FLUCORIC Capsule Ref.[50943] Active ingredients: Fluconazole

Hepatobiliary system

FLUCORIC should be administered with caution to patients with liver dysfunction.

FLUCORIC has been associated with cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of FLUCORIC-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Hepatotoxicity may be reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during FLUCORIC therapy should be monitored for the development of more serious hepatic injury. FLUCORIC should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to FLUCORIC.

Dermatological reactions

Patients have less frequently developed pruritus, rashes, urticaria, angioedema, dry skin, abnormal odour, exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis during treatment with FLUCORIC. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. AIDS patients are more prone to the development of severe cutaneous reactions to many medicines. If a rash, which is considered attributable to FLUCORIC, develops in a patient treated for a superficial fungal infection, further therapy with FLUCORIC should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and FLUCORIC discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

Anaphylaxis has been reported with the use of FLUCORIC.

Cardiovascular system

FLUCORIC has been associated with prolongation of the QT interval on the electrocardiogram. FLUCORIC causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicines (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been cases of QT prolongation and torsades de pointes in patients taking FLUCORIC. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medicines that may have been contributory. Patients with hypokalaemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular dysrhythmias and torsades de pointes.

FLUCORIC should be administered with caution to patients with these potentially prodysrhythmic conditions.

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of FLUCORIC and halofantrine is therefore not recommended (see section 4.5).

Renal system

FLUCORIC should be administered with caution to patients with renal dysfunction (see section 4.2).

Adrenal insufficiency

FLUCORIC may cause adrenal insufficiency relating to concomitant treatment with prednisone (see section 4.5, The effect of FLUCORIC on other medicines).

Cytochrome P450

FLUCORIC is a moderate CYP2C9 and CYP3A4 inhibitor. FLUCORIC is also a strong inhibitor of CYP2C19. FLUCORIC-treated patients who are concomitantly treated with medicines with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see section 4.5).

Terfenadine

The co-administration of FLUCORIC at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).

Candidiasis

Studies have shown an increasing prevalence of infections with Candida species other than C. albicans. These are often inherently resistant (e.g. C. krusei and C. auris) or show reduced susceptibility to FLUCORIC (C. glabrata). Such infections may require alternative antifungal therapy secondary to treatment failure. Therefore, health care providers are advised to take into account the prevalence of resistance in various Candida species to FLUCORIC.

Excipients

FLUCORIC capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant use of the following other medicines is contraindicated

Cisapride

There have been reports of cardiac events including torsades de pointes in patients to whom FLUCORIC and cisapride were co-administered. A controlled study found that concomitant FLUCORIC 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with FLUCORIC and cisapride is contraindicated in patients receiving FLUCORIC (see section 4.3).

Terfenadine

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of FLUCORIC failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of FLUCORIC demonstrated that FLUCORIC taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of FLUCORIC at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of FLUCORIC at doses lower than 400 mg per day with terfenadine should be carefully monitored (see section 4.3).

Astemizole

Concomitant administration of FLUCORIC with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and torsades de pointes. Co-administration of FLUCORIC and astemizole is contraindicated (see section 4.3).

Pimozide

Although not studied in vitro or in vivo, concomitant administration of FLUCORIC with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and torsades de pointes. Co-administration of FLUCORIC and pimozide is contraindicated (see section 4.3).

Quinidine

Although not studied in vitro or in vivo, concomitant administration of FLUCORIC with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and torsades de pointes. Co-administration of FLUCORIC and quinidine is contraindicated (see section 4.3).

Erythromycin

Concomitant use of FLUCORIC and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden death. Coadministration of FLUCORIC and erythromycin is contraindicated (see section 4.3).

Concomitant use of the following other medicines cannot be recommended

Halofantrine

FLUCORIC can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

Concomitant use of FLUCORIC and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4).

Concomitant use that should be used with caution

Amiodarone

Concomitant administration of FLUCORIC with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of FLUCORIC and amiodarone is necessary, notably with high dose FLUCORIC (800 mg) (see section 4.4).

Concomitant use of the following medicines leads to precautions and dose adjustments

The effect of other medicines on FLUCORIC

Hydrochlorothiazide:

In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving FLUCORIC increased plasma concentrations of FLUCORIC by 40%. An effect of this magnitude may necessitate a change in the FLUCORIC dose regimen in subjects receiving concomitant diuretics.

Rifampicin:

Concomitant administration of FLUCORIC and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of FLUCORIC. In patients receiving concomitant rifampicin, an increase of the FLUCORIC dose should be considered.

Interaction studies have shown that when oral FLUCORIC is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of absorption occurs.

The effect of FLUCORIC on other medicines

FLUCORIC is a moderate inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 3A4. FLUCORIC is also a strong inhibitor of the isoenzyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other medicines metabolised by CYP2C9, CYP2C19 and CYP3A4 co-administered with FLUCORIC. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of FLUCORIC persists for 4–5 days after discontinuation of FLUCORIC treatment due to the long half-life of FLUCORIC (see section 4.3).

Alfentanil:

A study observed a reduction in clearance and distribution volume as well as prolongation of t½ of alfentanil following concomitant treatment with FLUCORIC. A possible mechanism of action is FLUCORIC’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline:

FLUCORIC increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or Samitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B:

Concurrent administration of FLUCORIC and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicines in systemic infection with Aspergillus fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants:

In an interaction study, FLUCORIC increased the prothrombin time/international normalised ratio (INR) (12%) after warfarin administration in healthy males. In post-marketing experience, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria, and melena) have been reported, in association with increases in prothrombin time/INR in patients receiving FLUCORIC concurrently with warfarin. Prothrombin time in patients receiving coumarin-type (warfarin) or indanedione anticoagulants should be carefully monitored. Dose adjustment of these anticoagulants may be necessary.

Azithromycin:

There was no significant pharmacokinetic interaction between FLUCORIC and azithromycin.

Benzodiazepines (short-acting), i.e. midazolam, triazolam:

Following oral administration of midazolam, FLUCORIC resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of FLUCORIC than with FLUCORIC administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with FLUCORIC, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. FLUCORIC increases the AUC of triazolam (single dose) by approximately 50%, C_max by 20–32% and increases t½ by 25–50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine:

FLUCORIC inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium channel blockers:

Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolised by CYP3A4. FLUCORIC has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib:

During concomitant treatment with FLUCORIC (200 mg daily) and celecoxib (200 mg) the celecoxib C_max and AUC increased by 68% and 134%, respectively. A 50% reduction of the celecoxib dose may be necessary when combined with FLUCORIC.

Ciclosporin:

FLUCORIC significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

Cyclophosphamide:

Combination therapy with cyclophosphamide and FLUCORIC results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Endogenous steroid:

No adverse effect has been seen on endogenous steroid levels or on ACTH stimulated cortisol response.

Fentanyl:

One fatal case of possible fentanyl FLUCORIC interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomised crossover study with twelve healthy volunteers it was shown that FLUCORIC delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

HMG-CoA reductase inhibitors:

The risk of myopathy and rhabdomyolysis increases when FLUCORIC is co-administered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine kinase is observed, or myopathy/rhabdomyolysis is diagnosed or suspected.

Ibrutinib:

Moderate inhibitors of CYP3A4 such as FLUCORIC increase plasma ibrutinib concentrations and may increase risk of toxicity. If the combination cannot be avoided, reduce the dose of ibrutinib to 280 mg once daily (two capsules) for the duration of the inhibitor use and provide close clinical monitoring.

Losartan:

FLUCORIC inhibits the metabolism of losartan to its active metabolite (E-3174) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored regularly.

Methadone:

FLUCORIC may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs):

The C_max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with FLUCORIC compared to administration of flurbiprofen alone. Similarly, the C_max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when FLUCORIC was co-administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, FLUCORIC has the potential to increase the systemic exposure of other NSAIDs that are metabolised by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Olaparib:

Moderate inhibitors of CYP3A4 such as FLUCORIC increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, limit the dose of olaparib to 200 mg twice daily.

Oral contraceptives:

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

Phenytoin:

FLUCORIC inhibits the hepatic metabolism of phenytoin. With co-administration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone:

There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal insufficiency when a three-month therapy with FLUCORIC was discontinued. The discontinuation of FLUCORIC presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with FLUCORIC and prednisone should be carefully monitored for adrenal insufficiency when FLUCORIC is discontinued (see section 4.4).

Rifabutin:

There have been reports that an interaction exists when FLUCORIC is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom FLUCORIC and rifabutin were co-administered. Patients receiving rifabutin and FLUCORIC concomitantly should be carefully monitored.

Saquinavir:

FLUCORIC increases the AUC of saquinavir with approximately 50%, C_max by approximately 55% and decreases the clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus:

FLUCORIC increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulfonylureas:

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

Tacrolimus:

FLUCORIC may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Theophylline:

In a placebo-controlled interaction study, the administration of FLUCORIC 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving FLUCORIC and therapy modified appropriately if signs of toxicity develop.

Tofacitinib:

Exposure of tofacitinib is increased when tofacitinib is co-administered with medicines that result in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g. FLUCORIC). Therefore, it is recommended to reduce tofacitinib dose to 5 mg once daily when it is combined with these medicines.

Tolvaptan:

Exposure to tolvaptan is significantly increased (200% in AUC; 80% in C_max) when tolvaptan, a CYP3A4 substrate, is co-administered with FLUCORIC, a moderate CYP3A4 inhibitor, with risk of significant increase in adverse reactions particularly significant diuresis, dehydration and acute renal failure. In case of concomitant use, the tolvaptan dose should be reduced as instructed in the tolvaptan prescribing information and the patient should be frequently monitored for any adverse reactions associated with tolvaptan.

Vinca alkaloids:

Although not studied, FLUCORIC may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A:

Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and FLUCORIC, pseudotumour cerebri, which disappeared after discontinuation of FLUCORIC treatment occurred. Potential central nervous system (CNS) adverse events should be monitored for when this combination of medicines is used.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor):

Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2,5 days) and oral FLUCORIC (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase in C_max, and AUCτ, of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and FLUCORIC did not eliminate or diminish this effect. Concomitant administration of voriconazole and FLUCORIC at any dose is not recommended.

Zidovudine:

FLUCORIC increases C_max and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with FLUCORIC. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

Medical practitioners should be aware that drug-drug interaction studies with other medicines have not been conducted, but such interactions may occur.

Women of childbearing potential/contraception in males and females

Effective contraceptive measures must be used in women of childbearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.

Pregnancy

FLUCORIC is contraindicated for use during pregnancy (see section 4.3). There have been reports of congenital abnormalities in infants whose mothers were treated with FLUCORIC.

There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) FLUCORIC therapy for coccidioidomycosis.

A few published case reports describe a distinctive and a rare pattern of birth defects among infants whose mother received high-dose (400 to 800 mg/day) FLUCORIC during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.

Breastfeeding

FLUCORIC is found in breast milk at concentrations similar to plasma.

FLUCORIC should not be used in mothers breastfeeding their infants.

When driving vehicles or operating machines, it should be taken into account that dizziness or seizures may occur.

Paediatric population

The pattern and incidence of adverse events and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.