Diflucan (Fluconazole)

Diflucan (Fluconazole) 50mg, 200 mg Capsules

Under what local brands and in what dosages is generic Fluconazole sold in pharmacies of Britain, United States, and Canada?

In pharmacies of the United States, Great Britain and Canada the pharmacists offer you to buy Fluconazole according to your prescription or without a prescription under such brand names and in such strengths and dosage forms:

UK	US	Canada
Azocan 50mg Capsules Azocan 100mg Capsules Azocan 150mg Capsules Azocan-P 150mg Capsules Boots Thrush 150mg Capsule Diflucan 150 Capsules Fluconazole 50mg Capsules Fluconazole 100mg Capsules Fluconazole 150mg Capsules Fluconazole 200mg Capsules	Diflucan 50mg Tablets Diflucan 100mg Tablets Diflucan 150 mg Tablets Diflucan 200 mg Tablets Fluconazole 50mg Tablets Fluconazole 100mg Tablets Fluconazole 150 mg Tablets Fluconazole 200 mg Tablets Fluconazole for Oral Suspension 50mg/5ml Fluconazole Oral Suspension 200mg/5ml	Diflucan Tab 50mg Diflucan Tab 100mg Diflucan Inj 2 mg/ml Diflucan PWS 50mg/5ml Fluconazole Injection 2mg/ml Mylan-Fluconazole 50mg Tablets Mylan-Fluconazole 100mg Tabs Novo-Fluconazole 50mg Tablets Novo-Fluconazole 100mg Tabs Novo-Fluconazole 150mg Tabs

What Diflucan capsules are and what they are used for

Read indications for use if you want to order  Fluconazole online

Diflucan is one of a group of medicines called “antifungals”. The active ingredient is fluconazole.

Diflucan is used to treat infections caused by fungi including yeasts and. may also be used to stop you from getting a fungal infection. The most common cause of fungal infections is a yeast called Candida.

You may be given this medicine by your doctor to treat the following types of fungal infections

• Genital thrush, infection of the vagina or penis.
• Mucosal thrush, infection of the mouth or throat.
• Skin infections – e.g. athlete’s foot, ringworm, jock itch.
• Internal (systemic) fungal infections caused by:
  • Candida and found in the blood stream, body organs (e.g.heart, lungs) or urinary tract
  • Cryptococcus, e.g. meningitis and infections of other sites such as the lungs and skin

You may also be given Diflucan to:

• stop you from getting a fungal infection (if your immune system is not working properly).
• stop an infection caused by Cryptococcus from coming back (in AIDS patients).

Before you take Diflucan

Before buy Fluconazole online, read information about the drug

Do not take Diflucan if you

• have ever had an allergic reaction to: any of the ingredients of Diflucan other medicines you have taken to treat a fungal infection. The symptoms may include itching, reddening of the skin or difficulty in breathing.
• are taking terfenadine (an antihistamine for allergies)
• are taking cisapride (used for stomach upsets)

Take special care with Diflucan

Tell your doctor if you:

• have liver or kidney problems
• suffer from heart disease, including heart rhythm problems
• have abnormal levels of potassium, calcium or magnesium in your blood?

Taking other medicines

Tell your doctor, immediately if you are taking Terfenadine (an antihistamine for treating allergies) or Cisapride (used for stomach upsets) as these should not be taken with Diflucan.

There are some medicines that may interact with Diflucan. Make sure your doctor knows if you are taking any of the following medicines:

1. warfarin (or similar drugs) that thin the blood to prevent blood clots
2. medicines  for  diabetes   such  as  chlorpropamide,   glibenclamide,   glipizide  or tolbutamide
3. water tablets, such as hydrochlorothiazide, used to treat fluid retention and high blood pressure
4. midazolam used to help you sleep or for anxiety
5. phenytoin (used to control epilepsy)
6. rifampicin or rifabutin (antibiotics for infections)
7. ciclosporin or tacrolimus (to prevent transplant rejection)
8. theophylline (used to control asthma)
9. astemizole (an antihistamine for treating allergies)
10. zidovudine, also known as AZT (used in HIV-infected patients)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

You should not take Diflucan while you are pregnant or if you are breast feeding.

Driving and using machines

Treatment with Diflucan is unlikely to affect your ability to drive or use machinery.

Important information about some of the ingredients

This medicine contains a small amount of lactose (sugar), if you have been told by your doctor that you have an intolerance to some sugars, please contact your doctor before taking this medicine.

How to take Diflucan

When you buy cheap Fluconazole you must know how to use it

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

The usual doses of this medicine for different infections are below.

AdultsGenital thrush	150mg as a single dose
Mucosal thrush – dose depends on where the infection is located	50mg once daily for 7-14 days or 14-30    days.    Sometimes    doses    are increased to 100 mg
Fungal skin infections	50mg       once       daily      for      2-4 weeks(Athlete’s foot  may be up to 6 weeks)
Internal fungal infections	400mg  on the  first  day then  200-400mg once daily for 6-8 weeks or longer if needed.
To stop you from getting fungal infections	50-400mg once daily while you are at risk of getting an infection
To stop infection caused by Cryptococcus from coming back	100-200mg once daily indefinitely

A maximum dosage of 400mg daily should not be exceeded in children.

Use of Diflucan for treating genital Candida infections in children under 16 years old is not recommended.

Doctors sometimes prescribe different doses to these. The label on the pack will tell you what dose you should take. If you are still not sure, ask your doctor or pharmacist.

Swallow the capsule whole with a glass of water. It is best to take your capsules at the same time each day. You may take your medicine with or without a meal.

Elderly

The usual adult dose should be given unless you have kidney problems.

Patients with kidney problems

Your doctor may modify your dose, depending on your kidney function.

If you take more Diflucan than you should

Taking too many capsules at once may make you unwell. Contact your doctor or your nearest hospital casualty department at once.

If you forget to take Diflucan

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.

You will find more about Diflucan on the back of this leaflet.

Possible side effects

Read side effects if you want cheap Fluconazole no prescription

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

A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately.

Sudden wheezing, difficulty in breathing or tightness in chest

Swelling of eyelids, face or lips

Itching all over the body reddening of the skin or itchy red spots

Skin rash

Severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue).

If you are an ADDS patient you are more likely to get severe skin reactions to drugs including Diflucan.

Very common side effects which may affect more than 1 person in 10 are listed below:

• feeling sick
• stomach discomfort
• diarrhoea
• wind
• rash
• headache

These undesirable effects are usually mild. If they cause you discomfort or are long lasting, check with your doctor or pharmacist.

Other side effects

• itching
• being sick
• seizure
• lower than normal white   blood cells that help defend against infections and blood cells that help to stop bleeding
• high blood levels of cholesterol, fats or salt
• liver damage and yellowing of the skin and eyes (Jaundice)
• hair loss
• dizziness
• altered sense of taste
• change in heart rate or rhythm

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Diflucan

Before purchase Fluconazole, you must read how to store

Keep out of the reach and sight of children

Do not store above 30°C.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Diflucan contains

The active substance is 50mg fluconazole or 200mg fluconazole depending on which strength you have been prescribed.

The other ingredients are:

Colouring agent:

50mg

– Titanium dioxide (E171)

– Patent blue V (El31)

200mg

– Titanium dioxide (El71)

– Erythrosine (El27)

-Indigotine(E132)

Other inactive ingredients:

– Colloidal silicon dioxide

– Gelatin (sapsule shell)

– Lactose

– Magnesium stearate

– Maize starch

– Sodium lauryl sulphate

What Diflucan 50mg and 200mg capsule looks like and contents of the pack

Diflucan 50 mg capsules are light turquoise blue (cap and body), containing a white powder. They have “FLU 50” and “PFIZER” printed on them.

Diflucan 200 mg capsules are purple (cap and body), containing a white powder. They have “FLU 200” and “PFIZER” printed on them.

Diflucan 50mg and 200mg come in blister packs of 7 capsules.

Fluconazole: Cautions

Fluconazole generally is well tolerated. However, there have been rare reports of serious hepatotoxicity (including some fatalities) in patients receiving fluconazole. Adverse effects have been reported in about 5-30% of patients receiving fluconazole for 7 days or longer and have been severe enough to require discontinuance of the drug in about 1-2.% of patients. In addition, adverse effects have been reported in 26-31% of women receiving a single dose of fluconazole for the treatment of vulvovaginal candidiasis.

The manufacturer states that adverse effects have been reported more frequently in patients with human immunodeficiency virus (HIV) infections than in patients without HIV infections; however, the proportion of patients requiring discontinuance of the drug because of severe adverse effects is similar in both groups.

Evaluation of some adverse effects and establishment of a causal relationship to fluconazole have been difficult since the drug has been used in many patients with serious underlying diseases, including leukemia, cancer, and acquired immunodeficiency syndrome (AIDS), who were receiving multiple drugs concomitantly. In some cases, the underlying fungal infection being treated (e.g., meningitis) may have caused or contributed to the reported effect (e.g., nervous system effects).

GI Effects

Mild to moderate nausea, vomiting, abdominal pain, and diarrhea have been reported in about 1.5-8.% of patients receiving fluconazole. Only rarely were such adverse GI effects severe enough to require discontinuance of the drug. Flatus, bloating, dry mouth, hiccups, heartburn, and anorexia have been reported rarely. Adverse GI effects have been reported in about 15% of women receiving a single dose of fluconazole for the treatment of vulvovaginal candidiasis; abdominal pain, nausea, diarrhea, dyspepsia, and dysgeusia occurred in about 6, 7, 3, 1, and 1% of such women, respectively.

Dermatologic and Sensitivity Reactions

Rash, including diffuse rash accompanied by eosinophilia, and pruritus have been reported in up to about 5% of patients receiving fluconazole. Exfoliative skin disorders have been reported rarely in patients with serious underlying disease (principally AIDS or malignancy) receiving fluconazole; fatalities have been reported. Stevens-Johnson syndrome, which can be fatal, also has been reported in patients receiving fluconazole. However, a definite causal relationship between exfoliative skin eruptions and the drug has not been established, since most patients were receiving multiple drugs concomitantly with fluconazole. Anaphylaxis has been reported rarely in patients receiving fluconazole. Angioedema and anaphylactic reactions have been reported rarely in women who received a single oral dose of fluconazole for the treatment of vulvovaginal candidiasis.

Hepatic Effects

Serious hepatic reactions (e.g., necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported rarely in patients receiving fluconazole therapy. The manufacturer states that a clear relationship between these hepatic effects and daily dosage, duration of therapy, gender, or age has not been demonstrated. While hepatotoxicity usually has been reversible, fatalities have been reported. Fatalities principally have occurred in patients with serious underlying disease (e.g., AIDS, malignancy) who were receiving fluconazole concomitantly with other drugs; however, at least one fatality involved an immunocompetent geriatric individual with renal impairment who developed fulminant hepatic necrosis within 10 days after fluconazole therapy was initiated.

Mild, transient increases (1.5-3 times the upper limit of normal) in serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, Gamma-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP), and bilirubin have been reported in about 5-7% of patients receiving fluconazole. In most reported cases, concentrations returned to pretreatment levels either during or after fluconazole therapy and were not associated with hepatotoxicity. However, higher increases in serum transaminase concentrations (8 or more times the upper limit of normal), which required discontinuance of the drug, have been reported in about 1% of patients receiving fluconazole. Any patient who develops abnormal liver function test results while receiving fluconazole should be closely monitored for the development of more severe hepatic injury.

Nervous System Effects

Dizziness and headache have been reported in up to about 2% of patients receiving fluconazole. Somnolence, delirium/coma, dysesthesia, psychiatric disturbances, malaise, paresthesia of hands and feet, and fatigue have been reported rarely. Seizures also have been reported and have occurred in at least one AIDS patient immediately following administration of a single 100-mg oral dose of the drug. Adverse nervous system effects have been reported in about 14-20% of women receiving a single dose of fluconazole for the treatment of vulvovaginal candidiasis; headache and dizziness occurred in about 13 and 1% of such women, respectively.

Hematologic Effects

Eosinophilia has been reported in some patients receiving fluconazole. Anemia, leukopenia, neutropenia, and thrombocytopenia also have been reported. In at least one AIDS patient, thrombocytopenia occurred during fluconazole therapy and resolved following discontinuance of the drug. Severe thrombocytopenia that required treatment and necessitated discontinuance of fluconazole therapy also has been reported.

Endocrine Effects

Studies using usual dosages of fluconazole have not shown evidence of adverse effects related to possible inhibition of testosterone or steroid synthesis. In one study in healthy premenopausal women receiving fluconazole, there was no effect on serum estradiol concentrations or on serum cortisol stimulation response. Results of studies in men receiving oral fluconazole dosages of 25-400 mg once daily for up to 30 days indicate that serum testosterone concentrations are unaffected by the drug. The manufacturer states that in healthy adults who receive fluconazole dosages of 200-400 mg once daily for up to 14 days, there are only small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, or ACTH-stimulated cortisol response.

Other Adverse Effects

Fever, edema, pleural effusion, oliguria, hypotension, arthralgia/myalgia, and finger stiffness have been reported rarely in patients receiving fluconazole.

Hypokalemia, which required potassium replacement therapy and/or discontinuance of fluconazole, has occurred occasionally, including in several neutropenic patients with acute myeloid leukemia. Increased serum creatinine and BUN concentrations also have been reported. Mild (1.5-2 times the upper limit of normal) increases in serum concentrations of creatine kinase (CK, creatine phosphokinase, CPK) have been reported in at least one patient with coccidioidal meningitis who received fluconazole concomitantly with intrathecal amphotericin B. Alopecia has been reported in patients receiving fluconazole. In a retrospective study of patients who received fluconazole (100-800 mg daily) for the treatment of systemic fungal infections, alopecia was reported in up to 20% of patients.

Alopecia occurred in both men and women, usually was evident at about 3 months (range: 2 weeks to 7 months) after initiation of fluconazole therapy, and resolved in most patients within about 6 months after discontinuance of the drug or dosage reduction. Alopecia involved varying degrees of loss of scalp hair in all patients, but about 30% of patients also reported substantial loss of facial, axillary, pubic, leg, or chest hair.

Precautions and Contraindications

Although serious adverse hepatic effects have been reported only rarely with fluconazole, the possibility that these effects may occur during fluconazole therapy should be considered.

Fluconazole therapy should be discontinued if signs and symptoms consistent with liver disease develop. If abnormal liver function test results occur during fluconazole therapy, the patient should be monitored for the development of more severe hepatic injury.

Use of fluconazole may result in overgrowth of nonsusceptible strains of Candida other than C. albicans, including C. krusei. Superinfection caused by nonsusceptible strains of Candida has been reported in some patients receiving fluconazole; these patients may require alternative antifungal therapy.

Because potentially fatal exfoliative skin disorders have been reported rarely in patients with a serious underlying disease receiving fluconazole, the possibility that these effects can occur should be considered. Immunocompromised patients (e.g., patients with HIV infections) who develop rash during fluconazole therapy should be monitored closely and the drug discontinued if the lesions progress. Fluconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the respective formulation.

Although information concerning cross-sensitivity between fluconazole and other triazole or imidazole antifungal agents is not available, the manufacturer states that fluconazole should be used with caution in individuals hypersensitive to other azoles.

Pediatric Precautions

The manufacturer states that efficacy of fluconazole in children younger than 6 months has not been established; however, the drug has been used safely and effectively in neonates and children younger than 6 months of age (including neonates as young as 1 day of age).

Adverse effects reported in children receiving fluconazole generally have been similar to those reported in adults. In phase II/III trials in pediatric patients 1 day to 17 years of age who received fluconazole in dosages up to 15 mg/kg daily, adverse effects occurred in 13% and were severe enough to require discontinuance of the drug in 2.3% of patients.

GI effect, including vomiting, abdominal pain, nausea, and diarrhea, occurred in 2-5% of these pediatric patients. Adverse effects reported when oral or IV fluconazole has been used in neonates and infants (3-6 mg/kg daily) have included transient increases in serum transaminase concentrations, vomiting, and eosinophilia; severe thrombophlebitis was reported in at least one neonate.

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when fluconazole was tested with or without metabolic inactivation in 4 strains of Salmonella typhimurium or in the mouse lymphoma L5178Y system. In addition, there was no evidence of chromosomal mutations in vivo on murine bone marrow cells following administration of fluconazole or in vitro on human lymphocytes exposed to fluconazole concentrations of 1 mg/mL.

There was no evidence of carcinogenicity in studies in mice and rats receiving oral fluconazole dosages of 2.5-10 mg/kg daily (approximately 2-7 times the usual human dosage) for 24 months. However, there was an increased incidence of hepatocellular adenomas in male rats receiving an oral fluconazole dosage of 5 or 10 mg/kg daily.

Pregnancy, Fertitlity and Lactation

There are no adequate and controlled studies to date using fluconazole in pregnant women. Fluconazole has been administered during pregnancy.

While results of several studies evaluating pregnancy outcomes did not indicate an increased risk for congenital malformations in infants born to women who received fluconazole during pregnancy, data from these studies indicate that there has been at least one case each of congenital dislocation of the hip, lacrimal stenosis, partial syndactyly, ventricular septum deficiency, polydactyly or syndactyly, heart defect, or spina bifida in infants born to women who received the drug during pregnancy. In addition, there have been at least 3 reports of congenital abnormalities (craniofacial, skeletal, cardiac) in infants born to women who received fluconazole (400-800 mg daily) for the treatment of coccidioidomycosis during the first trimester.

The manufacturer states that the relationship between fluconazole and these effects is unclear.

Fluconazole should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. In several reproduction studies in pregnant rabbits receiving oral fluconazole dosages of 5, 10, 20, 25, or 75 mg/kg once daily during organogenesis, maternal weight gain was impaired at all dosage levels and abortions occurred with the 75-mg/kg dosage (approximately 20-60 times the usual human dosage); no adverse fetal effects were detected. In studies in pregnant rats receiving oral fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at dosages of 25 mg/kg once daily.

Although there were no fetal effects in rats receiving 5- or 10-mg/kg oral dosages once daily, increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification occurred in those receiving oral dosages of 25 mg/kg or greater once daily.

When oral fluconazole dosages of 80 mg/kg once daily (approximately 20-60 times the usual human dosage) to 320 mg/kg once daily were used in these rats, there was an increase in embryolethality and fetal abnormalities (i.e., wavy ribs, cleft palate, abnormal craniofacial ossification). These adverse effects in rats may be attributed to a species-specific effect of fluconazole on estrogen synthesis since lowered estrogen is known to cause effects on pregnancy, organogenesis, and parturition.

There is no evidence to date that estrogen concentrations are decreased in women receiving fluconazole. Reproduction studies in male and female rats receiving fluconazole in an oral dosage of 5, 10, or 20 mg/kg once daily or an IV dosage of 5, 25, or 75 mg/kg once daily did not reveal evidence of impaired fertility; however, onset of parturition was delayed slightly with the 20-mg/kg oral dosage. In one study in rats receiving an IV fluconazole dosage of 5, 20, or 40 mg/kg once daily, dystocia and prolongation of parturition occurred in a few dams with the 20-mg/kg (approximately 5-15 times the usual human dosage) and 40-mg/kg dosages but not with the 5-mg/kg dosage.

Disturbances in parturition in rats were reflected by a slight increase in the number of stillborn pups and a decrease in neonatal survival; these effects presumably are related to a species-specific estrogen-lowering effect caused by high doses of fluconazole.

Fluconazole is distributed into human milk at concentrations similar to those achieved in plasma. Administration of a single 150-mg oral dose to several nursing women resulted in peak plasma fluconazole concentrations of 2.61 mcg/mL (range: 1.57-3.65 mcg/mL). Therefore, the manufacturer states that fluconazole should not be used in nursing women.

Fluconazole: Side Effects

Fluconazole is an antifungal triazole that was derived from the older imidazoles. It has a lower molecular weight and is soluble in water. It can be administered orally and parenterally.

Pharmacokinetics

After oral administration, its systemic availability is about 90%; maximum plasma concentrations are seen in 1-2 hours, its half-life is about 30 hours and steady state is reached within 5-7 days.

Fluconazole has low protein binding (about 12%), is hardly metabolized, and about 80% of it is excreted in the urine. Hemodialysis reduces plasma concentrations by about half in 3 hours. Tissue and body fluid penetration is good. The CSF concentration ratio is 0.5-0.9, the resultant concentrations being adequate for the treatment of cryptococcal meningitis.

Penetration into the eye is good, and fluconazole has been used successfully in fungal endophthalmitis. In a patient in whom the concentrations of fluconazole in bile were studied, the concentrations after the first dose were about the same as in serum, but 10-12 hours after the dose, bile concentrations were higher than serum concentrations. Sputum concentrations are similar to plasma concentrations. Concentrations in vaginal secretions are slightly lower than in plasma, but persist for longer.

Like ketoconazole, fluconazole is a potent inhibitor of cytochrome P450, but with much higher specificity for fungal enzymes compared with human enzymes. Clinical interaction studies and some in vitro studies have suggested that azole antifungal drugs inhibit P glycoprotein. In a cell line in which human P glycopro-tein was overexpressed, itraconazole and ketoconazole inhibited P glycoprotein function, with 50% inhibitory concentrations of about 2 and 6 µmol/l respectively; however, fluconazole had no effect.

Observational studies

The prophylactic use of oral fluconazole to prevent invasive Candida infections in 260 critically ill surgical patients has been investigated in a prospective, randomized, placebo-controlled trial in a single-center, tertiary-care surgical intensive care unit. The patients were randomly assigned to receive either oral fluconazole 400 mg/day or placebo. The risk of presumed and proven Candida infections in the patients who received fluconazole was significantly less than the risk in those who received placebo. After adjusting for several potentially confounding effects, fluconazole reduced the risk of presumed and proven fungal infection by 55%. There was no difference in death rate between fluconazole and placebo. The authors concluded that enteral fluconazole safely reduced the incidence of fungal infections in this high-risk population.

Comparative studies

Amphotericin

Fluconazole and amphotericin as empirical antifungal drugs in febrile neutropenic patients have been investigated in a prospective, randomized, multicenter study in 317 patients randomized to either fluconazole (400 mg qds) or amphotericin deoxycholate (0.5 mg/kg qds). Adverse events (fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred significantly more often in patients who were given amphotericin (128/151 patients, 81%) than in those given fluconazole (20/158 patients, 13%). Eleven patients treated with amphotericin, but only one treated with fluconazole, were withdrawn because of an adverse event. Overall mortality and mortality from fungal infections were similar in both groups. There was a satisfactory response in 68 % of the patients treated with fluconazole and 67% of those treated with amphotericin. Thus, fluconazole may be a safe and effective alternative to amphotericin for empirical therapy of febrile neutropenic patients; however, since fluconazole is ineffective against opportunistic molds, the possibility of an invasive infection by a filamentous fungus should be excluded before starting empirical therapy. Similarly, patients who take azoles for prophylaxis are not candidates for empirical therapy with fluconazole.

Conventional amphotericin deoxycholate (0.2 mg/kg qds) and fluconazole (400 mg qds) have been compared in a prospective, randomized study in 355 patients with allo-geneic and autologous bone marrow transplantation. The drugs were given prophylactically from day -1 until engraftment. There was no difference in the occurrence of invasive fungal infections, but amphotericin was significantly more toxic than fluconazole, especially in related allogeneic transplantation, after which 19% of patients developed toxi-city compared with none of those who received fluconazole.

Echinocandins

Caspofungin and fluconazole have been compared in adults with Candida esophagitis in a double-blind, randomized trial. Eligible patients had symptoms compatible with esophagitis, endoscopic mucosal plaques, and microscopic Candida. They were randomized to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once a day for 7-21 days. Most of them (154/1) had HIV infection, with a median CD4 count of 30 x 106/ 1. Favorable response rates were achieved in 66 of the 81 patients in the caspofungin arm and in 80 of the 94 patients in the fluconazole arm; symptoms had resolved in over 50% of the patients in both groups by the fifth day of treatment.

Drug-related adverse effects were reported in 41% of patients given caspofungin and 32% of those given fluconazole; the most common events in both groups were phlebitis, headache, fever, nausea, diarrhea, abdominal pain, and rashes. Drug-related laboratory abnormalities developed in 29% of patients given caspofungin and in 34% of those given fluconazole. The most frequent laboratory abnormalities included reduced white blood cell count, hemoglobin concentration, and serum albumin concentration, and increased alkaline phospha-tase and transaminases. No patient given caspofungin developed a serious drug-related adverse effect; therapy was withdrawn in only one patient (who was receiving fluconazole), because of an unspecified adverse effect.

Placebo-controlled studies

In a randomized, double-blind, placebo-controlled study in Saudi Arabia of oral fluconazole (200 mg/day for 6 weeks) in the treatment of cutaneous leishmaniasis, 106 patients were assigned to fluconazole and 103 to placebo. Follow-up data were available for 80 and 65 patients respectively. At the 3-month follow-up, healing of lesions was complete in 63 of the 80 patients who took fluconazole and 22 of the 65 patients who took placebo (relative risk of complete healing, 2.33; 95% CI = 1.63). Adverse effects were mild and similar in the two groups.

General adverse effects

Fluconazole is generally well tolerated. The most common adverse effects are nausea and vomiting. Abnormal liver function tests and slight increases in hepatic enzymes have been reported, and there have been anecdotal reports of hepatitis and hepatic failure. Early studies have shown no changes in testosterone concentrations or in the adrenal response to ACTH. Rashes and a few cases of exfoliative skin disorder have been reported and have been seen more frequently in patients with AIDS. Alopecia has been reported in a few cases with the use of high doses for prolonged periods of time. Rare instances of anaphylactoid reactions have been reported. Rare instances of hypersen-sitivity reactions have occurred in other individuals. Tumor-inducing effects have not been reported.

In a study using the UK General Practice Research Database to determine rates of drug-induced, rare, serious adverse effects on the liver, kidneys, skin, or blood, occurring within 45 days of completing a prescription or refill in 54 803 users of either fluconazole or itraconazole, three had illnesses for which a fluconazole-induced cause could not be ruled out; one with thrombocytopenia, one with neutropenia, and one with an abnormal liver function test just after receiving fluconazole. The rates were 2.8/100 000 prescriptions (95% for serious, adverse blood events and 1.4/100 000 prescriptions (95% CI = 0.25) for serious, adverse liver events. These results suggest that fluconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood.

Fluconazole: Organs and Systems

Second-Generation Effects Teratogenicity

The teratogenic activity of triazole and two triazole derivatives, flusilazole (an agricultural triazole monoderivative fungicide) and fluconazole, has been studied in vitro. Rat embryos 9.5 days old (1-3 somites) were exposed in vitro to triazole 500-5000 nmol/1, flusilazole 3.125-250 nmol/1, or fluconazole 62.5-500 µmol/l and examined after 48 hours in culture. There were similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at 6.25 µmol/l and higher for flusilazole and 125 µmol/l and higher for fluconazole. In contrast, there was little effect at the highest concentrations of triazole, suggesting no teratogenic activity. These investigations have confirmed the embryotoxic potential of antifungal triazole derivatives, specifically on the branchial apparatus.

However, teratogenic effects have not been found in humans. The risk of malformations and other outcomes in children exposed to fluconazole in utero has been examined in 165 women who had taken fluconazole just before or during pregnancy, mostly in the form of a single dose of 150 mg to treat vaginal candidiasis.

Birth outcomes (malformations, low birth weight, and preterm delivery) were compared with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies. The prevalence of malformation was 3.3% (four cases) among the 121 women who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (OR = 0.65; CI = 0.24). The risks of preterm delivery (OR = 1.17; CI = 0.63) and low birth weight (OR = 1.19; CI = 0.37) were not significantly increased in association with fluconazole. Thus, the study showed no increased risk of congenital malformations, low birth weight, or preterm birth in offspring to women who had used single doses of fluconazole before conception or during pregnancy.

The potential ability of fluconazole to modulate phenytoin teratogenesis has been studied in Swiss mice. Pretreatment with a non-embryotoxic dosage of fluconazole (10 mg) potentiated phenytoin teratogenesis; combined treatment of fluconazole 50 mg with phenytoin resulted in a significant increase in embryo deaths. The mechanism of this teratological interaction remains to be established.

Lactation

Fluconazole is found in breast milk at concentrations comparable with those found in the blood after single or multiple doses; this may be of clinical relevance.

Fluconazole: Susceptibility Factors

Age

In a group of children with fever, neutropenia, and neoplastic disease, there was an increase in renal fluconazole clearance. In infants and children, the volume of distribution of fluconazole is significantly higher and falls with age. With the exception of infants, who have a slower clearance rate, children clear the compound more rapidly. However, a second larger study reported slower elimination in children under 1 year of age, requiring dosage adjustments. Low birth-weight neonates have a particularly low clearance rate, which increases within weeks.

The use of fluconazole in 726 children under 1 year of age, reported in 78 publications, has been reviewed. They received a wide range of dosages for up to 162 days. Fluconazole was well tolerated and efficacious in the therapy of systemic candidiasis and candidemia in children under 1 year of age, including neonates and very low birth-weight infants. The daily dosage recommended by the manufacturers is 6 mg/kg, to be reduced in patients with impaired renal function in accordance with the guidelines given for adults.

The efficacy and safety of fluconazole in neonates with Candida fungemia has been evaluated in a multicenter prospective study. Fluconazole was safe and effective even in complicated cases, including infants of very low birth weights. Two of 50 neonates developed raised liver enzymes during fluconazole therapy and two others had raised serum creatinine concentrations. In none of them did these abnormalities necessitate discontinuation of antifungal therapy.

The safety profile of fluconazole has been assessed in 562 children (aged 0-17 years; 323 boys and 239 girls), enrolled into 12 clinical studies of prophylactic or therapeutic fluconazole in predominantly immunocompro-mised patients. Most of the children received multiple doses of fluconazole 1-12 mg/kg, given as oral suspension or intravenously. Overall, 58 children reported 80 treatment-related adverse effects. The most common adverse effects were associated with the gastrointestinal tract (7.7%), the skin (1.2%), or the liver and biliary system (0.5% or three patients).

Overall, 18 patients discontinued treatment owing to adverse effects, mainly gastrointestinal. Dosage and age did not affect the incidence and pattern of adverse effects. Treatment-related laboratory abnormalities included transiently raised alanine transaminase (4.9%), aspartate transaminase (2.7%), and alkaline phosphatase (2.3%). Although 99% of patients were taking concomitant drugs, there were no clinical or laboratory interactions. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies.

Adverse effects were reported by more patients treated with fluconazole (45 of 382; 12%) than by patients treated with comparator agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar in the two groups. Fluconazole was well tolerated, mirroring the favorable safety profile seen in adults.

In 34 otherwise healthy infants with oral candidiasis randomized to either nystatin oral suspension qds for 10 days or fluconazole suspension 3 mg/kg in a single daily dose for 7 days, 6 of 19 were cured by nystatin and all of 15 by fluconazole. Fluconazole was tolerated without apparent adverse events.

Renal disease

If the creatinine clearance is below 40 ml/minute fluconazole doses should be adjusted.

Fluconazole: Organs and Systems

Cardiovascular

Prolongation of the QT interval is a class effect of the antifungal azoles and has occasionally been reported with fluconazole, with a risk of torsade de pointes.

• A 68-year-old woman with Candida glabrata isolated from a presacral abscess developed torsade de pointes after 8 days treatment with oral fluconazole 150 mg/day. She had no other risk factors for torsade de pointes, including coronary artery disease, cardiomyopathy, congestive heart failure, or electrolyte abnormalities. The dysrhythmia resolved when fluconazole was withdrawn, but she continued to have ventricular extra beats and non-sustained ventricular tachycardia for 6 days.
• A 59-year-old woman with liver cirrhosis and Candida peritonitis developed long QT syndrome and torsade de pointes after intravenous therapy with 400-800 mg/day of fluconazole for 65 weeks, followed by intraperitoneal administration (150 mg/day). One day after the second intraperitoneal administration, she developed palpitation, multifocal ventricular extra beats, and syncope. In contrast to a normal electrocardiogram on admission, electrocardiography showed polymorphic ventricular extra beats, T wave inversion, alternating T wave amplitude, and a prolonged QTC interval of 606 ms. Torsade de pointes required cardiopulmonary resuscitation. The fluconazole plasma concentration was 216 µg/ml (usual target range at 400-800 mg/day: 18-28 µg/ml). Fluconazole was withdrawn and all conduction abnormalities reversed fully within 3 weeks.

These patients were not taking any concomitant drugs that prolong the QT interval, suggesting that fluconazole was to blame.

• A 25-year-old woman with worsening endocarditis had a prolonged QT interval at baseline and developed mono-morphic ventricular dysrhythmias, which were managed successfully with pacing and antidysrhythmic therapy, including amiodarone. Several days later, she was given high-dose fluconazole (800 mg/day) for fungemia and after 3 days had episodes of torsade de pointes.

In this case torsade de pointes developed in the presence of known risk factors — hypokalemia, hypomagnesemia, female sex, baseline QT interval prolongation, and ventricular dysrhythmias.

Nervous system

Central nervous system abnormalities constitute the major dose-limiting adverse effects of fluconazole and are observed at dosages over 1200 mg/day.

Dizziness, headache, and seizures were seen in 2-5% of 232 patients with severe systemic fungal infections taking fluconazole. In the same group there were three cases each of delirium and dysesthesia (1.3%). A possible effect of the underlying illness has to be considered. In 14 patients treated with fluconazole for cryptococcal meningitis, dizziness was reported in 14%.

Two Japanese patients developed clonic convulsions while taking fluconazole 800 mg/day.

• A 66-year-old woman with complicated invasive Candida tropicalis infection but no renal impairment took fluconazole 800 mg/day. On the 21st day she developed clonic convulsions. The fluconazole trough concentration at the time of the event was 82 µg/ml.
• A 62-year-old man with deteriorating renal and hepatic function after coronary artery bypass surgery was given fluconazole 400 mg bd for a fungal sternal wound infection. On the 15th day he developed seizures. His trough plasma fluconazole concentration was 88 µg/ml. Nineteen days after dosage adjustment to 400 mg qds, he had another seizure. The trough fluconazole concentration was 103 µg/ml, probably because of deteriorating renal function.

In both cases, the seizures abated after dosage reduction. These case reports suggest an association between trough plasma fluconazole concentrations of 80 µg/ml and central nervous system toxicity; they re-emphasize the need for careful monitoring and dosage adjustment of fluconazole in patients with reduced renal function.

Endocrine

Preliminary studies concerning a possible effect on testosterone concentrations and the adrenal response to adrenocorticotropic hormone did not show any changes. However, determinations were performed after only 14 days of fluconazole administration.

• Two critically ill patients, a 77-year-old man with esophageal cancer and a 66-year-old woman with multiple organ failure, developed reversible adrenal insufficiency temporally related to the use of high-dose fluconazole (800 mg loading dose followed by 400 mg/day), as assessed by short stimulation tests with cosyntropin (ACTH). Although anecdotal, these data suggest that the possibility that high-dose fluconazole can cause adrenal insufficiency in already compromised critically ill patients needs to be investigated further.
• A 63-year-old man received high-dose cyclophosphamide for peripheral blood stem-cell harvesting, having been taking fluconazole 200 mg/day. On day 3 he developed atrial fibrillation and his blood pressure fell to 78 mmHg. A rapid ACTH stimulation test showed a blunted adrenal response. He was suspected of having adrenal failure, and fluconazole was withdrawn. A rapid ACTH test was normal on day 14. To clarify the association between adrenal failure and fluconazole, he was rechallenged with fluconazole 400 mg/day from day 16 and a rapid ACTH test was performed on day 21; it showed a blunted adrenal response.

Mineral balance

Hypokalemia was observed in only a few patients taking fluconazole, which contrasts with experience with itraconazole. However, hyperkalemia was reported in one paper.

Hematologic

Cytopenias occur but seem to be mild. Occasionally, more marked changes have been described, but these could have been connected with the underlying disease. In a single placebo-controlled study of fluconazole prophylaxis using a relatively high dose of 400 mg/day, a posthoc analysis suggested prolongation of granulocytopenia after intensive chemotherapy for hematological neoplasms in the fluconazole group. This may have been due to an interaction with the antineoplastic drug.

Leukopenia with eosinophilia has been attributed to fluconazole.

• A 75-year-old man with non-Hodgkin’s lymphoma and cryptococcal meningoencephalitis developed neutropenia with eosinophilia associated with fluconazole. After 1 week of fluconazole 400 mg/day his total leukocyte count began to fall and his eosinophil count increased. Concurrent medications included levothyr-oxine, famotidine, and co-trimoxazole. The last two drugs were withdrawn and he was given G-CSF.

However, his leukocyte count continued to fall and 4 days later reached a nadir of 700 x 106/1; the platelet count remained normal. The leukopenia and eosinophi-lia resolved promptly after withdrawal of fluconazole.

Since the leukopenia and eosinophilia did not resolve until fluconazole was withdrawn, an effect of the compound was plausible. This case and two other reported cases emphasize the importance of recognizing fluconazole as a rare but potential cause of bone marrow suppression in patients in whom drug-induced agranulocytosis is suspected. In one study in patients with AIDS taking prophylactic maintenance fluconazole for cryptococcal meningitis, there was a higher rate of hematological toxicity with fluconazole than with placebo, but this probably reflected the greater proportional and absolute amounts of zidovudine used in the fluconazole group; there was no serious hematotoxicity.

Gastrointestinal

Nausea and vomiting are mentioned in most reports of patients taking fluconazole, with an incidence of 10-15%. Anorexia, mild abdominal pain, and diarrhea have been reported, but none was severe.

Liver

Raised liver enzyme activities have been reported in most studies. In some articles this effect was described as transient, in others as disappearing after withdrawal. The incidence varies from a few percent of cases to 35^-5%, but occasionally the effect has been recorded in all cases treated. A temporal relation between these liver function changes and fluconazole treatment has been shown in many cases. Severe liver toxicity has not been reported. While asymptomatic rises in transaminases were noted in some children with neoplastic disease who were treated concomitantly with fluconazole in a small study, there were no significant changes in a larger study in cancer patients treated with placebo or fluconazole 400 mg.

• A 45-year-old woman with protracted cryptococcal meningoencephalitis developed fulminant hepatic failure secondary to high fluconazole serum concentrations, possibly precipitated by renal dysfunction induced by concomitant amphotericin therapy or concomitant therapy with lisinopril, atenolol, or amlodipine. Four days after the withdrawal of fluconazole 400 mg/day the serum concentration of fluconazole was 40 µg/ml.

This case points to the potential risks of fluconazole therapy in the setting of renal insufficiency, in particular with higher dosages (400 mg/day and more).

Skin

Rashes of several types occur with fluconazole and are more frequent in immunocompromised patients.

The risk of serious skin disorders has been estimated in 61 858 users of oral antifungal drugs, aged 20-79 years, identified in the UK General Practice Research Database. They had received at least one prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral antifungal drugs) was 3.9 per 10 000 person-years (95% CI = 2.9). Incidence rates for current use were 15 per 10 000 person-years (1 for itraconazole, 11.1 (3 for terbinafine, 10 (1 for fluconazole, and 4.6. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

Pruritus has also been reported. A few cases of Stevens-Johnson disease have been reported worldwide, as well as a few instances of fixed-drug eruption. In cases of hypersensitivity, desensitization has reportedly been used with success.

Fixed drug eruption caused by systemic fluconazole has been reported.

• A 36-year-old woman with a history of atopy and recurrent Candida vaginitis developed a fixed drug eruption while taking fluconazole 150 mg/day. Local provocation with 10% fluconazole in petrolatum applied at the site of a previous site of fixed drug eruption reproduced the eruption clinically and histopathologically.

Nails

A patient developed a longitudinal band of pigmentation in the diseased nail after fluconazole therapy for onychomycosis at a dosage of 150 mg once a week for 4 weeks.