Fluconazole Stella

Fluconazole.

Active ingredient: Fluconazole 150 mg.
Excipients/Inactive Ingredients: Lactose monohydrate, wheat starch, sodium starch glycolate, talc, magnesium stearate, empty capsule.
Components of empty capsule: FD&C blue 1, FD&C red 3, titanium dioxide, gelatin, printing ink.
Components of printing ink (WHITE SB-0007P): Shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, titanium dioxide.

Fluconazole is indicated in the following fungal infections.
Fluconazole is indicated in adults for the treatment of: Coccidioidomycosis; Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria; Vaginal candidiasis, acute or recurrent, when local therapy is not appropriate; Candidal balanitis when local therapy is not appropriate; Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal candida infections when systemic therapy is indicated; Tinea unguinium (onychomycosis) when other agents are not considered appropriate.
Fluconazole is indicated in adults for the prophylaxis of: Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at high risk of experiencing relapse; To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year); Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem Cell Transplantation).

Administration: Fluconazole is administered orally.
The physician should prescribe the most appropriate pharmaceutical form and strength according to age, weight and dose. The capsule formulation is not adapted for use in infants and small children.
The capsules should be swallowed whole and independent of food intake.
Dosage: 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.
Adults: Treatment: Coccidioidomycosis: Use 200 mg to 400 mg once daily. Duration of treatment is 11 months up to 24 months or longer depending on the patient. 800 mg daily may be considered for some infections and especially for meningeal disease.
Mucosal candidiasis including: Oropharyngeal candidiasis: Loading dose is 200 mg to 400 mg on Day 1. Subsequent dose is 100 mg to 200 mg once daily. Duration of treatment is 7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function.
Oesophageal candidiasis: Loading dose is 200 mg to 400 mg on Day 1. Subsequent dose is 100 mg to 200 mg once daily. Duration of treatment is 14 to 30 days (until oesophageal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function.
Candiduria: Use 200 mg to 400 mg once daily. Duration of treatment is 7 to 21 days. Longer periods may be used in patients with severely compromised immune function.
Vaginal candidiasis: Acute vaginal candidiasis: Use 150 mg as a single dose.
Recurrent vaginal candidiasis (4 or more episodes a year): Use 150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by 150 mg once weekly maintenance dose (Maintenance dose: 6 months).
Candidal balanitis: Use 150 mg as a single dose.
Dermatomycosis including: Tinea pedis, tinea corporis, tinea cruris and dermal candida infections: Use 150 mg once weekly. Duration of treatment is 2 to 4 weeks; tinea pedis may require treatment for up to 6 weeks.
Tinea versicolor: Use 300 mg to 400 mg once weekly. Duration of treatment is 1 to 3 weeks.
Tinea unguinium (onychomycosis): Use 150 mg once weekly. Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally requires 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured.
Prophylaxis: Relapse of oropharyngeal or oesophageal candidiasis in the patients infected with HIV: Use 100 mg to 200 mg once daily. Duration of treatment is an indefinite period for patients with chronic immune suppression.
To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year): Use 150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by 150 mg once weekly maintenance dose (Maintenance dose: 6 months).
Prophylaxis of candidal infections in the patients with prolonged neutropenia: Use 200 mg to 400 mg once daily. Treatment should start several days before the anticipated onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count rises above 1000 cells per mm³.
Special populations: Elderly: Dosage should be adjusted based on the renal function.
Renal impairment: The drug is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 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: See table.

Click on icon to see table/diagram/image

Patients on haemodialysis should receive 100% of the recommended dose after each haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.
Hepatic impairment: Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction.
(For dosages other than 150 mg or multiple of 150 mg (e.g. 300 mg), physicians should consider other registered products in the market.)

There have been reports of overdose with fluconazole. Hallucination and paranoid behaviour have been concomitantly reported.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.
Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%.

Hypersensitivity to the active substance, to related azole substances, or to any of the excipients in the product.
Co-administration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple-dose interaction study. Co-administration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4, such as cisapride, astemizole, pimozide, quinidine and erythromycin, are contraindicated in patients receiving fluconazole.

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.
Renal system: Fluconazole should be administered with caution to patients with renal dysfunction.
Adrenal insufficiency: Ketoconazole is known to cause adrenal insufficiency, and this could also, although rarely seen, be applicable to fluconazole.
Hepatobiliary system: Fluconazole should be administered with caution to patients with liver dysfunction.
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 (I_kr).
Fluconazole should be administered with caution to patients with potentially proarrhythmic conditions.
Co-administration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated.
Halofantrine: Halofantrine has been shown to prolong 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: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued.
Hypersensitivity: In rare cases, anaphylaxis has been reported.
Cytochrome P450: Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Fluconazole-treated patients, who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored.
Terfenadine: The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Excipient: The product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on 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.

Pregnancy: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high-dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug 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.
Studies in animals have shown reproductive toxicity.
Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary.
Fluconazole in high doses and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections.
Lactation: Fluconazole passes into breast milk to reach concentrations similar to those in plasma. Breast-feeding may be maintained after a single dose of 150 mg fluconazole. Breast-feeding is not recommended after repeated use or after high-dose fluconazole. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fluconazole and any potential adverse effects on the breast-fed child from fluconazole or from the underlying maternal condition.

The most frequently (≥1/100 to <1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash.
The following adverse reactions have been observed and reported during treatment with fluconazole with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Blood and the lymphatic system disorders: Uncommon: Anaemia.
Rare: Agranulocytosis, leukopenia, thrombocytopenia, neutropenia.
Immune system disorders: Rare: Anaphylaxis.
Metabolism and nutrition disorders: Uncommon: Decreased appetite.
Rare: Hypercholesterolaemia, hypertriglyceridaemia, hypokalemia.
Psychiatric disorders: Uncommon: Somnolence, insomnia.
Nervous system disorders: Common: Headache.
Uncommon: Seizures, paraesthesia, dizziness, taste perversion.
Rare: Tremor.
Ear and labyrinth disorders: Uncommon: Vertigo.
Cardiac disorders: Rare: Torsades de pointes, QT prolongation.
Gastrointestinal disorders: Common: Abdominal pain, vomiting, diarrhoea, nausea.
Uncommon: Constipation, dyspepsia, flatulence, dry mouth.
Hepatobiliary disorders: Common: Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased.
Uncommon: Cholestasis, jaundice, bilirubin increased.
Rare: Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage.
Skin and subcutaneous tissue disorders: Common: Rash.
Uncommon: Drug eruption - including Fixed Drug Eruption, urticaria, pruritus, increased sweating.
Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, dermatitis exfoliative, angioedema, face oedema, alopecia.
Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders: Uncommon: Myalgia.
General disorders and administration site conditions: Uncommon: Fatigue, malaise, asthenia, fever.

Concomitant use of the following other medicinal products cannot be recommended: 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.
Concomitant use that should be used with caution: 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).
Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole: 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.
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.
The effect of fluconazole on other medicinal products: Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is also a strong inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned as follows, there is a risk of increased plasma concentration of other compounds metabolised 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 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.
Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 μg/kg) in healthy volunteers, the alfentanil AUC₁₀ increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 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.
Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) 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.
Benzodiazepines (short acting), i.e. midazolam, triazolam: 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, isradipine, 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.
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.
Ibrutinib: Moderate inhibitors of CYP3A4, such as fluconazole, 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.
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.
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.
Immunosuppressors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. 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.
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.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174) 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: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when co-administered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was co-administered 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 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.
Phenytoin: With co-administration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.
Prednisone: Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.
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.
Sulfonylureas: Fluconazole 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 dose is recommended during co-administration.
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 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 one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS-related undesirable effects have developed in the form of pseudotumour 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 and oral fluconazole to 8 healthy male subjects resulted in an increase in Cmax and AUC of voriconazole by an average of 57% and 79%, 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.
Oral contraceptives: There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol 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.

Store in a well-closed container, in a dry place. Do not store above 30°C.

Antifungals

J02AC01 - fluconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

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