekness) and creatine kinase (CK)
levels. HMG-CoA therapy should be discontinued if CK levels show a marked
increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.
Losartan (CYP2C9 substrate): Fluconazole inhibits the conversion of losartan to its
active metabolite (E-3174), which is responsible for a large part of the angiotensin II
receptor antagonism that occurs with losartan therapy. Concomitant treatment with
fluconazole might lead to increased concentrations of losartan and decreased
concentrations of the active metabolite. It is recommended that patients receiving the
combination be monitored for continued control of their hypertension.

Oral contraceptives: Two pharmacokinetic studies have been performed with a
combined oral contraceptive and multiple dosing of fluconazole. 50 mg fluconazole
did not influence any of the hormone concentrations, but 200 mg daily increased
AUC ethinylestradiol and levonorgestrel by 40 and 24%, respectively. Thus, it is
unlikely that multiple dosing of fluconazole at these doses is unlikely to impair the
efficacy of combined oral contraceptive pills.
Phenytoin (CYP2C9 substrate): Intake of fluconazole 200 mg concomitantly with
phenytoin 250 mg intravenously increased the phenytoin AUC by 75% and Cmin by
128 %. If it is necessary to administer both substances concomitantly, the plasma
concentration of phenytoin must be controlled, and the phenytoin dose adjusted, in
order to avoid toxic concentrations.
Prednisone (CYP3A4 substrate): A liver transplant recipient receiving prednisone
experienced an Addisonian crisis when a three-month course of fluconazole was
discontinued. The withdrawal of fluconazole was likely to have caused an increase in
CYP3A4 activity, leading to an increase in the degradation of prednisone. Patients
receiving long-term therapy with fluconazole and prednisone should be closely
monitored for signs of adrenal insufficiency when fluconazole is withdrawn.
Rifabutin (CYP3A4 substrate): There have been reports that concomitant
administration of fluconazole and rifabutin can lead to increased serum levels of
rifabutin. Uveitis in patients treated concomitantly with fluconazole and rifabutin has
been reported. Patients who receive rifabutin and fluconazole concomitantly must be
closely followed.
Sulphonylureas (CYP2C9 substrate): It has been demonstrated that fluconazole
prolongs the plasma half-life of concomitantly administered sulphonylurea drugs
(chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers.
Fluconazole and oral sulphonylurea derivatives may be used concomitantly in
diabetics, but the possibility of development of hypoglycaemia must be kept in mind.
Tacrolimus and sirolimus (CYP3A4 substrates): Concomitant intake of fluconazole
and tacrolimus 0.15 mg/kg b.i.d. increased tacrolimus Cmin 1.4 and 3.1-fold with
fluconazole doses of 100 mg and 200 mg, respectively. Renal toxicity has been
reported in patients concomitantly receiving fluconazole and tacrolimus. Although no
interaction studies have been conducted with fluconazole and sirolimus, a similar
interaction as with tacrolimus might be expected. Patients who receive tacrolimus or
sirolimus and fluconazole concomitantly must be closely monitored for
tacrolimus/sirolimus plasma levels and toxicity (anaemia, leucopenia,
thrombocytopenia, hypokalaemia, diarrhoea).
Theophylline: In a placebo controlled interaction study, intake of fluconazole 200 mg
for 14 days resulted in an 18% decrease in the mean plasma clearance of
theophylline. Patients being treated with high doses of theophylline or with any other
reason to be at increased risk of theophylline toxicity should be

observed carefully during concomitant treatment with fluconazole and the dose of
theophylline must be adjusted as necessary.
Trimetrexate: Medicaments such as fluconazole that inhibit the P450 enzyme system
may cause interactions that increase trimetrexate plasma concentrations. If it is not
possible to avoid concomitant administration of trimetrexate and fluconazole,
trimetrexate serum levels and trimetrexate toxicity (bone marrow suppression, renal
and hepatic dysfunction, and gastrointestinal ulceration) must be monitored carefully.
Zidovudine: Interaction studies showed increased zidovudine AUC by approximately
20% and 70% when taken concomitantly with fluconazole 200 mg or 400 mg daily,
respectively, probably due to inhibiton of glucuronidation. Patients receiving this
combination must be monitored for zidovudine related side-effects.
Medicinal products affecting the metabolism and/or excretion of fluconazole:
Hydrochlorothiazide: In a pharmacokinetic interaction study with healthy volunteers
who concomitantly received fluconazole and multiple doses of hydrochlorothiazide
the plasma concentrations of fluconazole increased by 40%. An effect of this size
should not necessitate a change in the fluconazole dose regimen in patients who are
concomitantly treated with diuretics, although the prescriber should bear this in mind.
Rifampicin (CYP45O inducer): Concomitant intake of fluconazole and rifampicin
resulted in a 25% reduction of AUC and 20% reduction in the half-life of fluconazole.
An increase in the dosage of fluconazole should be considered in patients
concomitantly receiving rifampicin.
Pharmacodynamic interactions
Medicinal products that prolong QT interval: There have been cases reported in
which fluconazole might have contributed to QT prolongation leading to serious
cardiac arrhythmias. Patients treated concomitantly with fluconazole and other drugs
that prolong QT interval should be carefully monitored, since an additive effect
cannot be excluded.
Amphotericin B: In vitro and in vivo animal studies have found antagonism between
amphotericin B and azole derivatives. The mechanism of action of imidazoles is to
inhibit ergosterol synthesis in fungal cell membranes. Amphotericin B acts by binding
to sterols in the cell membrane and changing membrane permeability. Clinical effects
of this antagonism are to date unknown.
A similar effect may occur with amphotericin B cholesteryl sulfate complex.

Interaction studies have shown that no clinically significant change in absorption of
fluconazole occurs with oral use together with food, cimetidine, antacids or after
radiation therapy of the whole body in connection with bone marrow transplantation.

4.6

Fertility, pregnancy and lactation
There are no adequate and well controlled studies in pregnant women. There
have been reports of multiple congenital abnormalities in infants whose mothers were
being treated for 3 or more months with high dose (400-800 mg/day) fluconazole
therapy for coccidioidomycosis. The relationship between fluconazole and these
events is unclear.
Fluconazole should not be used for the treatment of vaginal candidasis during
pregnancy.

Use during lactation
Fluconazole is found in human breast milk at concentrations similar to plasma, hence
its use in nursing mothers is not recommended.

4.7

4.8

Effects on ability to drive and use machines
Experience with fluconazole indicates that therapy is unlikely to impair a
patient's ability to drive or use machinery. However, when driving or
operating machines it should be taken into account that occasionally
dizziness or seizures may occur.

Undesirable effects
The most common side effects observed during clinical trials and associated with
fluconazole are:
Central and Peripheral Nervous System:
Headache.
Dermatological:
Skin rash, accompanies by eosinophilia and pruritis has been reported in about 5% of
patients receiving fluconazole.

Gastrointestinal:
Abdominal pain, diarrhoea, flatulence, nausea.
In some patients, particularly those with serious underlying diseases such as AIDS
and cancer, changes in renal and haematological function test results and hepatic
abnormalities have been observed during treatment with fluconazole and comparative
agents, but the clinical significance and relationship to treatment is uncertain (see
Section 4.4 "Special warnings and precautions for use").
Liver/Biliary:
Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase,
elevated bilirubin, alanine aminotransferase (ALAT) and elevated aspartate
aminotransferase (ASAT).
In addition, the following adverse events have occurred during post-marketing:
Allergic reactions:
Anaphylaxis (including angio-oedema, facial oedema and pruritis).
Dermatological:
Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and
toxic epidermal necrolysis.
Central and Peripheral Nervous System:
Dizziness, seizures.
Gastrointestinal:
Dyspepsia, vomiting.
Haematopoietic and Lymphatic:
Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.
Immunological Anaphylaxis:

(including angioedema, face oedema, pruritus).
Liver/Biliary:
Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.
Metabolic/Nutritional:
Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.
Other senses:
Taste perversion.

4.9

Overdose
In the event of overdosage, supportive measures and symptomatic treatment, with
gastric lavage if necessary, may be adequate.
As fluconazole is largely excreted in the urine, forced volume diuresis would
probably increase the elimination rate. A three hour haemodialysis session decreases
plasma levels by approximately 50%.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC Code: JO2A CO1. The ATC-classification is: Antimycotics for systemic use;
triazole derivatives.
Fluconazole belongs to the group of triazole antimycotics, specifically inhibiting
fungal ergosterol synthesis.

5.2

Pharmacokinetic properties
After oral administration fluconazole is well absorbed and plasma levels (and
systemic bioavailability) are over 90% of the levels achieved after intravenous

administration. Oral absorption is not affected by concomitant food intake. Peak
plasma concentrations in the fasting state occur between 0.5 and 1.5 hours
post-dose with a plasma elimination half-life of approximately 30 hours. Plasma
concentrations are proportional to dose. Ninety percent steady-state levels are
reached by day 4 -5 with multiple once daily dosing.
Administration of a loading dose (on day 1) of twice the usual daily dose enables
plasma levels to approximate to 90% steady-state levels by day 2. The apparent
volume of distribution approximates to total body water. Plasma protein binding is
low (11-12%).
Fluconazole achieves good penetration in all body fluids studied. The levels of
fluconazole in saliva and sputum are similar to plasma levels. In patients with
fungal meningitis, fluconazole levels in the CSF are approximately 80% of the
corresponding plasma levels.
High skin concentrations of fluconazole, above serum concentrations are achieved
in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole
accumulates in the stratum corneum. At a dose of 50mg once daily, the
concentration of fluconazole after 12 days was 73 microgram/g and 7 days after
cessation of treatment the concentration was still 5.8 microgram/g
The major route of excretion is renal, with approximately 80% of the
administered dose appearing in the urine as unchanged drug. Fluconazole
clearance is proportional to creatinine clearance. There is no evidence of
circulating metabolites.
The long plasma elimination half-life provides the basis for single dose therapy
for genital candidiasis and once daily dosing for other indications.
Children metabolise fluconazole more rapidly. The half-life in children of 5-15
years is between 15.2 –17.6 hours, about half that of adults.

5.3

Preclinical safety data
Preclinical data from conventional studies on repeat-dose/general toxicity,
genotoxicity or carcinogenicity indicate no special hazard for humans not
already considered in other sections of the SPC.
In reproduction toxicity studies in rat an increased incidence of hydronephrosis
and extension of renal pelvis was reported and embryonal lethality was
increased. An increase in anatomical variations and delayed ossification was
noted as well as prolonged delivery and dystocia, effects consistent with
inhibition of oestrogen synthesis in rat. In reproduction toxicity studies in
rabbits abortions were recorded. These effects were observed only at
exposures in excess of the maximum human exposure.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule contents:
Lactose
Maize starch
Colloidal anhydrous silica
Talc
Sodium lauryl sulphate
Capsule shells:
Gelatin
Patent blue (E131)
Titanium dioxide (E171)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)

6.2

Incompatibilities
None.

6.3

Shelf life
24 months.

6.4

Special precautions for storage
Do not store above 25ºC. Store in the original package.

6.5

Nature and contents of container
Blister strip composed of: 25 micron Aluminium foil with 250 micron white
opaque PVC film coated with 60 gsm PVdC.
Pack containing 1 capsule.

6.6

Special precautions for disposal
No special precautions are required.

7. MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited
Hillbrow House
Hillbrow Road
Esher
Surrey
KT10 9NW

8

MARKETING AUTHORISATION NUMBER(S)
PL 36390/0029

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/02/2012

10

DATE OF REVISION OF THE TEXT
28/11/2012

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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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