Posology : מינונים

4.2       Posology and method of administration                                                                       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
Posology                                                                                                        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
The dose should be based on the nature and severity of the fungal infection. Treatment of infections            greater significantly increases plasma levels of terfenadine when taken concomitantly. The
requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate            combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see
that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence             section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with
of active infection.                                                                                            terfenadine should be carefully monitored.

Adults                                                                                                          Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
Indications                                           Posology                   Duration of treatment               prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and
Cryptococcosis             - Treatment of             Loading dose: 400 mg       Usually at least 6 to 8             astemizole is contraindicated (see section 4.3).
cryptococcal meningitis on Day 1                      weeks. In life
Subsequent dose: 200       threatening infections              Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
mg to 400 mg once          the daily dose can be               pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
daily                      increased to 800 mg                 concentrations can lead to QT prolongation and rare occurrences of torsades de pointes.
- Maintenance therapy 200 mg once daily               Indefinitely at a daily             Coadministration of fluconazole and pimozide is contraindicated (see section 4.3).
to prevent relapse of                                 dose of 200 mg
cryptococcal meningitis                                                                   Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
in patients with high risk                                                                quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated
of recurrence.                                                                            with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole
200 mg to 400 mg once 11 months up to 24                       and quinidine is contraindicated (see section 4.3).
Coccidioidomycosis                                    daily                 months or longer
depending on the                         Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the
patient. 800 mg daily                    risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart
may be considered for                    death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3).
some infections and
especially for                           Concomitant use of the following other medicinal products cannot be recommended:
meningeal disease
Loading dose: 800 mg  In general, the                          Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
Invasive candidiasis                                  on Day 1              recommended duration                     effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase
Subsequent dose: 400 of therapy for                            the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden
mg once daily         candidemia is for 2                      heart death. This combination should be avoided (see section 4.4).
weeks after first
negative blood culture                   Concomitant use that should be used with caution:
result and resolution of
signs and symptoms                       Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT
attributable to                          prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is
candidemia.                              necessary, notably with high dose fluconazole (800 mg).
- Oropharyngeal            Loading dose: 200 mg  7 to 21 days (until
candidiasis                to 400 mg on Day 1    oropharyngeal                            Concomitant use of the following other medicinal products lead to precautions and dose
Treatment of mucosal                                  Subsequent dose: 100 candidiasis is in                         adjustments:
candidiasis                                           mg to 200 mg once     remission).                              The effect of other medicinal products on fluconazole-
daily                 Longer periods may be
used in patients with                    Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in
severely compromised                     the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an
immune function                          increase of the fluconazole dose should be considered.
- Oesophageal              Loading dose: 200 mg  14 to 30 days (until
candidiasis                to 400 mg on Day 1    oesophageal                              Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine,
Subsequent dose: 100 candidiasis is in                          antacids or following total body irradiation for bone marrow transplantation, no clinically significant
mg to 200 mg once     remission).                               impairment of fluconazole absorption occurs.
daily                 Longer periods may be
used in patients with                    Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose
severely compromised                     hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of
immune function                          fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
- Candiduria               200 mg to 400 mg once 7 to 21 days. Longer                     dose regimen in subjects receiving concomitant diuretics.
daily                 periods may be used in                   The effect of fluconazole on other medicinal products
patients with severely
compromised immune                       Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4.
function.                                Fluconazole is also a strong inhibitor of the isozyme CYP2C19. In addition to the
- Chronic atrophic         50 mg once daily      14 days                                  observed/documented interactions mentioned below, there is a risk of increased plasma
candidiasis                                                                               concentration of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4
- Chronic                  50 mg to 100 mg once       Up to 28 days. Longer               coadministered with fluconazole. Therefore caution should be exercised when using these
mucocutaneous              daily                      periods depending on                combinations and the patients should be carefully monitored. The enzyme inhibiting effect of
candidiasis                                           both the severity of                fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life
infection or underlying             of fluconazole (see section 4.3).
immune
compromisation and                  Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20
infection                           μg/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of
- Oropharyngeal            100 mg to 200 mg daily     An indefinite period for            CYP3A4.
candidiasis                or 200 mg 3 times per      patients with chronic
week.                      immune suppression                  Dose adjustment of alfentanil may be necessary.
- Oesophageal              100 mg to 200 mg daily     An indefinite period for
Prevention of relapse      candidiasis                or 200 mg 3 times per      patients with chronic               Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-
of mucosal                                            week                       immune suppression                  nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
candidiasis in                                                                                                       after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary.
patients infected with
HIV who are at high                                                                                                  Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
risk of experiencing                                                                                                 and immunosuppressed mice showed the following results: a small additive antifungal effect in
relapse                                                                                                              systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
Prophylaxis of                                        200 mg to 400 mg once Treatment should start                   neoformans, and antagonism of the two medicinal products in systemic infection with Aspergillus
candidal infections                                   daily                 several days before the                  fumigatus. The clinical significance of results obtained in these studies is unknown.
anticipated onset of
neutropenia and                          Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events
continue for 7 days                      (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in
after recovery from                      association with increases in prothrombin time in patients receiving fluconazole concurrently with
neutropenia after the                    warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was
neutrophil count rises                   prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9.
above 1000 cells per                     In patients receiving coumarin-type or indanedione anticoagulants concurrently with fluconazole
3
mm .                                     the prothrombin time should be carefully monitored. Dose adjustment of the anticoagulant may be
necessary.
Special populations
Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of
Elderly                                                                                                         midazolam, fluconazole resulted in substantial increases in midazolam concentrations and
Dosage should be adjusted based on the renal function (see “Renal impairment”).                                 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
Renal impairment                                                                                                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
Fluconazole is predominantly excreted in the urine as unchanged active substance. No                            at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in
adjustments in single dose therapy are necessary. In patients (including paediatric population) with            patients being treated with fluconazole, consideration should be given to decreasing the
impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to             benzodiazepine dose, and the patients should be appropriately monitored.
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:                  Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
Creatinine clearance (ml/min)        Percent of recommended dose                                            carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
>50                                  100 %                                                                  Dose adjustment of carbamazepine may be necessary depending on concentration
≤ 50(no haemodialysis)               50 %                                                                   measurements/effect.
Haemodialysis                        100% after each haemodialysis
Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine,
Patients on haemodialysis should receive 100% of the recommended dose after each                                verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase
haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their                  the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events
creatinine clearance.                                                                                           is recommended.

Hepatic impairment                                                                                              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
Limited data are available in patients with hepatic impairment, therefore fluconazole should be                 may be necessary when combined with fluconazole.
administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8).
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
Paediatric population                                                                                           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.
A maximum dose of 400 mg daily should not be exceeded in paediatric population.
Date: 31/03/21
Baxter Pharmaceuticals India Private Limited




Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction
As with similar infections in adults, the duration of treatment is based on the clinical and                    was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the
mycological response. Fluconazole is administered as a single daily dose.                                       elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory
depression. Patients should be monitored closely for the potential risk of respiratory depression.
For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The                     Dosage adjustment of fentanyl may be necessary.
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               HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
below).                                                                                                         fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4,
Pantone




such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant
Infants, toddlers and children (from 28 days to 11 years old):                                                  therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatine kinase should be monitored. HMG-CoA reductase inhibitors should
Indication                            Posology                        Recommendations                      be discontinued if a marked increase in creatine kinase is observed or myopathy/rhabdomyolysis is
- Mucosal candidiasis               Initial dose: 6 mg/kg               Initial dose may be used on the               diagnosed or suspected.
Subsequent dose: 3 mg/kg once       first day to achieve steady state
daily                               levels more rapidly                           Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole increase plasma ibrutinib
- Invasive candidiasis              Dose: 6 to 12 mg/kg once daily      Depending on the severity of the               concentrations and may increase risk of toxicity. If the combination cannot be avoided, reduce the
- Cryptococcal meningitis                                               disease                                        dose of ibrutinib to 280 mg once daily (two capsules) for the duration of the inhibitor use and provide
- Maintenance therapy to prevent Dose: 6 mg/kg once daily               Depending on the severity of the               close clinical monitoring.
relapse of cryptococcal                                                 disease                                       Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator
(5)




meningitis in children with high                                                                                       (CFTR) potentiator, increased ivacaftor exposure by 3-fold and hydroxymethyl-ivacaftor (M1)
risk of recurrence                                                                                                     exposure by 1.9-fold. A reduction of the ivacaftor dose to 150 mg once daily is recommended for
Pantone




- Prophylaxis of Candida in      Dose: 3 to 12 mg/kg once daily         Depending on the extent and                    patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.
immunocompromised patients                                              duration of the induced
neutropenia (see Adults                       Olaparib: Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma
posology)                                     concentrations; concomitant use is not recommended. If the combination cannot be avoided, limit
Adolescents (from 12 to 17 years old):                                                                          the dose of olaparib to 200 mg twice daily.
Size of Artwork (In mm) : 600x175




Depending on the weight and pubertal development, the prescriber would need to assess which                     Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):
posology (adults or children) is the most appropriate. Clinical data indicate that children have a              Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During
higher fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults                   concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a
corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure.                    1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of
GSM of Paper/Board : 60 GSM




ciclosporin depending on ciclosporin concentration.
Term newborn infants (0 to 27 days):
Neonates excrete fluconazole slowly.                                                                            Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations
Pantone




Plant Location : Injectable




of everolimus through inhibition of CYP3A4.
Artwork Control Key No.:




There are few pharmacokinetic data to support this posology in term newborn infants (see section
Artwork Req. No: 27737




5.2).                                                                                                           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
Age group                            Posology                      Recommendations                         dose adjustment of sirolimus depending on the effect/concentration measurements.
(4)




Term newborn infants                The same mg/kg dose as for          A maximum dose of 12 mg/kg
(0 to 14 days)                      infants, toddlers and children      every 72 hours should not be                  Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
Language : English




should be given every 72 hours      exceeded                                      up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
Term newborn infants                The same mg/kg dose as for          A maximum dose of 12 mg/kg                    significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
(from 15 to 27 days)                infants, toddlers and children      every 48 hours should not be                  Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered
should be given every 48 hours      exceeded                                      tacrolimus should be decreased depending on tacrolimus concentration.

Method of administration                                                                                        Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is
Pantone




Fluconazole Baxter 2 mg/ml may be administered either orally or by intravenous infusion(solution                responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with
for infusion), the route being dependent on the clinical state of the patient. On transferring from the         losartan. Patients should have their blood pressure monitored continuously.
intravenous to the oral route, or vice versa, there is no need to change the daily dose.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment
Intravenous infusion should be administrated at a rate not exceeding 10 ml/minute. Fluconazole                  of methadone may be necessary.
Baxter 2 mg/ml is formulated in sodium chloride 9 mg/ml (0.9%) solution for infusion, each 200 mg
(100 ml bottle) containing 15 mmol each of Na+ and C1-. Because Fluconazole Baxter 2 mg/ml is                  Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and
available as a dilute sodium chloride solution, in patients requiring sodium or fluid restriction,             81%, respectively, when coadministered with fluconazole compared to administration of
consideration should be given to the rate of fluid administration.                                             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
(3)




For instruction on dilution of the medicinal product before administration, see section 6.6.                    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
Pantone