Diflucan

[Posted 04/26/2016]

AUDIENCE: Internal Medicine, Family Practice, OB/GYN

ISSUE: FDA is evaluating the results of a Danish study that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole (Diflucan) for yeast infections. FDA is also reviewing additional data and will communicate final conclusions and recommendations when the review is complete.

The current FDA drug label states that data available from studies in people do not suggest an increased risk of problems during pregnancy or abnormalities in developing babies when women are exposed to a single 150 mg dose of oral fluconazole to treat vaginal yeast infections. However, high doses of oral fluconazole (400-800 mg/day) taken by pregnant women for much longer than a single dose have resulted in reports of abnormalities at birth. In the Danish study, most of the oral fluconazole use appeared to be one or two doses of 150 mg.

BACKGROUND: Oral fluconazole is used to treat yeast infections of the vaginal area, mouth, and esophagus. It is also used to treat a fungal infection of the brain and spinal cord called cryptococcal meningitis that most often affects people with weakened immune systems, and used to prevent yeast infections that can spread to the rest of the body in cancer patients who have a weakened immune system. It is available under the brand name Diflucan and also as generics.

RECOMMENDATION: Until FDA's review is complete and more is understood about this study and other available data, FDA advises cautious prescribing of oral fluconazole in pregnancy.

Health care professionals should be aware that the Centers for Disease Control and Prevention guidelines recommend only using topical antifungal products to treat pregnant women with vulvovaginal yeast infections, including for longer periods than usual if these infections persist or recur.

Patients who are pregnant or actively trying to get pregnant should talk to their health care professionals about alternative treatment options for yeast infections.

For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.

• Diflucan^®

DIFLUCAN is generally well tolerated.

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 have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

In Patients Receiving A Single Dose For Vaginal Candidiasis

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

In Patients Receiving Multiple Doses For Other Infections

Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.

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

The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.

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

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

Post-Marketing Experience

In addition, the following adverse events have occurred during post-marketing experience.

Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported.

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

Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)

Central Nervous System: Seizures, dizziness.

Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.

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

Other Senses: Taste perversion.

Musculoskeletal System: myalgia.

Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.

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

Adverse Reactions In Children

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

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

Percentage of Patients With Treatment-Related Side Effects

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

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

Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.

DIFLUCAN®
(fluconazole) Tablets

This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN.

What Is DIFLUCAN?

DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away.

DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections.

What Is a Vaginal Yeast Infection?

It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life.

Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections.

If you get a vaginal yeast infection, you may have any of the following symptoms:

• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese

What To Tell Your Doctor Before You Start DIFLUCAN?

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

• diabetes medicines such as glyburide, tolbutamide, glipizide
• blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine
• blood thinners such as warfarin
• cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
• rifampin or rifabutin for tuberculosis
• astemizole for allergies
• phenytoin or carbamazepine to control seizures
• theophylline to control asthma
• cisapride for heartburn
• quinidine (used to correct disturbances in heart rhythm)
• amitriptyline or nortriptyline for depression
• pimozide for psychiatric illness
• amphotericin B or voriconazole for fungal infections
• erythromycin for bacterial infections
• cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer
• fentanyl, afentanil or methadone for chronic pain
• halofantrine for malaria
• lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
• non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
• prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders
• antiviral medications used to treat HIV like saquinavir or zidovudine
• tofacitinib for rheumatoid arthritis
• vitamin A nutritional supplement

Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions.

• are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other fungal infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist.

Who Should Not Take DIFLUCAN?

To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN.

How Should I Take DIFLUCAN

Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day.

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

Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.

What Should I Avoid while Taking DIFLUCAN?

Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN.

What Are the Possible Side Effects of DIFLUCAN?

Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate.

The most common side effects of DIFLUCAN are:

• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes

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

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

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

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

What to Do For an Overdose

In case of an accidental overdose, call your doctor right away or go to the nearest emergency room.

How to Store DIFLUCAN

Keep DIFLUCAN and all medicines out of the reach of children.

General Advice about Pres cription Medicines

Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals.

You can also visit the DIFLUCAN Internet site atwww.diflucan.com.

Like all medicines, Diflucan may cause some side effects that are usually mild to moderate.

The most common side effects of Diflucan are:

• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes

Allergic reactions to Diflucan are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include:

• shortness of breath
• coughing
• wheezing
• fever
• chills
• throbbing of the heart or ears
• swelling of the eyelids, face, mouth, neck, or any other part of the body
• skin rash, hives, blisters or skin peeling

Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if:

• your skin or eyes become yellow
• your urine turns a darker color
• your stools (bowel movements) are light-colored
• you vomit or feel like vomiting
• you have severe skin itching

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

Before receiving this medication, tell your doctor if you:

• are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies
• have any liver problems
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether Diflucan is right for you.
• are breastfeeding. Diflucan can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other fungal infections.
• are allergic to any of the ingredients in this medication 

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

• Take Diflucan by mouth with or without food. You can take Diflucan at any time of the day.
• Diflucan keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor.
• Just swallow 1 Diflucan tablet to treat your vaginal yeast infection.
• Diflucan is also available as an injectable to be injected into the vein (IV) by a healtchare professional. 
• Some medicines can affect how well Diflucan works. Check with your doctor before starting any new medicines within seven days of taking Diflucan.

Take Diflucan exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The Diflucan dose your doctor recommends will be based on the following the condition being treated

• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your age

The recommended dose of Diflucan for the treatment of vaginal candidiasis in adults is 150 mg as a one-time dose.

The recommended dose of Diflucan for the treatment of oropharyngeal candidiasis in adults is 200 mg on the first day, followed by 100 mg once daily.

The recommended dose of Diflucan for the treatment of esophageal candidiasis in adults is 200 mg on the first day, followed by 100 mg to 400 mg once daily.

The recommended dose of Diflucan for the treatment of systemic candida infections in adults is up to 400 mg once daily.

The recommended dose of Diflucan for the treatment of UTIs and peritonitis in adults is 50 mg to 200 mg once daily.

The recommended dose of Diflucan for the treatment of cryptococcal meningitis in adults is 400 mg on the first day, followed by 200 mg to 400 mg once daily.

The recommended dose of Diflucan to prevent infection in adults undergoing bone marrow transplant is 400 mg once daily.

The recommended dose of Diflucan for the treatment of oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily.

The recommended dose of Diflucan for the treatment of esophageal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg to 12 mg/kg once daily.

The recommended dose of Diflucan for the treatment of systemic candida infections in children is 6-12 mg/kg once daily.

The recommended dose of Diflucan for the treatment of cryptococcal meningitis in children is 12 mg/kg on the first day, followed by 6 mg/kg to 12 mg/kg once daily.

Do not use this medication if you are allergic to fluconazole, or similar drugs such as clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Nizoral), miconazole (Monistat, Oravig), sertaconazole (Ertaczo), sulconazole (Exelderm), terconazole (Terazol), tioconazole (Vagistat-1), or voriconazole (Vfend).

You should not use fluconazole if you are also taking cisapride (Propulsid).

Before taking fluconazole, tell your doctor if you have liver disease, kidney disease, a heart rhythm disorder, or a history of Long QT syndrome.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medication. Fluconazole will not treat a viral infection such as the common cold or flu.

Do not use this medication if you are allergic to fluconazole, or similar drugs such as clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Nizoral), miconazole (Monistat, Oravig), sertaconazole (Ertaczo), sulconazole (Exelderm), terconazole (Terazol), tioconazole (Vagistat-1), or voriconazole (Vfend).

You should not use fluconazole if you are also taking cisapride (Propulsid).

To make sure you can safely take fluconazole, tell your doctor if you have any of these other conditions:

• liver disease;
• kidney disease;
• a heart rhythm disorder; or
• a personal or family history of Long QT syndrome.

FDA pregnancy category D. Do not take more than 1 dose of fluconazole if you are pregnant. Long-term use of fluconazole can harm an unborn baby or cause birth defects. Use effective birth control, and tell your doctor if you become pregnant during treatment.

A single dose of fluconazole taken to treat a vaginal yeast infection is not expected to harm an unborn baby.

Fluconazole can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Antifungal; azole (triazole derivative).1 5 51 68 84 124

Absorption

Bioavailability

Pharmacokinetics are similar following IV or oral administration.1 61 105

Rapidly and almost completely absorbed from GI tract;1 2 51 61 67 68 peak plasma concentrations attained within 1–2 hours.1 68 99 105

Oral bioavailability ≥90% in healthy, fasting adults.1 61 68 105 124 131

Oral bioavailability in HIV-infected adults appears to be similar to that reported for healthy adults.219 223

Unlike some imidazoles (e.g., ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH.1 16 61 68 91 124 249 250

Oral suspensions are bioequivalent to tablets.1

Food

Administration with a high-fat meal does not affect fluconazole peak plasma concentrations or AUC compared with administration in the fasting state.1

Distribution

Extent

Widely distributed into body tissues and fluids following oral or IV administration.1 61 62 64 76 102 103 105

Concentrations attained in urine and skin may be 10 times higher than concurrent plasma concentrations.1 105

Concentrations attained in saliva,1 61 105 sputum,1 13 61 105 nails,1 blister fluid,1 105 blister skin,1 105 and vaginal tissue1 are approximately equal to concurrent plasma concentrations.1 13 61 99 105

Unlike some azoles (e.g., itraconazole, ketoconazole), fluconazole readily distributes into CSF following oral or IV administration;1 2 3 14 15 29 30 36 54 61 62 102 105 CSF concentrations may be 50–94% of concurrent plasma concentrations, regardless of the degree of meningeal inflammation.1 2 3 14 15 29 30 54 61 62 67 102 105

Crosses the placenta in rats; not known whether crosses the placenta in humans.117

Distributed into human milk in concentrations similar to those attained in plasma.1 261

Plasma Protein Binding

Unlike some azoles (e.g., itraconazole, ketoconazole, miconazole), which are highly protein bound, fluconazole is only 11–12% bound to plasma proteins.1 2 3 12 51 62 67 78 84 105 124

Elimination

Elimination Route

Eliminated principally by renal excretion.1 2

Approximately 60–80% of a single oral or IV dose excreted in urine unchanged;1 2 3 12 51 61 68 105 117 about 11% is excreted in urine as metabolites.1 51 61 105

Small amounts excreted in feces.68

Removed by hemodialysis.1 37

Removed by peritoneal dialysis.47

Half-life

Adults with normal renal function: Approximately 30 hours (range: 20–50 hours).1 2 3 12 13 14 61 62 67 68 78 105

Children: 19.5–25 hours following a single oral dose in those 9 months to 13 years of age and 15.2–17.6 hours following multiple IV doses in those 5–15 years of age.1

Neonates: Decreases over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13).259

Special Populations

Elimination half-life not affected by impaired hepatic function.117

In impaired renal function, plasma concentrations are higher and half-life prolonged;1 37 57 67 105 elimination half-life is inversely proportional to Clcr.1

Renal clearance may be lower in geriatric patients than in younger adults,1 124 apparently because of decreased kidney function in this age group.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

In the U.S.

• Diflucan

In Canada

• CanesOral

Available Dosage Forms:

• Powder for Suspension
• Tablet
• Capsule

Therapeutic Class: Antifungal

Chemical Class: Triazole

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• chills
• clay-colored stools
• cough
• dark urine
• diarrhea
• difficulty with swallowing
• dizziness
• fast heartbeat
• fever
• general feeling of tiredness or weakness
• headache
• hives, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• nausea and vomiting
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• stomach pain, continuing
• tightness in the chest
• unpleasant breath odor
• unusual tiredness or weakness
• upper right abdominal or stomach pain
• vomiting of blood
• yellow eyes and skin

• Black, tarry stools
• blistering, peeling, or loosening of the skin
• chest pain or discomfort
• convulsions
• decreased urine
• dry mouth
• fainting
• hoarseness
• increased thirst
• irregular or slow heart rate
• joint or muscle pain
• loss of bladder control
• lower back or side pain
• mood changes
• muscle pain or cramps
• muscle spasm or jerking of all extremities
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pale skin
• red skin lesions, often with a purple center
• red, irritated eyes
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• sudden loss of consciousness
• swollen glands
• unusual bleeding or bruising

Get emergency help immediately if any of the following symptoms of overdose occur:

• Fearfulness, suspiciousness, or other mental changes
• seeing, hearing, or feeling things that are not there

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• change in taste or bad, unusual, or unpleasant (after) taste
• heartburn
• indigestion
• stomach discomfort or upset

• Hair loss or thinning of the hair

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Cryptococcal meningitis

In a multicenter study comparing Diflucan (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and Diflucan patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83–9.)

Vaginal candidiasis

Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation.

The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group.

Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg Diflucan tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (≥4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis.

Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred.

Pediatric Studies

An open-label, comparative study of the efficacy and safety of Diflucan (2–3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole.

Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients.

The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving Diflucan and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for Diflucan and 23% for nystatin.

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved 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.

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.

Fluconazole should be administered with caution to patients with renal dysfunction.

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored.

Diflucan Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.

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

Single Dose

The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with Diflucan (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.)

Drug Interactions

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) Diflucan 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 below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered 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. Clinically or potentially significant drug interactions between Diflucan and the following agents/classes have been observed. These are described in greater detail below:

Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Tofacitinib
Triazolam
Oral Contraceptives
Pimozide
Quinidine
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
Vitamin A
Zidovudine

Clinically significant hypoglycemia may be precipitated by the use of Diflucan with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined Diflucan and glyburide use. Diflucan reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When Diflucan is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Prothrombin time may be increased in patients receiving concomitant Diflucan and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving Diflucan and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Diflucan increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving Diflucan and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Diflucan significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving Diflucan and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies). This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Rifampin enhances the metabolism of concurrently administered Diflucan. Depending on clinical circumstances, consideration should be given to increasing the dose of Diflucan when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Diflucan increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving Diflucan and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that Diflucan taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.

There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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

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 short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20–32%, and increases t½ by 25–50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

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

Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS.)

In a pharmacokinetic interaction study, coadministration 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.

A study observed a reduction in clearance and distribution volume as well as prolongation of T½ 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.

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

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

An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

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

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

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

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.

One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

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

Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are 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.

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

Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

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

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.

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

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

Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 µg/mL) showed no evidence of chromosomal mutations.

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5–15× the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.)

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.

Pregnancy Category D

A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400–800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.)

Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400–800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies.

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

In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no 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 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in 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 a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition

Nursing Mothers

Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when Diflucan is administered to a nursing woman.

Pediatric Use

An open-label, randomized, controlled trial has shown Diflucan to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.)

The use of Diflucan in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)

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

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

The safety profile of Diflucan in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.)

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

Geriatric Use

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

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

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

Diflucan Tablets

Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister.

Diflucan Tablets are supplied as follows:

Diflucan 50 mg Tablets: Engraved with "Diflucan" and "50" on the front and "ROERIG" on the back.

  NDC 0049-3410-30        Bottles of 30

Diflucan 100 mg Tablets: Engraved with "Diflucan" and "100" on the front and "ROERIG" on the back.

  NDC 0049-3420-30        Bottles of 30
  NDC 0049-3420-41        Unit dose package of 100

Diflucan 150 mg Tablets: Engraved with "Diflucan" and "150" on the front and "ROERIG" on the back.

  NDC 0049-3500-79        Unit dose package of 1

Diflucan 200 mg Tablets: Engraved with "Diflucan" and "200" on the front and "ROERIG" on the back.

  NDC 0049-3430-30        Bottles of 30
  NDC 0049-3430-41        Unit dose package of 100

Store tablets below 86°F (30°C).

Diflucan for Oral Suspension

Diflucan for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows:

  NDC 0049-3440-19        Fluconazole 350 mg per bottle
  NDC 0049-3450-19        Fluconazole 1400 mg per bottle

Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.

Diflucan®
(Fluconazole Tablet)

200 mg

Distributed by
ROERIG
DIV OF PFIZER INC, NY, NY 10017
MADE IN USA (includes foreign content)

13041700

EXP & LOT AREA

UNIT DOSE

Pfizer

NDC 0049-3430-41

Diflucan®
(Fluconazole Tablets)

200 mg

For in-institution use only

100 Tablets
Rx only

Diflucan (fluconazole) is an antifungal medicine.

Diflucan is used to treat infections caused by fungus, which can invade any part of the body including the mouth, throat, esophagus, lungs, bladder, genital area, and the blood.

Diflucan is also used to prevent fungal infection in people who have a weak immune system caused by cancer treatment, bone marrow transplant, or diseases such as AIDS.

You should not use Diflucan if you are allergic to fluconazole, or if you also take cisapride, erythromycin, pimozide, or quinidine.

To make sure Diflucan is safe for you, tell your doctor if you have:

• liver disease;

• HIV or AIDS;

• cancer;

• heart disease or heart rhythm disorder;

• a personal or family history of Long QT syndrome;

• kidney disease; or

• if you are allergic to other antifungal medicine (such as ketoconazole, itraconazole, miconazole, posaconazole, voriconazole, and others).

Diflucan oral suspension (liquid) contains sucrose. Talk to your doctor before using this form of fluconazole if you have a problem digesting sugars or milk.

A single dose of Diflucan taken to treat a vaginal yeast infection is not expected to harm an unborn baby.

Do not take more than 1 dose of Diflucan if you are pregnant. Long-term use of high doses fluconazole can harm an unborn baby or cause birth defects. Tell your doctor if you become pregnant during treatment.

Diflucan can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking Diflucan for more than 1 dose.

Fluconazole can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.