FORCAN Tablets (Fluconazole)

Table of Content

Qualitative and Quantitative Composition

FORCAN 100 Tablets

Each uncoated tablet contains:

Fluconazole……….100 mg

Excipients…………………………. q.s.

Dosage Form and Strength

Tablet for oral use

100 mg

Clinical Particulars

Therapeutic Indications

 FORCAN Tablets (fluconazole) are indicated for the treatment of the following:

  • Systemic candidiasis
  • Mucosal candidiasis
  • Cryptococosis
  • Prevention of fungal infection in patients with malignancy

Posology and Method of Administration (12 years of age and over)

Posology

The dose should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.

Dosage and Administration in Adults

Systemic Candida Infections

Adult: Initially, 400 mg, followed by 200-400 mg once daily. Treatment duration is based on clinical and mycological response, but is usually at least 6-8 wk in cryptococcal meningitis. To prevent relapse after a primary course of treatment for acute cryptococcal meningitis in AIDS patients: 100-200 mg daily.

Child: <2 wk 6-12 mg/kg 72 hrly; 2-4 wk 6-12 mg/kg 48 hrly; >4 wk 6-12 mg/kg daily. Max: 400 mg daily.

Renal impairment: Haemodialysis patients: Usual dose given after each session.

Mucosal Candidiasis

Adult: 50 mg daily, may increase to 100 mg daily if needed. Treatment duration: 7-14 days (oropharyngeal candidiasis, except in severely immunocompromised patients), 14 days (atrophic oral candidiasis associated w/ dentures), 14-30 days (other mucosal candidiasis including oesophagitis).

Child: <2 wk Initially, 6 mg/kg, followed by 3 mg/kg 72 hrly; 2-4 wk Initially, 6 mg/kg, followed by 3 mg/kg 48 hrly; >4 wk Initially, 6 mg/kg, followed by 3 mg/kg daily. Max: 400 mg daily.

Renal impairment: Haemodialysis patients: Usual dose given after each session.

Cryptococcal Infections

Adult: Initially, 400 mg, followed by 200-400 mg once daily. Treatment duration is based on clinical and mycological response, but is usually at least 6-8 wk in cryptococcal meningitis. To prevent relapse after a primary course of treatment for acute cryptococcal meningitis in AIDS patients: 100-200 mg daily.

Child: <2 wk 6-12 mg/kg 72 hrly; 2-4 wk 6-12 mg/kg 48 hrly; >4 wk 6-12 mg/kg daily. Max: 400 mg daily

Renal impairment: Haemodialysis patients: Usual dose given after each session.

Prophylaxis of Fungal Infections in Immunocompromised Patients

Adult: 50-400 mg daily.

Child: <2 wk 3-12 mg/kg 72 hrly; 2-4 wk 3-12 mg/kg 48 hrly; >4 wk 3-12 mg/kg daily. Max: 400 mg daily.

Renal impairment: Haemodialysis patients: Usual dose given after each session.

Dosage in Patients with Impaired Renal Function

Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:

Creatinine Clearance (mL/min)

Percent of Recommended Dose

>50

100%

≤50 (no dialysis)

50%

Regular dialysis

100% after each dialysis

These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition.

When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults:

Males:               Weight (kg) × (140 – age)     
                72 × serum creatinine (mg/100 mL)

Females: 0.85 × above value

Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children:

K ×   linear length or height (cm)   
           serum creatinine (mg/100 mL)

(Where K=0.55 for children older than 1 year and 0.45 for infants.)

Administration

FORCAN Tablets are administered orally. FORCAN Tablets can be taken with or without food.

Contraindications

  • FORCAN Tablets (fluconazole) are contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients.
  • There is no information regarding cross-hypersensitivity between FORCAN Tablets and other azole antifungal agents.
  • Caution should be used in prescribing FORCAN Tablets to patients with hypersensitivity to other azoles.
  • Co-administration of terfenadine is contraindicated in patients receiving FORCAN Tablets at multiple doses of 400 mg or higher based upon results of a multiple-dose interaction study.
  • Co-administration of other drugs known to prolong the QT interval and that are metabolised via the enzyme CYP3A4, such as cisapride, astemizole, pimozide and quinidine, are contraindicated in patients receiving fluconazole.

Special Warnings and Precautions for Use

Hepatobiliary System

Fluconazole should be administered with caution to patients with liver dysfunction. It has been associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to the total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury.

The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician.

Tinea capitis

Fluconazole has been studied for the treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, FORCAN Tablets should not be used for tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep Endemic Mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

Anaphylaxis

In rare cases, anaphylaxis has been reported.

Renal System

FORCAN Tablets should be administered with caution to patients with renal dysfunction.

Adrenal Insufficiency

Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole. Reversible cases of adrenal insufficiency have been reported in patients receiving fluconazole.

Prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Cardiovascular System

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

FORCAN Tablets should be administered with caution to patients with potentially pro-arrhythmic conditions.

Co-administration of other medicinal products known to prolong the QT interval and which are metabolised via the CYP450 3A4 are contraindicated.

Halofantrine

Halofantrine has been shown to prolong the QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is, therefore, not recommended.

Dermatological Reactions

Exfoliative skin disorders during treatment with Fluconazole have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with Fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

Potential for Foetal Harm

There are no adequate and well-controlled clinical trials of fluconazole in pregnant women. Case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high-dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If FORCAN Tablets are used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the foetus. Effective contraceptive measures should be considered in women of childbearing potential who are being treated with FORCAN Tablets 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

Hypersensitivity

In rare cases, anaphylaxis has been reported.

Terfenadine

The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Drug Interactions

Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with FORCAN who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 co-administered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between FORCAN and the following agents/classes have been observed and are described in greater detail below:

Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 μg/kg) in healthy volunteers, the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg).

Amitriptyline, Nortriptyline: Fluconazole increases the effect of amitriptyline

andnortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary

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

Anticoagulants: In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria, and melaena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type or indanedione anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of the anticoagulant may be necessary.

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Co-administration of fluconazole and astemizole is contraindicated.

Azithromycin: An open-label, randomised, three-way crossover study in 18 healthy subjects assessed the effect of a single 1,200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin

Benzodiazepines : Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored.

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

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

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

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

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

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin, depending on ciclosporin concentration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Co-administration of fluconazole and erythromycin is contraindicated. Concomitant use of the following other medicinal products cannot be recommended:

Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary.

HMG CoA Reductase Inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is 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.

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and, consequently, sudden heart death. This combination should be avoided.

Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.

Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold and hydroxymethyl-ivacaftor (M1) exposure by 1.9-fold. A reduction of the ivacaftor dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when co-administered with fluconazole compared with administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer were increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg) compared with administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole 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 dose of NSAIDs may be needed.

Olaparib: Moderate inhibitors of CYP3A4 such as fluconazole 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 fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl oestradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Oral Hypoglycaemics: Clinically significant hypoglycaemia may be precipitated by the use of fluconazole with oral hypoglycaemic agents; one fatality has been reported from hypoglycaemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide and glipizide and increases the plasma concentration of these agents.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With co-administration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de pointes. Co-administration of fluconazole and pimozide is contraindicated.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when 3-month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity, which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Co-administration of fluconazole and quinidine is contraindicated

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

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

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

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

Sulphonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (e.g. chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of the sulphonylurea dose is recommended during co-administration.

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

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

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 using a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study with a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

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

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

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

Vitamin A: Based on a case report in 1 patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, central nervous system (CNS)-related undesirable effects have developed in the form of pseudo tumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS-related undesirable effects should be borne in mind.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibitor): Co-administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUC of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse events is recommended if voriconazole is used sequentially after fluconazole.

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

Use in Special Population

Pregnancy

Teratogenic Effects

Potential for Foetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the foetus. A few published case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high-dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. Effective contraceptive measures should be considered in women of childbearing potential who are being treated with fluconazole 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. If fluconazole is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies. There are no adequate and well-controlled studies of fluconazole in pregnant women.

Human Data: Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole 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. These effects are similar to those seen in animal studies.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

Lactation

Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL at 5.2 hours post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended paediatric dose for oropharyngeal candidiasis (labelled paediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules ) for lactation-associated Candida of the breasts reported no serious adverse reactions in infants. Caution should be exercised when fluconazole is administered to a nursing mother.

Pediatric Use

An open-label, randomized, controlled trial has shown FORCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age.

The use of FORCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children.

In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of FORCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy.

The efficacy of FORCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children.

The safety profile of FORCAN n children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days.

Efficacy of FORCAN has not been established in infants less than 6 months of age. A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with FORCAN.

Geriatric Use

In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a causal relationship to drug exposure.

Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function.

Effects on the Ability to Drive and Use Machines

No studies have been performed on the effects of fluconazole on the ability to drive or use machines.

Patients should be warned about the potential for dizziness or seizures while taking fluconazole and should be advised not to drive or operate machines if any of these symptoms occur.

Undesirable Effects

Fluconazole is generally well tolerated.

Based on individual case study reports, patient treated with fluconazole may experience hyperpigmentation adverse event.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and aematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

In Patients Receiving a Single Dose for Vaginal Candidiasis

During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to fluconazole was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single-dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhoea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angio-oedema and anaphylactic reaction have been reported in marketing experience.

In Patients Receiving Multiple Doses for Other Infections

Of over 4,000 patients treated with fluconazole in clinical trials for 7 days or more, 16% experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.

Clinical adverse events were reported more frequently in HIV-infected patients (21%) than in non-HIV-infected patients (13%); however, the patterns in HIV infected and non-HIV-infected patients were similar. The proportion of patients discontinuing therapy due to clinical adverse events was similar in the two groups (1.5%).

The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4,048 patients receiving fluconazole for 7 or more days in clinical trials: nausea, 3.7%; headache, 1.9%; skin rash, 1.8%; vomiting, 1.7%; abdominal pain, 1.7%; and diarrhoea, 1.5%.

Hepatobiliary System

In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole (see 4.4 Special Warnings and Precautions for Use, Hepatobiliary System). The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole.

In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulphonylurea hypoglycaemic agents.

Post marketing Experience

In addition, the following adverse events have occurred during postmarketing experience:

Immunologic: In rare cases, anaphylaxis (including angio-oedema, face oedema and pruritus) has been reported

Body as a Whole: Asthenia, fatigue, fever, malaise

Cardiovascular: QT prolongation, torsades de pointes

CNS: Seizures, dizziness

Haematopoietic and Lymphatic: Leucopaenia, including neutropaenia and agranulocytosis, thrombocytopaenia

Metabolic: Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia

Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting

Other Senses: Taste perversion

Musculoskeletal System: Myalgia

Nervous System: Insomnia, paraesthesia, somnolence, tremor, vertigo

Skin and Appendages: Acute generalized exanthematous pustulosis, drug eruption including fixed drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see WARNINGS), alopecia.

Paediatric

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

In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024.

By reporting the side effects, you can help provide more information on the safety of this product.

Overdose

There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behaviour.

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted.

Fluconazole is largely excreted in urine; forced volume diuresis would probably increase the elimination rate.  A 3-hour haemodialysis session decreases plasma levels by approximately 50%.

Pharmacological Properties

Pharmacodynamic Properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives,

Mechanism of Action

Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.

Antimicrobial Activity

Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Candida albicans
Candida glabrata (many isolates are intermediately susceptible)
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following fungi exhibit an in vitro MIC less than or equal to the susceptible breakpoint for fluconazole (https://www.fda.gov/STIC) against isolates of similar genus or organism group. However, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials:

Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., C. krusei). Such cases may require alternative antifungal therapy.

Pharmacokinetic Properties

The pharmacokinetic properties of fluconazole are similar following administration by the IV or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with IV administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of (fluconazole)  leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose-proportional.

The Cmax and AUC data from a food-effect study involving administration of (fluconazole) to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, (fluconazole) may be taken without regard to meals.

Steady-state concentrations are reached within 5–10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein-binding is low (11 to 12%). Following either single or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post-dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid to plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole is markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of Fluconazole may need to be reduced in patients with impaired renal function A 3-hour haemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response.

Pharmacokinetics in Children

In children, the following pharmacokinetic data {mean (%cv)} have been reported:

Age
Studied

Dose
(mg/kg)

Clearance
(mL/min/kg)

Half-life
(Hours)

Cmax
(µg/mL)

Vdss
(L/kg)

9 months–
13 years

Single-Oral
2 mg/kg

0.40 (38%)
N=14

25.0

2.9 (22%)
N=16

9 months–
13 years

Single-Oral
8 mg/kg

0.51 (60%)
N=15

19.5

9.8 (20%)
N=15

5–15 years

Multiple IV
2 mg/kg

0.49 (40%)
N=4

17.4

5.5 (25%)
N=5

0.722 (36%)
N=4

5–15 years

Multiple IV
4 mg/kg

0.59 (64%)
N=5

15.2

11.4 (44%)
N=6

0.729 (33%)
N=5

5–15 years

Multiple IV
8 mg/kg

0.66 (31%)
N=7

17.6

14.1 (22%)
N=8

1.069 (37%)
N=7

Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg.

In premature newborns (gestational age: 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg 6 days later, and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours 6 days later, and 46.6 hours 12 days later.

Pharmacokinetics in the Elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older, receiving a single 50 mg oral dose of fluconazole. Of these patients, 10 were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 mcg∙h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Co-administration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0 to 24 hours, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-life–creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life–creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Animal Data

Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on body surface area comparison), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse foetal effects were observed.

In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no foetal effects at 5 mg/kg or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryo-lethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal craniofacial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis, and parturition.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5 mg/kg/day, 5 mg/kg/day, or 10 mg/kg/day (approximately 2 to 7 times the recommended human dose). Male rats treated with 5 mg/kg/day and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1,000 mcg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg, 10 mg/kg, or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5 mg/kg, 20 mg/kg, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5 to 15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of stillborn pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.

Description

Fluconazole is a triazole antifungal agents. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis.

Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is:

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

See on the pack.

Packaging Information

Pack of 10 tablets.

Storage and Handling Instructions

Store in a cool, dry place. Protect from light.

Keep out of the reach of children.

Patient Counselling Information

What is FORCAN and what is it used for?

FORCAN Tablets is part of a group of medicines called ‘antifungals’. The active substance is fluconazole. It is used to treat fungal infections.

It is used for the following treatment

Vaginal candidiasis (vaginal yeast infections due to Candida).

Oropharyngeal and esophageal candidiasis, FORCAN Tablets were also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections, including candidaemia, disseminated candidiasis, and pneumonia.

Cryptococcal meningitis. Studies comparing fluconazole with amphotericin B in non-HIV-infected patients have not been conducted.

Prophylaxis. FORCAN Tablets are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.

What do you need to know before you take FORCAN Tablets?

Do not take FORCAN Tablets

- if you are allergic to fluconazole, to other medicines you have taken to treat fungal infections or to any of the other ingredients of this medicine (the symptoms may include itching, reddening of the skin or difficulty in breathing);

Before you use FORCAN Tablets, tell your doctor about the following:

Do not take FORCAN if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including:

  • diabetes medicines such as glyburide, tolbutamide, glipizide
  • blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine
  • blood thinners such as warfarin
  • cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
  • rifampin or rifabutin for tuberculosis
  • astemizole for allergies
  • phenytoin or carbamazepine to control seizures
  • theophylline to control asthma
  • cisapride for heartburn
  • quinidine (used to correct disturbances in heart rhythm)
  • amiodarone (used for treating uneven heartbeats ‘arrhythmias’)
  • amitriptyline or nortriptyline for depression
  • pimozide for psychiatric illness
  • amphotericin B or voriconazole for fungal infections
  • erythromycin for bacterial infections
  • olaparib, cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer
  • fentanyl, afentanil or methadone for chronic pain
  • halofantrine for malaria
  • lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
  • non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
  • prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders
  • antiviral medications used to treat HIV like saquinavir or zidovudine
  • tofacitinib for rheumatoid arthritis
  • vitamin A nutritional supplement
  • Since there are many brand names for these medicines, check with your doctor if you have any questions.
  • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies
  • have any liver problems.
  • have any other medical conditions
  • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether FORCAN is right for you. Women who can become pregnant should think about using effective birth control while taking FORCAN.
  • are breastfeeding. FORCAN can pass through breast milk to the baby.
  • are allergic to any other medicines including those used to treat yeast and other fungal infections.
  • are allergic to any of the ingredients in FORCAN. The main ingredient of FORCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharma

FORCAN Tablets with food and drink

You can take your medicine with or without a meal.

Driving and using machines

When driving vehicles or using machines, it should be taken into account that occasionally dizziness or fits may occur.

How should you take FORCAN Tablets?

Always take your medicine exactly as your doctor has told you. You should check with your doctor if you are not sure.

Take FORCAN by mouth with or without food. You can take FORCAN at any time of the day. Swallow the tablet whole with a glass of water. It is best to take your tablets at the same time each day.

FORCAN keeps working for several days to treat the infection. Generally, the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor.

If you take more FORCAN Tablets than prescribed,

Taking too many tablets at once may make you unwell. Contact your doctor or your nearest hospital casualty department at once. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). Symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate

If you forget to take FORCAN Tablets

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, do not take the dose that you missed.

If you have any further questions on the use of this medicine, ask your doctor.

What are the Possible Side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most common side effects of FORCAN are:

•headache

•diarrhea

•nausea or upset stomach

•dizziness

•stomach pain

•changes in the way food tastes

Allergic reactions to FORCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling.

Tell your doctor if you experience skin rash, fever, swollen glands, increase in a type of white blood cell (eosinophilia), and inflammation of internal organs (liver, lungs, heart, kidneys, and large intestine) as they may be signs of a hypersensitivity reaction (Drug Reaction or rash with Eosinophilia and Systemic Symptoms (DRESS)).

FORCAN has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching.

In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking FORCAN.

FORCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor.

Cases of reversible adrenal insufficiency have been reported with FORCAN. Tell your doctor is you experience chronic, or long-lasting fatigue, muscle weakness, loss of appetite, weight loss or abdominal pain.

How should you store FORCAN Tablets?

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the pack after expiry. The expiry date refers to the last day of the month.

Store below 30°C.

Do not throw away any medicines via wastewater or household waste. Ask your doctor how to throw away medicines you no longer use. These measures will help protect the environment.

Details of the Manufacturers

Cipla Ltd.

L-139 to L-146

Verna Industrial Estate

Verna Salcette,

Goa -403 722

License No

536

Date of Revision

01/11/2019