Fodisis

Fluconazole.

Each capsule contains: Fluconazole 150 mg.

Pharmacology: Fluconazole, a triazole antifungal agent, is a potent and specific inhibitor of fungal sterol synthesis.
Orally administered Fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp., including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp.; and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidioides immitis, including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals.

Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
Systemic candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium, and pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic of immunosuppressive therapy, or with other factors predisposing to candidal infection may be treated.
Mucosal candidiasis. These include oropharyngeal, esophageal, non-invasive broncho-pulmonary infections, candiduria, mucocutaneous and chronic oral atropic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated. Prevention of relapse of oropharyngeal candidiasis in patients with AIDS.
Genital candidiasis. Vaginal candidiasis, acute or recurrent; Candidal balanitis.
Prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy.
Dermatomycosis including tinea pedis, tines corporis, tinea cruris, tinea versicolor, and dermal candida infections.

The daily dose of FODISIS should be based on the nature and severity of the fungal infections. Most cases of vaginal candidiasis respond to single dose therapy.
Therapy for those types of infections requiring multiple dose treatment 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. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Adults: For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 mg to 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis.
For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patients receives a full course of primary therapy. FODISIS may be administered indefinitely at a daily dose of 200 mg.
For candidemia, disseminated candidiasis and other invasive candidal infections, the usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response, the dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response.
For oropharyngeal candidiasis, the usual dose is 50 mg to 100 mg once daily for 7-14 days. If necessary, treatment can be continued for longer periods in patients with severely compromised immune function.
For atropic oral candidiasis associated with dentures, the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures with denture.
For other candidal infections of mucosa except genital candidiasis (e.g. esophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis, etc.) the usual effective dose is 50 to 100 mg daily, give for 14-30 days. For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the patient receives a full course of primary therapy. FODISIS may be administered at a 150 mg once weekly dose.
For Candida balanitis, FODISIS 150 mg should be administered as a single oral dose.
The recommended FODISIS dosage for the prevention of candidiasis is 50 to 400 mg once daily, based on patient's risk for developing fungal infection. For patients at high risk of systemic infection, e.g. patients who are anticipated to have profound or prolonged neutropenia, the recommended daily dose is 400 mg once daily. FODISIS administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cell per mm³.
A higher dose of 100 mg once dally may be used in patients at risk of severe recurrent infections.
For dermal infections including tinea pedis, corporis, cruris and candida infections, the recommended dosage is 150 mg once weekly or 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. For tinea versicolor the recommended dose is 50 mg once daily for 2 to 4 weeks. Duration of treatment should not exceed 6 weeks.
For the treatment of vaginal candidiasis, FODISIS 150 mg should be administered as a single dose.
Children: As stated in the precautions, use in children below the age of 16 years is not recommended. However, when the treating physician considers FODISIS therapy imperative, the following daily doses for children aged 1 year and older with normal renal function are recommended: 1-2 mg/kg for superficial candidal infections and 3-6 mg/kg for systemic candidal/cryptococcal infections. These recommendations approximate the doses used in adults on a mg/kg basis.
However, preliminary data in children aged 5-13, indicate FODISIS elimination may be faster than in adults. Therefore, for serious or life-threatening infections, higher daily doses used maybe required. Daily doses up to 12 mg/kg have been used in a small number of children. The maximum approved adult daily dose of 400 mg should not be exceeded.
For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults, dependent on the degree of renal impairment.
Elderly: Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance <50 mL/min) the dosage schedule should be adjusted as described as follows.
Renal Impairment: FODISIS is predominantly excreted in the urine as unchanged drug. No adjustments in single-dose therapy are necessary. In patients with impaired renal function who will receive multiple doses of FODISIS, 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: See table.


Click on icon to see table/diagram/image


Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.
When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patients) should be based on the following equation: See equation.


Click on icon to see table/diagram/image

Hallucinations and paranoid behaviour.
In the event of the overdosage, 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 hemodialysis session decreases plasma levels by approximately 50%.

Fluconazole should not be used in patients with known sensitivity to the drug, any of the inert ingredients or to related azole compounds.
Co-administration of Terfenadine is contraindicated in patients receiving Fluconazole at multiple doses of 400 mg per day or higher. Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as Cisapride, Astemizole, Erythromycin, Pimozide and Quinidine are contraindicated in patients receiving Fluconazole (see Precautions and Interactions).
Co-administration of Cisapride is contraindicated in patients receiving Fluconazole (see Interactions).

Fluconazole should be administered with caution to patients with liver dysfunction.
Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical condition. In cases of Fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during Fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to Fluconazole.
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 drugs. If a rash, which is considered attributable to Fluconazole, develops in a patient treated for for a superficial fungal infection, further therapy with this agent should be discontinued.
If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and Fluconazole discontinued if bullous lesions or erythema multiforme develop.
The co-administration of Fluconazole at doses lower than 400 mg per day with Terfenadine should be carefully monitored (see Interactions).
In rare cases, as with other azoles, anaphylaxis has been reported.
Some azoles, including Fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. QT prolongation and torsade de pointes can occur in patients taking Fluconazole, these reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
Fluconazole should be administered with caution to patients with renal dysfunction (see also Dosage & Administration).
Fluconazole is a potent CYP2C9 and CYP2C19 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see Interactions).
Effects on Ability to Drive and Use Machines: The therapy is unlikely to impair a patient ability to drive or use machinery.
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

Pregnancy: There are no adequate and well controlled studies in pregnant women.
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 fetus.
Lactation: Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

Fluconazole is generally well tolerated.
The most common adverse reactions associated with Fluconazole are: Nervous system disorders: Headache.
Gastrointestinal disorders: Abdominal pain, diarrhea, flatulence, nausea.
Hepatobiliary disorders: Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT, elevated SGPT.
Skin and subcutaneous tissue disorders: Rash.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal, and hematological function test results and hepatic abnormalities (see Precautions) have been observed during treatment with Fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.
Psychiatric disorders (uncommon): Insomnia, somnolence.
Ear and labyrinth disorders (uncommon): Vertigo.
Musculoskeletal, connective tissue and bone disorders (uncommon): Myalgia.
General disorders and administration site conditions (uncommon): Fatigue, malaise, asthenia, fever.
Skin and subcutaneous tissue disorders (uncommon): Increased sweating, drug eruption, acute generalized exanthematous-pustulosis (rare).
Hepatobiliary disorders (rare): Hepatocellular damage.
In addition, the following adverse effects have occurred during post-marketing: Blood and lymphatic system disorders: Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.
Immune system disorders: Anaphylaxis (including angioedema, face edema pruritus, urticaria).
Metabolism and nutrition disorders: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Nervous system disorders: Dizziness, seizures, paresthesia, taste perversion, tremor.
Cardiac disorders: QT prolongation, torsades de pointes (see Precautions).
Gastrointestinal disorders: Dyspepsia, vomiting, dry mouth.
Hepatobiliary disorders: Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.
Skin and subcutaneous tissue disorders: Alopecia, exfoliate skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Anticoagulants: Fluconazole increased the prothrombin time after Warfarin administration. 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. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored.
Azithromycin: There was no significant pharmacokinetic interaction between Fluconazole and Azithromycin.
Benzodiazepines (short acting): Following oral administration of Midazolam, Fluconazole resulted in substantial increases in Midazolam concentrations and psychomotor effects. This effect on Midazolam appears to be more pronounced following oral administration of Fluconazole than with Fluconazole administered intravenously. If concomitant Benzodiazepine therapy is necessary in patients being treated with Fluconazole, consideration should be given to decreasing the Benzodiazepine dosage, and the patients should be appropriately monitored.
Cisapride: Co-administered of Cisapride is contraindicated in patients receiving Fluconazole (see Contraindications).
Cyclosporin: Cyclosporin plasma concentration monitoring in patients receiving Fluconazole is recommended.
Hydrochlorothiazide: Co-administration of Hydrochlorothiazide and Fluconazole increase plasma concentration of Fluconazole. An effect of this magnitude should not necessitate a change in the Fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Oral contraceptives: Multiple dose use of Fluconazole is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Phenytoin: Concomitant administration of Fluconazole and Phenytoin may increase the levels of Phenytoin to a clinical significant degree. If it is necessary to administer both drugs concomitantly, Phenytoin levels should be monitored and the Phenytoin dose adjusted to maintain therapeutic levels.
Rifabutin: There have been report that an interactions exists when Fluconazole is administered concomitantly with Rifabutin, leading to increased serum levels of Rifabutin and uveitis. Patients receiving Rifabutin and Fluconazole concomitantly should be carefully monitored.
Rifampicin: Concomitant administration of Fluconazole and Rifampicin resulted in decrease AUC and shorter half-life of Fluconazole. In patients receiving concomitant Rifampicin, an increase of the Fluconazole dose should be considered.
Sulfonylurea: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (Chlorpropamide, Glibenclamide, Glipizide and Tolbutamide). Fluconazole and oral sulfonylurea maybe co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during co-administration.
Tacrolimus: There have been reports that an interaction exists when Fluconazole is administered concomitantly with Tacrolimus, leading to increased serum levels of Tacrolimus and nephrotoxicity. Patients receiving Tacrolimus and Fluconazole concomitantly should be carefully monitored.
Terfenadine: The combined use of Fluconazole at doses of 400 mg or greater with Terfenadine is contraindicated (see Contraindications). The co-administration of Fluconazole at doses lower than 400 mg per day with Terfenadine should be carefully monitored.
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 (see Contraindications).
Pimozide: Concomitant administration of Fluconazole and Pimozide may result in inhibition of Pimozide metabolism. Increased Pimozide plasma concentrations can lead to QT prolongation and occurrences of torsade de pointes. Co-administration of Fluconazole and Pimozide is contraindicated (see Contraindications).
Quinidine: Concomitant administration of Fluconazole and Quinidine may result in inhibition of Quinidine metabolism. Increased Pimozide plasma concentrations can lead to QT prolongation and occurrences of torsade de pointes. Co-administration of Fluconazole and Quinidine is contraindicated (see Contraindications).
Theophylline: Patients who are receiving high doses Theophylline or who are otherwise at increased risk for Theophylline toxicity should be observed for signs of Theophylline toxicity while receiving Fluconazole, and therapy modified appropriately if signs of toxicity develop.
The effect of Fluconazole on other medicinal products: Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19 and a moderate inhibitor of CYP3A4. In addition to the observed/documented interactions mentioned as follows, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 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 (see Contraindications).
Alfentanil: There have been reported a reduction in clearance and distribution volume as well as prolongation of T1/2 of Alfentanil following concomitant treatment with Fluconazole. A possible mechanism of action is Fluconazole's inhibition of CYP3A4. Dosage 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 after one week. Dosage of amitriptyline should be adjusted, if necessary.
Amphotericin B: Fluconazole increase the AUC of triazolam (single dose) and increases T1/2 due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increase serum Carbamazepine. 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 antagonist (Nifedipine, Isradipine, Amlodipine, Verapamil, and Felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonist. Frequent monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with Fluconazole and Celecoxib Cmax and AUC increased. 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: Fluconazole delayed the elimination of Fentanyl significantly. Elevated Fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase Halofantrine plasma concentration due to an inhibitory effect of CYP3A4.
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 patients should be observed for symptoms of myopathy and rhabdomyolysis and creatinine 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.
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. Dosage adjustment of Methadone may be necessary.
Non-steroidal anti-inflammatory drugs: Fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized 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.
Prednisone: Liver-transplanted patient treated with Prednisone developed acute adrenal cortex insufficiency when a three months 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 discontinued.
Saquinavir: Fluconazole increase the AUC and decreases clearance of Saquinavir due to inhibition of Saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of Saquinavir may be necessary.
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 dosage adjustment of Sirolimus depending on the effect/concentration measurements.
Tofacitinib: Exposure of Tofacitinib is increased when Tofacitinib is co-administered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. Fluconazole). Dosage adjustment of Tofacitinib may be necessary.
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: 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 pseudotumor 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.
Zidovudine: Fluconazole increases Cmax and AUC of Zidovudine due to decrease in oral Zidovudine clearance. The half-life of Zidovudine was likewise prolonged following combination therapy with Fluconazole. Patients receiving this combination should be monitored for the development of Zidovudine-related adverse reactions. Dosage reduction of Zidovudine may be considered.
Voriconazole: Concomitant administration of Voriconazole and Fluconazole at any dose is not recommended.
Erythromycin: Concomitant use of Fluconazole and Erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Co-administration of Fluconazole and Erythromycin is contraindicated (see Contraindications).
The use of Fluconazole in patients concurrently taking Astemizole or other drugs metabolized by the cytochrome P-450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering Fluconazole. Patients should be carefully monitored.
The use of Fluconazole in patients concurrently taking Astemizole or other drugs metabolized by the cytochrome P-450 system may be associated with elevations in serum level of these drugs. Caution should be used when co-administering Fluconazole. Patients should be carefully monitored.
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.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but such interactions may occur.

Store below 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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