Fluconazole 150 MG Capsule SMPC - Taj Pharmaceuticals

Fluconazole 150 mg Capsule SMPC, Taj Phar maceuticals
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4.3 Contraindications
RX Fluconazole should not be used in patients with
known hypersensitivity to the drug, any of the
FLUCONAZOLE inert ingredients listed in section 6.1 or to related
azole compounds.
CAPSULE Coadministration of terfenadine is
150MG contraindicated in patients receiving fluconazole
at multiple doses of 400mg per day or higher
1.NAME OF THE MEDICINAL PRODUCT based upon results of a multiple dose interaction
study. Coadministration of other medicinal
Fluconazole 150 mg Capsule products known to prolong the QT interval and
2. QUALITATIVE AND QUANTITATIVE which are metabolised via the cytochrome P450
COMPOSITION (CYP) 3A4 such as cisapride, astemizole,
pimozide, quinidine and erythromycin are
Each capsule contains 150 mg fluconazole. contraindicated in patients receiving fluconazole
Excipients with known effect: (see section 4.4 and 4.5).
Also contains Lactose Monohydrate and Sunset Fluconazole should not be used in patients with
Yellow E110. porphyria.
For full list of excipients, see section 6.1. 4.4 Special Warnings and precautions for use
3. PHARMACEUTICAL FORM Renal system
Capsules, hard. Fluconazole should be administered with caution

to patients with renal dysfunction (see section
Fluconazole 150 mg Capsules are yellow 4.2).
capsules.
Adrenal insufficiency
4. CLINICAL PARTICULARS
Ketoconazole is known to cause adrenal
4.1 Therapeutic indications insufficiency, and this could also, although
Fluconazole 150mg capsule is indicated for the rarely seen, be applicable to fluconazole.
treatment of candidal vaginitis, acute or
recurrent. It should also be used for treatment of Adrenal insufficiency relating to concomitant
partners with associated candidal balanitis. treatment with Prednisone is described in section
4.5 'The effect of fluconazole on other
4.2 Posology and method of administration medicinal products'.
Fluconazole is administered orally. Hepatobiliary system
Adults (16 to 60 years): Fluconazole should be administered with caution
to patients with liver dysfunction. Fluconazole
One capsule should be swallowed whole.
has been associated with rare cases of serious
Children (under 16 years): hepatic toxicity including fatalities, primarily in
patients with serious underlying medical
Paediatric use is not recommended. conditions. In cases of fluconazole-associated
Elderly: hepatotoxicity, no obvious relationship to total
daily dose, duration of therapy, sex or age of
Not recommended in patients over 60 years. patient has been observed. Fluconazole
Renal Impairment: hepatotoxicity has usually been reversible on
discontinuation of therapy.
There is no separate dosage schedule in patients
with renal impairment for single dose therapy. Patients who develop abnormal liver function
tests during fluconazole therapy should be
monitored closely for the development of more Patients have rarely developed exfoliative
serious hepatic injury. The patient should be cutaneous reactions, such as Stevens-Johnson
informed of suggestive symptoms of serious syndrome and toxic epidermal necrolysis, during
hepatic effect (important asthenia, anorexia, treatment with fluconazole. AIDS patients are
persistent nausea, vomiting and jaundice). more prone to the development of severe
Fluconazole should be discontinued immediately cutaneous reactions to many drugs. If a rash,
if clinical signs or symptoms consistent with which is considered attributable to fluconazole,
liver disease develop that may be attributable to develops in a patient treated for a superficial
fluconazole and the patient should consult a fungal infection, further therapy with this agent
physician. should be discontinued. If patients with
invasive/systemic fungal infections develop
Cardiovascular system rashes, they should be monitored closely and
Some azoles, including fluconazole, have been fluconazole discontinued if bullous lesions or
associated with prolongation of the QT interval erythema multiforme develop.
on the electrocardiogram. Fluconazole causes Hypersensitivity
QT prolongation via the inhibition of Rectifier
Potassium Channel current (Ikr). The QT In rare cases, as with other azoles, anaphylaxis
prolongation caused by other medicinal products has been reported (see section 4.3).
(such as amiodarone) may be amplified via the
Cytochrome P450
inhibition of cytochrome P450 (CYP) 3A4.
During post- marketing surveillance, there have Fluconazole is a moderate CYP2C9 and
been very rare cases of QT prolongation and CYP3A4 inhibitor. Fluconazole is also a strong
torsade de pointes in patients taking fluconazole. inhibitor of CYP2C19. Fluconazole treated
These reports included seriously ill patients with patients who are concomitantly treated with
multiple confounding risk factors, such as drugs with a narrow therapeutic window
structural heart disease, electrolyte abnormalities metabolised through CYP2C9, CYP2C19 and
and concomitant medicines that may have been CYP3A4, should be monitored (see section 4.5
contributory. Patients with hypokalemia and Interaction with Other Medicaments and Other
advanced cardiac failure are at an increased risk Forms of Interaction)
for the occurrence of life threatening ventricular
arrhythmias and torsades de pointes. Terfenadine
Fluconazole should be administered with caution The coadministration of fluconazole at doses

to patients with these potentially proarrythmic lower than 400mg per day with terfenadine
conditions. should be carefully monitored (see section 4.3
Contraindications and 4.5 Interaction with Other
Coadministration of other medicinal products Medicaments and Other Forms of Interaction).
known to prolong the QT interval and which are
metabolised via the cytochrome P450 (CYP) Excipients
3A4 are contraindicated (see sections 4.3 and Fluconazole Capsules contain lactose and should
4.5). not be given to patients with rare hereditary
Halofantrine problems of galactose intolerance, total lactase
deficiency or glucose-galactose malabsorption.
Halofantrine has been shown to prolong QTc
interval at the recommended therapeutic dose The product intended for pharmacy availability
and is a substrate of CYP3A4. The concomitant without prescription will carry a leaflet which
use of fluconazole and halofantrine is therefore will advise the patient:
not recommended (see section 4.5). Do not use Fluconazole 150mg capsule
Dermatological reactions without first consulting your doctor:
• If you are under 16 or over 60 years of age.
• If you are allergic to any of the ingredients in Recurrent use (men and women): Patients
Fluconazole 150mg capsule or other antifungals should be advised to consult their physician if
and other thrush treatments. the symptoms have not been relieved within one
week of taking Fluconazole. A further capsule
• If you are taking any medicine other than the can be used if the candidal infection returns after
contraceptive pill.
7 days. However, if the candidal infection recurs
• If you are taking the antihistamine terfenadine more than twice within six months, patients
or the prescription medicine cisapride. should be advised to consult their physician.
• If you have had thrush more than twice in the This product contains lactose. Patients with rare
last six months. hereditary problems of galactose intolerance,
total lactase deficiency or glucose-galactose
• If you have any disease or illness affecting malabsorption should not take this medicine.
your liver or kidneys or have had unexplained
jaundice. 4.5 Interaction with other medicinal
products and other forms of interaction
• If you suffer from any other chronic disease or
illness. Concomitant use of the following other
medicinal products is contraindicated:
• If you or your partner have had exposure to a
sexually transmitted disease. Cisapride: There have been reports of cardiac
events including torsade de pointes in patients to
• If you are unsure about the cause of your whom fluconazole and cisapride were
symptoms. coadministered. A controlled study found that
Women only: concomitant fluconazole 200mg once daily and
cisapride 20mg four times a day yielded a
• If you are pregnant, suspect you might be significant increase in cisapride plasma levels
pregnant or are breast feeding. and prolongation of QT interval. Concomitant
• If you have any abnormal or irregular vaginal treatment with fluconazole and cisapride is
bleeding or a blood stained discharge. contraindicated (see section 4.3).
• If you have vulval or vaginal sores, ulcers or Terfenadine: Because of the occurrence of
blisters. serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients
• If you are experiencing lower abdominal pain receiving azole antifungals in conjunction with
or burning on passing urine. terfenadine, interaction studies have been
performed. One study at a 200mg daily dose of
Men only:
fluconazole failed to demonstrate a prolongation
• If your sexual partner does not have vaginal in QTc interval. Another study at a 400mg and
thrush. 800mg daily dose of fluconazole demonstrated
that fluconazole taken in doses of 400mg per
• If you have penile sores, ulcers or blisters. day or greater significantly increases plasma
• If you have an abnormal penile discharge levels of terfenadine when taken concomitantly.
(leakage). The combined use of fluconazole at doses of
400mg or greater with terfenadine is
• If your penis has started to smell. contraindicated (see section 4.3). The
• If you have pain on passing urine. coadministration of fluconazole at doses lower
than 400mg per day with terfenadine should be
The product should never be used again if the carefully monitored.
patient experiences a rash or anaphylaxis
follows the use of the drug. Astemizole: Concomitant administration of
fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased
plasma concentrations of astemizole can lead to Concomitant use of the following other
QT prolongation and rare occurrences of torsade medicinal products lead to precautions and
de pointes. Coadministration of fluconazole and dose adjustments:
astemizole is contraindicated (see section 4.3).
The effect of other medicinal products on
Pimozide: Although not studied in vitro or in fluconazole
vivo, concomitant administration of fluconazole
with pimozide may result in inhibition of Hydrochlorothiazide: In a pharmacokinetic
pimozide metabolism. Increased pimozide interaction study, co-administration of multiple-
dose hydrochlorothiazide to healthy volunteers
plasma concentrations can lead to QT
receiving fluconazole increased plasma
prolongation and rare occurrences of torsade de
pointes. Coadministration of fluconazole and concentrations of fluconazole by 40%. An effect
pimozide is contraindicated (see section 4.3). of this magnitude should not necessitate a
change in the fluconazole dose regimen in
Quinidine: Although not studied in vitro or in subjects receiving concomitant diuretics.
vivo, concomitant administration of fluconazole
with quinidine may result in inhibition of Rifampicin: Concomitant administration of
fluconazole and rifampicin resulting in a 25%
quinidine metabolism. Use of quinidine has been
associated with QT prolongation and rare decrease in the AUC and 20% shorter half-life
occurrences of torsades de pointes. of fluconazole. In patients receiving concomitant
Coadministration of fluconazole and quinidine is rifampicin, an increase of the fluconazole dose
contraindicated (see section 4.3). should be considered.
Erythromycin: Concomitant use of fluconazole Interaction studies have shown that when oral
and erythromycin has the potential to increase fluconazole is coadministered with food,
cimetidine, antacids or following total body
the risk of cardiotoxicity (prolonged QT interval,
irradiation for bone marrow transplantation, no
torsades de pointes) and consequently sudden
heart death. Coadministration of fluconazole and clinically significant impairment of fluconazole
absorption occurs.
erythromycin is contraindicated (see section
4.3). The effect of fluconazole on other medicinal
Concomitant use of the following other products
medicinal products cannot be recommended: Fluconazole is a moderate inhibitor of
Halofantrine: Fluconazole can increase cytochrome P450 (CYP) isoenzyme 2C9 and a
halofantrine plasma concentration due to an moderate inhibitor of CYP3A4. Fluconazole is
inhibitory effect on CYP3A4. Concomitant use also a strong inhibitor of the isozyme
of Fluconazole and halofantrine has the potential CYP2C19.In addition to the
to increase the risk of cardiotoxicity (prolonged observed/documented interactions mentioned
QT interval, torsades de pointes) and below there is a risk of increased plasma
consequently sudden heart death. This concentration of other compounds metabolised
combination should be avoided (see section 4.4). by CYP2C9, CYP2C19 and CYP3A4 co-
administered with fluconazole. Therefore
Concomitant use that should be used with caution should be exercised when using these
caution: combinations and the patients should be
carefully monitored. The enzyme inhibiting
Amiodarone: concomitant administration of
effect of fluconazole persists 4-5 days after
fluconazole with amiodarone may increase QT discontinuation of fluconazole treatment due to
prolongation. Therefore, caution should be taken the long half-life of fluconazole (See section
when both drugs are combined, notably with 4.3)
high dose fluconazole (800mg).
Alfentanil: A study observed a reduction in
clearance and distribution volume as well as
prolongation of T½ of alfentanil following
concomitant treatment with fluconazole. During orally increased the midazolam AUC and half-
concomitant treatment with fluconazole (400 life 3.7-fold and 2.2-fold, respectively.
mg) and intravenous alfentanil (20 μg/kg) in Fluconazole 200 mg daily given concurrently
healthy volunteers the alfentanil AUC 10 with triazolam 0.25 mg orally increased the
increased 2-fold. A possible mechanism of triazolam AUC and half-life 4.4- fold and 2.3-
action is fluconazole's inhibition of CYP3A4. fold, respectively. Potentiated and prolonged
effects of triazolam have been observed at
Dosage adjustment of alfentanil may be
concomitant treatment with fluconazole. If
necessary.
concomitant benzodiazepine therapy is
Amitriptyline, nortriptyline: Fluconazole necessary in patients being treated with
increases the effect of amitriptyline and fluconazole, consideration should be given to
nortriptyline. 5- nortriptyline and/or S- decreasing the benzodiazepine dosage, and the
amitriptyline may be measured at initiation of patients should be appropriately monitored.
the combination therapy and after one week.
Carbamazepine: Fluconazole inhibits the
Dosage of amitriptyline/nortriptyline should be metabolism of carbamazepine and an increase in
adjusted, if necessary.
serum carbamazepine of 30% has been
Amphotericin B: Concurrent administration of observed. There is a risk of developing
fluconazole and amphotericin B in infected carbamazepine toxicity. Dosage adjustment of
normal and immunosuppressed mice showed the carbamazepine may be necessary depending on
following results: a small additive antifungal concentrating measurements/effect.
effect in systemic infection with C. albicans, no Calcium Channel Blockers: Certain
interaction in intracranial infection with
dihydropyridine calcium channel antagonists
Cryptococcus neoformans, and antagonism of
(nifedipine, isradipine, amlodipine, verapamil
the two drugs in systemic infection with and felodipine) are metabolised by CYP3A4.
A.fumigatus. The clinical significance of results Fluconazole has the potential to increase
obtained in these studies is unknown. thesystemic exposure of the calcium channel
Anticoagulants: In post-marketing experience, as antagonists. Frequent monitoring for adverse
with other azole antifungals, bleeding events events is recommended.
(bruising, epistaxis, gastrointestinal bleeding, Celecoxib: During concomitant treatment with
haematuria and melena) have been reported, in fluconazole (200mg daily) and celecoxib
association with increases in prothrombin time (200mg) the celecoxib Cmax and AUC
in patients receiving fluconazole concurrently increased by 68% and 134%, respectively. Half
with warfarin. During concomitant treatment
of the celecoxib dose may be necessary when
with fluconazole and warfarin the prothrombin combined with fluconazole.
time was prolonged up to 2-fold, probably due to
an inhibition of the warfarin metabolism through Cyclophosphamide: combination therapy with
CYP2C9. cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine.
In patients receiving coumarin-type or The combination may be used while taking
indanedione anticoagulants concurrently with
increased consideration to the risk of increased
fluconazole the prothrombin time should be serum bilirubin and serum creatinine.
carefully monitored. Dose adjustment of the
anticoagulant may be necessary. Fentanyl: One fatal case of possible fentanyl
fluconazole interaction was reported. The author
Benzodiazepines (Short Acting), i.e. midazolam, judged that the patient died from fentanyl
triazolam: Following oral administration of intoxication. Furthermore, in a randomised
midazolam, fluconazole resulted in substantial crossover study with twelve healthy volunteers it
increases in midazolam concentrations and was shown that fluconazole delayed the
psychomotor effects. Concomitant intake of elimination of fentanyl significantly.
fluconazole 200 mg and midazolam 7.5 mg
Elevated fentanyl concentration may lead to Tacrolimus: Fluconazole may increase the serum
respiratory depression. Patients should be concentrations of orally administered tacrolimus
monitored closely for the potential risk of up to 5 times due to inhibition of tacrolimus
respiratory depression. Dosage adjustment of metabolism through CYP3A4 in the intestines.
fentanyl may be necessary. No significant pharmacokinetic changes have
been observed when tacrolimus is given
HMG-CoA reductase inhibitors: The risk of intravenously.
myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA Increased tacrolimus levels have been associated
reductase inhibitors metabolised through with nephrotoxicity. Dosage of orally
CYP3A4, such as atorvastatin and simvastatin or administered tacrolimus should be decreased
through CYP2C9, such as fluvastatin. If depending on tacrolimus concentration.
concomitant therapy is necessary, the patient
should be observed for symptoms of myopathy Losartan: Fluconazole inhibits the metabolism of
losartan to its active metabolite (E-31 74) which
and rhabdomyolysis and creatinine kinase
should be monitored. HMG-CoA reductase is responsible for most of the angiotensin II-
inhibitors should be discontinued if a marked receptor antagonism which occurs during
increase in creatinine kinase is observed or treatment with losartan. Patients should have
their blood pressure monitored continuously.
myopathy/rhabdomyolysis is diagnosed or
suspected. Methadone: Fluconazole may enhance the serum
Olaparib: Moderate inhibitors of CYP3A4 such concentration of methadone. Dosage adjustment
of methadone may be necessary.
as fluconazole increase olaparib plasma
concentrations; concomitant use is not Non-steroidal anti-inflammatory drugs: The
recommended. If the combination cannot be Cmax and AUC of flurbiprofen was increased
avoided, limit the dose of olaparib to 200 mg by 23% and 81%, respectively, when
twice daily. coadministered with fluconazole compared to
Immunosuppressors (i.e. ciclosporin, administration of flurbiprofen alone. Similarly,
everolimus, sirolimus and tacrolimus): the Cmax and AUC of the pharmacologically
active isomer (S-(+)- ibuprofen) was increased
Ciclosporin: Fluconazole significantly increases by 15% and 82%, respectively, when
the concentration and AUC of ciclosporin. fluconazole was coadministered with racemic
During concomitant treatment with fluconazole ibuprofen (400mg) compared to administration
200 mg daily and ciclosporin (2.7 mg/kg/day) of racemic ibuprofen alone.
there was a 1.8-fold increase in ciclosporin
AUC. This combination may be used by Although not specifically studied, fluconazole
has the potential to increase the systemic
reducing the dosage of ciclosporin depending on
ciclosporin concentration. exposure or other NSAIDs that are metabolised
by CYP2C9 (e.g. naproxen, lornoxicam,
Everolimus: Although not studied in vivo or in meloxicam, diclofenac). Frequent monitoring for
vitro, fluconazole may increase serum adverse events and toxicity related to NSAIDs is
concentrations of everolimus through inhibition recommended. Adjustment of dosage of
of CYP3A4. NSAIDs may be needed.
Sirolimus: Fluconazole increases plasma Phenytoin: Fluconazole inhibits the hepatic
concentrations of sirolimus presumably by metabolism of phenytoin. Concomitant repeated
inhibiting the metabolism of sirolimus via administration of 200 mg fluconazole and 250
CYP3A4 and P-glycoprotein. This combination mg phenytoin intravenously, caused an increase
may be used with a dosage adjustment of of the phenytoin AUC24 by 75% and Cmin by
sirolimus depending on the effect/concentration 128%.With coadministration, serum phenytoin
measurements. concentration levels should be monitored in
order to avoid phenytoin toxicity.
Prednisone: There was a case report that a liver- inhibition of CYP3A4 and strong inhibition of
transplant patient treated with prednisone CYP2C19 (e.g., fluconazole). Therefore, it is
developed acute adrenal cortex insufficiency recommended to reduce tofacitinib dose to 5 mg
when a three month therapy with fluconazole once daily when it is combined with these drugs.
was discontinued. The discontinuation of
fluconazole presumably caused an enhanced Vinca Alkaloids: Although not studied,
CYP3A4 activity which led to increased fluconazole may increase the plasma levels of
the vinca alkaloids (e.g. vincristine and
metabolism of prednisone. Patients on long-term
vinblastine) and lead to neurotoxicity, which is
treatment with fluconazole and prednisone
possibly due to an inhibitory effect on CYP3A4.
should be carefully monitored for adrenal cortex
insufficiency when fluconazole is discontinued. Vitamin A: Based on a case-report in one patient
Rifabutin: Fluconazole increases serum receiving combination therapy with all-trans-
concentrations of rifabutin, leading to increase in retinoic acid (an acid form of vitamin A) and
fluconazole, CNS related undesirable effects
the AUC of rifabutin up to 80%. There have
been reports of uveitis in patients to whom have developed in the form of pseudotumour
fluconazole and rifabutin were co-administered. cerebri, which disappeared after discontinuation
In combination therapy, symptoms of rifabutin of fluconazole treatment. This combination may
toxicity should be taken into consideration. be used but the incidence of CNS related
undesirable effects should be borne in mind.
Saquinavir: Fluconazole increases the AUC and
Cmax of saquinavir with approximately 50% Voriconazole: (CYP2C9, CYP2C19 and
and 55% respectively, due to inhibition of CYP3A4 inhibitor): Coadministration of oral
voriconazole (400 mg Q12h for 1 day, then 200
saquinavir's hepatic metabolism by CYP3A4
mg Q12h for 2.5 days) and oral fluconazole (400
and inhibition of P-glycoprotein. Interaction
with saquinavir/ritonavir has not been studied mg on day 1, then 200 mg Q24h for 4 days) to 8
and might be more marked. Dosage adjustment healthy male subjects resulted in an increase in
of saquinavir may be necessary. Cmax and AUCτ of voriconazole by an average of
57% (90% CI: 20%, 107%) and 79% (90% CI:
Sulfonylureas: Fluconazole has been shown to 40%, 128%), respectively. The reduced dose
prolong the serum half-life of concomitantly and/or frequency of voriconazole and
administered oral sulfonylureas (e.g. fluconazole that would eliminate this effect have
chlorpropamide, glibenclamide, glipizide, not been established. Monitoring for
tolbutamide) in healthy volunteers. voriconazole associated adverse events is
recommended if voriconazole is used
Frequent monitoring of blood glucose and sequentially after fluconazole.
appropriate reduction of sulfonylurea dosage is
recommended during co-administration. Zidovudine: Fluconazole increases Cmax and
AUC of zidovudine by 84% and 74%,
Theophylline: In a placebo controlled interaction respectively, due to an approx. 45% decrease in
study, the administration of fluconazole 200mg oral zidovudine clearance. The half-life of
for 14 days resulted in an 18% decrease in the zidovudine was likewise prolonged by
mean plasma clearance rate of theophylline.
approximately 128% following combination
Patients who are receiving high dose
therapy with fluconazole. Patients receiving this
theophylline or who are otherwise at increased combination should be monitored for the
risk for theophylline toxicity should be observed development of zidovudine-related adverse
for signs of theophylline toxicity while receiving reactions. Dosage reduction of zidovudine may
fluconazole. Therapy should be modified if signs be considered.
of toxicity develop.
Azithromycin: An open-label, randomised,
Tofacitinib: Exposure of tofacitinib is increased three-way crossover study in 18 healthy subjects
when tofacitinib is co-administered with assessed the effect of a single 1200mg oral dose
medications that result in both moderate
of azithromycin on the pharmacokinetics of a
single 800mg oral dose of fluconazole as well as Fluconazole in high dose and/or in prolonged
the effects of fluconazole on the regimens should not be used during pregnancy
pharmacokinetics of azithromycin. There was no except for potentially life-threatening infections.
significant pharmacokinetic interaction between
fluconazole and azithromycin. Breast-feeding
Oral Contraceptives: Two pharmacokinetic Fluconazole passes into breast milk to reach
studies with a combined oral contraceptive have concentrations lower than those in plasma.
been performed using multiple doses of Breast- feeding may be maintained after a single
use of a standard dose 150 mg fluconazole or
fluconazole. There were no relavent effects on
less. Breast- feeding is not recommended after
hormone level in the 50mg fluconazole study,
while at 200mg daily, the AUCs of ethinyl repeated use or after high dose fluconazole. The
estradiol and levonorgestrel were increased 40% developmental and health benefits of breast-
and 24%, respectively. Thus, multiple dose use feeding should be considered along with the
mother's clinical need for Fluconazole and any
of fluconazole at these doses is unlikely to have
an effect on the efficacy of the combined oral potential adverse effects on the breast-fed child
contraceptive. from Fluconazole or from the underlying
maternal condition.
Ivacaftor: Co-administration with ivacaftor, a
cystic fibrosis transmembrane conductance Fertility
regulator (CFTR) potentiator, increased Fluconazole did not affect the fertility of male or
ivacaftor exposure by 3-fold and female rats (see section 5.3).
hydroxymethyl-ivacaftor (M1) exposure by 1.9-
fold. A reduction of the ivacaftor dose to 150 mg 4.7 Effects on ability to drive and use
once daily is recommended for patients taking machines
concomitant moderate CYP3A inhibitors, such No studies have been performed on the effects
as fluconazole and erythromycin. of Fluconazole on the ability to drive or use
machines. Patients should be warned about the
4.6 Fertility, Pregnancy and lactation potential for dizziness or seizures (see section
4.8) while taking Fluconazole and should be
Pregnancy
advised not to drive or operate machines if any
An observational study has suggested an of these symptoms occur.
increased risk of spontaneous abortion in women
treated with fluconazole during the first 4.8 Undesirable Effects
trimester. In some patients, particularly those with serious
underlying diseases such as AIDS and cancer,
There have been reports of multiple congenital changes in renal and haematological function
abnormalities (including brachycephalia, ears test results and hepatic abnormalities (see
dysplasia, giant anterior fontanelle, femoral section 4.4 Special Warnings and Special
bowing and radio-humeral synostosis) in infants Precautions for Use) have been observed during
whose mothers were treated for at least three or treatment with fluconazole and comparative
more months with high doses (400-800mg daily) agents, but the clinical significance and
of fluconazole for coccidioidomycosis. The relationship to treatment is uncertain.
relationship between fluconazole use and these
events is unclear. The most frequently (>1/10) reported adverse
reactions are headache, abdominal pain,
Studies in animals have shown reproductive diarrhoea, nausea, vomiting, alanine
toxicity (see section 5.3) aminotransferase increased, aspartate
aminotransferase increased, blood alkaline
Fluconazole in standard doses and short-term phosphatase increased and rash.
treatments should not be used in pregnancy
unless clearly necessary. The following undesirable effects have been
observed and reported during treatment with
fluconazole with the following frequencies: necrosis, hepatitis,

Very common (≥1/10); common (≥1/100 to hepatocellular damage
≤1/10); uncommon (≥1/1000, <1/100) rare Skin and Common Rash
(≥1/10000, <1/1000) and very rare (<1/10000) subcutaneous
Uncommon Pruritus, urticaria,
not known (cannot be estimated from the tissue disorders
increased sweating,
available data) drug eruption*
System Organ Frequency Undesirable effects Rare Toxic epidermal
Class necrolysis, Stevens-
Blood and the Uncommon Anaemia Johnson syndrome,
lymphatic acute generalised
Rare Agranulocytosis, exanthematous-
system leukopenia,
disorders pustulosis, dermatitis
neutropenia, exfoliative,
thrombocytopenia angioedema, face
Immune system Rare Anaphylaxis oedema, alopecia
disorders Not known Drug reaction with
Metabolism and Uncommon Decreased appetite eosinophilia and
nutrition Rare Hypertriglyceridaemia, systemic symptoms
disorders Hypercholeosterolaem (DRESS)
ia Musculoskeletal, Uncommon Myalgia
Hypokalaemia connective
Psychiatric Uncommon Insomnia, somnolence tissue and bone
disorders disorders
Nervous system Common Headache General Uncommon Fatigue, malaise,
disorders disorders and asthenia, fever
Uncommon Seizures, dizziness, administration
paraesthesia, taste site conditions
perversion
* Including Fixed Drug Eruption
Rare Tremor
Ear and Uncommon Vertigo Paediatric Population
labyrinth The pattern and incidence of side effects and
disorders
laboratory abnormalities recorded during
Cardiac Rare Torsade de pointes, paediatric clinical trials are comparable to those
disorders QT prolongation seen in adults.
Gastrointestinal Common Abdominal pain,
disorders diarrhoea, nausea, Reporting of suspected adverse reactions
vomiting
Reporting suspected adverse reactions after
Uncommon Dyspepsia, flatulence, authorization of the medicinal product is
dry mouth, important. It allows continued monitoring of the
constipation benefit/risk balance of the medical product.
Hepato-biliary Common Alanine
disorders aminotransferase 4.9 Overdose
increased, aspartate
aminotransferase
There have been reports of overdose with
increased, blood fluconazole and hallucination and paranoid
alkaline phosphatase behaviour have been concomitantly reported.
increased
In the event of overdose, symptomatic treatment
Uncommon Cholestasis, jaundice, (with supportive measures and gastric lavage if
bilirubin increased necessary) may be adequate.
Rare Hepatic failure,
hepatocellular
Fluconazole is largely excreted in the urine, immitis, Histoplasma capsulatum and

forced volume diuresis would probably increase Paracoccidioides brasiliensis.
the elimination rate. A three-hour hemodialysis
Pharmacokinetic/pharmacodynamic relationship
session decreases plasma levels by
approximately 50%. In animal studies, there is a correlation between
MIC values and efficacy against experimental
5. PHARMACOLOGICAL PROPERTIES
mycoses due to Candida spp. In clinical studies,
5.1 Pharmacodynamic properties there is an almost 1:1 linear relationship between
the AUC and the dose of fluconazole. There is
Pharmacotherapeutic group: Antimycotics for also a direct though imperfect relationship
systemic use, triazole derivatives, ATC code: between the AUC or dose and a successful
J02AC01. clinical response of oral candidosis and to a
lesser extent candidaemia to treatment. Similarly
Mechanism of action cure is less likely for infections caused by strains
Fluconazole is a triazole antifungal agent. Its with a higher fluconazole MIC.
primary mode of action is the inhibition of Mechanisms of resistance
fungal cytochrome P-450- mediated 14 alpha-
lanosterol demethylation, an essential step in Candida spp have developed a number of
fungal ergosterol biosynthesis. The resistance mechanisms to azole antifungal
accumulation of 14 alpha-methyl sterols agents. Fungal strains which have developed one
correlates with the subsequent loss of ergosterol or more of these resistance mechanisms are
in the fungal cell membrane and may be known to exhibit high minimum inhibitory
responsible for the antifungal activity of concentrations (MICs) to fluconazole which
fluconazole. Fluconazole has been shown to be impacts adversely efficacy in vivo and clinically.
more selective for fungal cytochrome P-450
There have been reports of superinfection with
enzymes than for various mammalian
cytochrome P-450 enzyme systems. Candida species other than C. albicans, which
are often inherently not susceptible to
Fluconazole 50 mg daily given up to 28 days has fluconazole (e.g. Candida krusei). Such cases
been shown not to effect testosterone plasma may require alternative antifungal therapy.
concentrations in males or steroid concentration
Breakpoints (according to EUCAST)
in females of child-bearing age. Fluconazole 200
mg to 400 mg daily has no clinically significant Based on analyses of
effect on endogenous steroid levels or on ACTH pharmacokinetic/pharmacodynamic (PK/PD)
stimulated response in healthy male volunteers. data, susceptibility in vitro and clinical Response
Interaction studies with antipyrine indicate that EUCAST-AFST (European Committee on
single or multiple doses of fluconazole 50 mg do Antimicrobial susceptibility Testing-
not affect its metabolism. subcommittee on Antifungal Susceptibility
Susceptibility in vitro: Testing) has determined breakpoints for
fluconazole for Candida species (EUCAST
In vitro, fluconazole displays antifungal activity Fluconazole rational document (2007)-version
against most clinically common Candida species 2). These have been divided into non-species
(including C. albicans, C. parapsilosis, C. related breakpoints; which have been determined
tropicalis). C. glabrata shows a wide range of mainly on the basis of PK/PD data and are
susceptibility while C. krusei is resistant to independent of MIC distributions of specific
fluconazole. species, and species related breakpoints for those
species most frequently associated with human
Fluconazole also exhibits activity in vitro infection. These breakpoints are given in the
against Cryptococcus neoformans and table below:
Cryptococcus. gattii as well as the endemic
moulds Blastomyces dermatiditis, Coccidioides
Antifung Species-related breakpoints Non- The apparent volume of distribution

al (S≤/R>) species approximates to total body water. Plasma protein
related binding is low (11- 12%).
breakpo
A
int Fluconazole achieves good penetration in all
S≤/R>
body fluids studied. The levels of fluconazole in
Candi Candi Candi Candida Candi saliva and sputum are similar to plasma levels.
da da da parapsil da
albica glabr kruse osis tropic In patients with fungal meningitis, fluconazole
ns ata i alis levels in the CSF are approximately 80% of the
Flucona 2/4 IE -- 2/4 2/4 2/4 corresponding plasma levels.
zole
High skin concentrations of fluconazole, above
S = Susceptible, R = Resistant serum concentrations, are achieved in the
A = Non-species related breakpoints have been stratum corneum, epidermis-dermis and eccrine
determined mainly on the basis of PK/PD data sweat. Fluconazole accumulates in the stratum
and are independent of MIC distributions of corneum. At a dose of 50mg once daily, the
specific species. They are for use only for concentration of fluconazole after 12 days was
organisms that do not have specific breakpoints. 73 μg /g and 7 days after cessation of treatment
the concentration was still 5.8 μg /g. At the 150
-- = Susceptibility testing not recommended as mg once-a-week dose, the concentration of
the species is a poor target for therapy with the fluconazole in stratum corneum on day 7 was
medicinal product. 23.4 μg/g and 7 days after the second dose was
IE = There is insufficient evidence that the still 7.1 μg/g.
species in question is a good target for therapy Concentration of fluconazole in nails after 4
with the medicinal product. months of 150 mg once-a-week dosing was 4.05
5.2 Pharmacokinetic properties μg/g in healthy and 1.8 μg/g in diseased nails;
and, fluconazole was still measurable in nail
The pharmacokinetic properties of fluconazole samples 6 months after the end of therapy.
are similar following administration by the
intravenous or oral route. Biotransformation
Absorption Fluconazole is metabolised only to a minor

extent. Of a radioactive dose, only 11% is
After oral administration fluconazole is well excreted in a changed form in the urine.
absorbed and plasma levels (and systemic Fluconazole is a selective inhibitor of the
bioavailability) are over 90% of the levels isozymes CYP2C9 and CYP3A4 (see section
achieved after intravenous administration. Oral 4.5). Fluconazole is also an inhibitor of the
administration is not affected by concomitant isozyme CYP2C19.
food intake. Peak plasma concentrations in the
fasting state occur between 0.5 – 1.5 hours post- Elimination
dose with a plasma elimination half-life of Plasma elimination half-life for fluconazole is
approximately 30 hours. Plasma concentrations approximately 30 hours. The major route of
are proportional to dose. Ninety percent steady- excretion is renal, with approximately 80% of
state levels are reached by day 4 – 5 with the administered dose appearing in the urine as
multiple once daily dosing. unchanged drug. Fluconazole clearance is
The administration of a loading dose on the first proportional to creatinine clearance. There is no
day, double that of the normal daily dose, raises evidence of circulating metabolites.
plasma levels to approximate to 90% steady- Its long plasma elimination half-life makes it
state levels by the second day. possible to administer a single dose in the
Distribution treatment of vaginal candidiasis, once daily and
once weekly dosing for other indications.
A study compared the saliva and plasma Pharmacokinetic data were assessed for 113
concentrations of a single fluconazole 100mg paediatric patients from 5 studies; 2 single-dose
dose administration in a capsule or in an oral studies, 2 multipledose studies, and a study in
suspension by rinsing and retaining in the mouth premature neonates. Data from one study were
for 2 minutes and swallowing. not interpretable due to changes in formulation
pathway through the study. Additional data were
The maximum concentration of fluconazole in available from a compassionate use study. After
saliva after the suspension was observed five
administration of 2-8 mg/kg fluconazole to
minutes after ingestion and was 182 times higher
children between the ages of 9 months to 15
than maximum saliva concentrations after the years, an AUC of about 38 μg·h/ml was found
capsule, which occurred four hours after per 1 mg/kg dose units. The average fluconazole
ingestion. plasma elimination half-life varied between 15
After about 4 hours, the saliva concentrations of and 18 hours and the distribution volume was
fluconazole were similar. The mean AUC (0-96) approximately 880 ml/kg after multiple doses. A
in saliva was significantly greater after the higher fluconazole plasma elimination half-life
suspension compared to the capsule. There was of approximately 24 hours was found after a
no significant difference in the elimination rate single dose. This is comparable with the
from saliva or the plasma pharmacokinetic fluconazole plasma elimination half-life after a
parameters for the two formulations. single administration of 3 mg/kg i.v. to children
of 11 days-11 months old. The distribution
Pharmacokinetics in renal impairment volume in this age group was about 950 ml/kg.
In patients with severe renal insufficiency, Experience with fluconazole in neonates is
(GFR< 20 ml/min) half life increased from 30 to limited to pharmacokinetic studies in premature
98 hours. Consequently, reduction of the dose is newborns. The mean age at first dose was 24
needed. Fluconazole is removed by hours (range 9-36 hours) and mean birth weight
haemodialysis and to a lesser extent by was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term
peritoneal dialysis. After three hours of neonates of average gestation around 28 weeks.
haemodialysis session, around 50% of Seven patients completed the protocol; a
fluconazole is eliminated from blood. maximum of five 6 mg/kg intravenous infusions
of fluconazole were administered every 72
Pharmacokinetics during lactation hours. The mean half-life (hours) was 74 (range
A pharmacokinetic study in ten lactating 44- 185) on day 1 which decreased, with time to
women, who had temporarily or permanently a mean of 53 (range 30-131) on day 7 and 47
stopped breast-feeding their infants, evaluated (range 27-68) on day 13. The area under the
fluconazole concentrations in plasma and breast curve (microgram.h/ml) was 271 (range 173-
milk for 48 hours following a single 150 mg 385) on day 1 and increased with a mean of 490
dose of Diflucan. Fluconazole was detected in (range 292-734) on day 7 and decreased with a
breast milk at an average concentration of mean of 360 (range 167-566) on day 13. The
approximately 98% of those in maternal plasma. volume of distribution (ml/kg) was 1183 (range
The mean peak breast milk concentration was 1070-1470) on day 1 and increased, with time,
2.61 mg/L at 5.2 hours post-dose. The estimated to a mean of 1184 (range 510-2130) on day 7
daily infant dose of fluconazole from breast milk and 1328 (range 1040-1680) on day 13.
(assuming mean milk consumption of 150 Pharmacokinetics in elderly
ml/kg/day) based on the mean peak milk
concentration is 0.39 mg/kg/day, which is A pharmacokinetic study was conducted in 22
approximately 40% of the recommended subjects, 65 years of age or older receiving a
neonatal dose (<2 weeks of age) or 13% of the single 50 mg oral dose of fluconazole. Ten of
recommended infant dose for mucosal these patients were concomitantly receiving
candidiasis. diuretics. The Cmax was 1.54 μg/ml and
occurred at 1.3 hours post-dose. The mean AUC
Pharmacokinetics in children was 76.4 ± 20.3 µg·h/ml , and the mean terminal
half-life was 46.2 hours. These pharmacokinetic The onset of parturition was slightly delayed at
parameter values are higher than analogous 20 mg/kg orally and dystocia and prolongation
values reported for normal young male of parturition were observed in a few dams at 20
volunteers. Coadministation of diuretics did not mg/kg and 40 mg/kg intravenously. The
significantly alter AUC or Cmax. In addition, disturbances in parturition were reflected by a
creatinine clearance (74 ml/min), the percent of slight increase in the number of still- born pups
medicinal product recovered unchanged in urine and decrease of neonatal survival at these doses.
(0-24 h, 22%) and the fluconazole renal The effects on parturition in rats are consistent
clearance estimates (0.124 ml/min/kg) for the with the species specific oestrogen-lowering
elderly were generally lower than those of property produced by high doses of fluconazole.
younger volunteers. Such a hormone change has not been observed
in women treated with fluconazole (see section
Thus, the alteration of fluconazole disposition in 5.1).
the elderly appears to be related to reduced renal
function characteristics of this group. 6. PHARMACEUTICAL PARTICULARS
5.3 Preclinical safety data
6.1 List of excipients
Effects in non-clinical studies were observed Lactose monohydrate
only at exposures considered sufficiently in Microcrystalline cellulose
excess of the human exposure indicating little
relevance to clinical use. Pregelatinised maize starch
Carcinogenesis: Fluconazole showed no Colloidal anhydrous silica
evidence of carcinogenic potential in mice and
Magnesium stearate
rats treated orally for 24 months at doses of 2.5,
5 or 10 mg/kg/day (approximately 2-7 times the Sodium lauryl sulphate
recommended human dose). Male rats treated
with 5 and 10mg/kg/day had an increased The capsule shells contain:
incidence of hepatocellular adenomas. Titanium dioxide E171
Mutagenesis: Fluconazole, with or without Quinoline yellow E104
metabolic activation, was negative in tests for
mutagenicity in 4 strains of S .typhimurium and Sunset yellow E110
in the mouse lymphoma L5178Y system. Gelatin.
Cytogenetic studies in vivo (murine bone
marrow cells, following oral administration of 6.2 Incompatibilities
fluconazole) and in vitro (human lymphocytes Not applicable.
exposed to fluconazole at 1000 ug/ml) showed
6.3 Shelf life
no evidence of chromosomal mutations.
36 months
Reproductive toxicity:: Fluconazole did not
6.4 Special precautions for storage
affect the fertility of male or female rats treated
No special precautions for storage
orally with daily doses of 5, 10 or 20 mg/kg or
with parenteral doses of 5, 25 or 75 mg/kg. 6.5 Nature and contents of container
Increases in foetal anatomical variants PVC/ Aluminium blister containing 1 capsule.
(supernumerary ribs, renal pelvis dilation) and
delays in ossification were observed at 25 and 6.6 Special precautions for disposal and other
50 mg/kg and higher doses. At doses ranging handling
from 80 mg/kg to 320 mg/kg embryolethality in Not applicable
rats was increased and foetal abnormalities
7. MANUFACTURER:
included wavy ribs, cleft palate, and abnormal
cranio-facial ossification.
Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
At: 615, GIDC, Kerala, Bavla, Dist. Ahmedabad
438225, Gujarat, INDIA
This leaflet was last revised in October 2019

Fluconazole 150 MG Capsule SMPC - Taj Pharmaceuticals

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3. PHARMACEUTICAL FORM Renal system

Capsules, hard. Fluconazole should be administered with caution

Fluconazole should be administered with caution The coadministration of fluconazole at doses

fluconazole with the following frequencies: necrosis, hepatitis,

Fluconazole is largely excreted in the urine, immitis, Histoplasma capsulatum and

Antifung Species-related breakpoints Non- The apparent volume of distribution

Absorption Fluconazole is metabolised only to a minor

Manufactured in India by:

This leaflet was last revised in October 2019

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