Axcel Fluconazole

Axcel Fluconazole

fluconazole

Manufacturer:

Kotra Pharma

Distributor:

Kotra Pharma
Full Prescribing Info
Contents
Fluconazole.
Description
Each capsule contains Fluconazole 150 mg.
Action
Pharmacology: Mechanism of Action: Fluconazole is a triazole antifungal. It is mainly against Blastomyces dermatitides, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Epidermophyton spp., Histoplasma capsulatum, Microsporum spp., and Trichophyton spp. Fluconazole is highly selective inhibitor of fungal sterol biosynthesis. It inhibits cytochrome P450-dependent enzymes that caused impairment of ergosterol synthesis in fungal cell membranes.
Pharmacokinetics: Fluconazole is well absorbed as oral doses. It is widely distributed and the distribution volume close to total body water. Multiple dose can leads to increasing the peak in plasma concentration. Concentration in breast milk, joint fluid, saliva, sputum, vaginal fluids and peritoneal fluid are similar with concentration in plasma. Mean peak plasma concentration in healthy subjects after 400mg oral dose reported as 6.72mcg/ml and peak concentration reached within 1 to 2 hours after oral dosing. Most of the dose is excreted unchanged in urine and about 11% as metabolites. The half-life elimination is 30 hours and increased in-patient with renal impairment. Fluconazole is removed by dialysis.
Indications/Uses
Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these result become available, anti-infective therapy should be adjusted accordingly.
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 theraphy 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, eye and pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors predisposing to candidal infection may be treated.
Mucosal candidiasis. These include oropharyngeal, esophageal non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic 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; and prophylaxis to reduce the incidence of recurrent vaginal candidiasis (3 or more episodes a year). 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, tinea corporis, tinea cruris, tinea versicolor, and dermal candida infections.
Dosage/Direction for Use
The daily dose of fluconazole should be based on the nature and severity of the fungal infection. 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.
Use in Adults: For Cryptococcal Meningitis and Cryptococcal Infections at Other Sites: Usual Dose: 400 mg on the 1st day followed by 200-400 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.
Prevention of Relapse of Cryptococcal Meningitis in Patients with AIDS: After the patient receives a full course of primary therapy, fluconazole 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 1st 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: usual dose is 50-100 mg once daily for 7-14 days. If necessary, treatment can be continued for longer periods in patients with severely compromised immune function. For atrophic oral candidiasis associated with dentures, the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
For other candidal infections of the mucosa except genital candidiasis, (e.g., esophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis, etc.) the usual effective dose is 50-100 mg daily, given 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, fluconazole may be administered at a 150 mg once weekly dose.
For the treatment of vaginal candidiasis, fluconazole 150 mg should be administered as a single oral dose. To reduce the incidence of recurrent vaginal candidiasis, a 150 mg once monthly dose may be used. The duration of therapy should be individualized, but ranges from 4-12 months. Some patients may require a more frequent dosing.
For Candida Balanitis, fluconazole 150 mg should be administered as a single oral dose.
The recommended fluconazole dosage for the prevention of candidiasis is 50-400 mg once daily, based on the patient's risk for developing fungal infection. For patients at risk of systemic infection eg, patients who are anticipated to have profound or prolonged neutropenia, the recommended daily dose are 400 mg once daily. Fluconazole administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells/mm3.
For dermal infections including tinea pedis, corporis, cruris and candida infections the recommended dosage: 150 mg once weekly or 50mg once daily. Duration of treatment is normally 2-4 weeks but tinea pedis may require treatment for up to 6 weeks.
For tinea versicolor, the recommended dose is 300 mg once weekly for 2 weeks; a 3rd weekly dose of 300 mg may be needed in some patients, whereas, in some patients, a single dose of 300-400 mg may be sufficient. An alternate dosing regimen is 50mg once daily for 2-4 weeks.
Use in Children: As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children. Fluconazole is administered as a single dose each day.
The recommended dosage of fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the 1st day to achieve steady-state levels more rapidly.
For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6-12 mg/kg daily, depending on the severity of the disease.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3-12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see Use in Adults). (For Children with impaired renal functions, see Use in Renal Impairment).
Use in Children below 4 weeks of age and younger: Neonates excrete fluconazole slowly. In the first 2 weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hrs. During weeks 2-4 of life, the same dose should be given every 48 hours.
*Capsule is not recommended for children.
Use in Elderly: Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance <50mL/min) the dosage schedule should be adjusted as described as follows.
Use in Renal Impairment: Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single-dose therapy are necessary. In patients (including children) with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50-400 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

These are suggested dose adjustments based on pharmacokinetics following administration of single dose. Further adjustment may be needed depending on clinical condition.
Overdosage
In the event of overdosage, symptomatic treatment may be adequate. Fluconazole is mostly excreted in urine; forced volume diuresis would probably increase the elimination rate.
Contraindications
Fluconazole should not be used in patients with known sensitivity to the drug, any of the inert ingredients or to related azole compounds.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of multiple doses interaction study (see Interactions).
Coadministration of cisapride is contraindicated in patients receiving fluconazole (see Interactions).
Fluconazole is generally unadvised in association with halofantrine.
Fluconazole should not be administered in the following cases: Hypersensitivity to fluconazole and/or other azole derivatives.
Pregnancy and lactation (see Use During Pregnancy and Lactation under Precautions and Use in Pregnancy & Lactation).
In combination with cisapride and pimozide (see Interactions).
Special Precautions
Fluconazole 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 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 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 <400 mg/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 of the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade 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 medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
Use During Pregnancy: There no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole theraphy for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Adverse fetal effects have been seen in animals only at high dose levels associated with maternal toxicity. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethalityin rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be result of known effects of lowered estrogen on pregnancy, organogenesis and parturition.
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.
Use During Lactation: Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
Use In Pregnancy & Lactation
Use During Pregnancy: There no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole theraphy for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Adverse fetal effects have been seen in animals only at high dose levels associated with maternal toxicity. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethalityin rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. 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.
Use During Lactation: Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
Side Effects
Fluconazole is generally well tolerated.
The most common undesirable effects observed during clinical trials and associated with fluconazole are: Nervous System Disorders: Headache.
Gastrointestinal Disorders: Abdominal pain, diarrhoea, flatulence and nausea.
Hepatobiliary Disorders: Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT and 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.
In addition, the following undesirable 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 and urticaria).
Metabolism and Nutrition Disorders: Hypercholesterolemia, hypertriglyceridemia and hypokalemia.
Nervous System Disorders: Dizziness, seizures and taste perversion.
Cardiac Disorders: QT prolongation and torsade de pointes (see Precautions).
Gastrointestinal Disorders: Dyspepsia and vomiting.
Hepatobiliary Disorders: Hepatic failure, hepatitis, hepatocellular necrosis and jaundice. Skin and Subcutaneous Tissue Disorders: Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Drug Interactions
Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. 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. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored.
Azithromycin: An open-label, randomized, 3-way crossover study in 18 healthy subjects assessed the effect of a single 1200mg 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 (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 IV. 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: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were co-administered. Cisapride increased the risk of ventricular arrhythmia troubles, notably torsade de pointes. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg 4 times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Co-administration of cisapride is contraindicated in patients receiving fluconazole (see Contraindications).
Cyclosporin: A kinetic study in renal transplant patients found fluconazole 200 mg daily to slowly increase cyclosporin concentrations. However, in another multiple dose study with 100 mg daily, fluconazole did not affect cyclosporin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Hydrochlorothiazide: In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. 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: Three kinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50-mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased by 40% and 24%, respectively. In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively. Thus, multiple doses use of fluconazole at these doses 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 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.
Pimozide: Combination with fluconazole will increase risk of ventricular arrhythmia troubles, notably torsade de pointes.
Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.
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.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be co-administered to diabetic patients but the possibility of a hypoglycemic episode should be borne in mind.
Tacrolimus: There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at 400 and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of ≥400 mg/day significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses ≥400 mg with terfenadine is contraindicated (see Contraindications). The co-administration of fluconazole at doses <400 mg/day with terfenadine should be carefully monitored.
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, and therapy modified appropriately if signs of toxicity develop.
Zidovudine: Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A 2nd randomized, 2-periods, 2-treatments crossover study examined zidovudine levels in HIV-infected patients. On 2 occasions, 21 days apart, patients received zidovudine 200 mg every 8 hrs either with or without fluconazole 400mg daily for 7 days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
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.
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.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but such interactions may occur.
Storage
Store below 30°C. Protect from light.
MIMS Class
ATC Classification
J02AC01 - fluconazole ; Belongs to the class of triazole derivatives. Used in the systemic treatment of mycotic infections.
Presentation/Packing
Cap 150 mg (blue body and cap, hard gelatin, size 1, printed "
Click on icon to see table/diagram/image
" on the capsule body) 1 x 1's.
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