1.FLUCONAZOLE HISTORY
How was Fluconazole discovered?

Fluconazole is the invention of Dr. Kenneth Richardson of Sandwich , England .

2.FLUCONAZOLE FACTS

The U.S FDA approved Fluconazole in January 1990 for treatment of oropharyngeal and esophageal candidiasis and for treatment of cryptococcal meningitis.

FDA approved Fluconazole for treatment of pediatric patients with cryptococcal meningitis and candida infections.

3.ABOUT FLUCONAZOLE MEDICATION

What are fungi?

Fungi are a major group of living things, originally considered plants but now treated as the separate kingdom Fungi. They occur in all environments on the planet and include important decomposers and parasites. Parasitic fungi infect animals, including humans, other mammals, birds, and insects, with consequences varying from mild itching to death. Other parasitic fungi infect plants.

Mold and yeast are two groups of plants in the fungus family. Both groups can cause allergic reactions. Fungal spores can circulate in the air and may cause allergic rhinitis when inhaled.

What are Fungal Infections?
Fungal infections are caused by microscopic plants (fungi) that can live on the skin. They can live on the dead tissues of the hair, nails, and outer skin layers.

Here are some common types of Fungal infections:

• Tinea is a type of Fungal infection of the hair, skin, or nails. When it's on the skin, tinea usually begins as a small red area the size of a pea. As it grows, it spreads out in a circle or ring. Tinea is often called ringworm because it may look like tiny worms are under the skin (but of course, they're not!). Because the fungi that cause tinea (ringworm) live on different parts of the body, they are named for the part of the body they infect. Scalp ringworm is found on the head, and body ringworm affects the arms, legs, or chest.
• Athlete's foot is another type of Fungal infection that usually appears between the toes but can also affect toenails and the bottom or sides of the feet.
• Jock itch is a Fungal infection of the groin and upper thighs. You might think only men and boys get it, but girls and women can get it, too.
• Candida is a type of yeast, similar to a fungus. It most often affects the skin around the nails or the soft, moist areas around body openings. Diaper rash in babies is one type of candidal infection, as is thrush (white patches often found in the mouths of babies.) Older girls and women may develop another form of candidal infection in and around the vagina. This is called a yeast infection.

• Oral Thrush (in the mouth) looks like white or red patches. It can cause sore throat, pain when swallowing, and nausea. It can also take away your appetite, make eating painful, and make food taste different. Treatments for oral thrush include mouthwash and tablets called troches. Some people try baking soda or hydrogen peroxide mixed with water to rinse the mouth. If the thrush is advanced, this isn't likely to work. Treatments for thrush include Fluconazole .
• Vaginal candidiasis is a common yeast infection of the vagina. A yeast infection may be the first sign that a woman is HIV+. Symptoms include severe itching, burning, and a thick discharge, often white in color. It is possible that an infection such as unrecognized TB may be causing a vaginal yeast infection. Nystatin tablets are used for treatment. Clotrimazole ointment is another treatment, which is sold over-the-counter as Gyne-Lotrimin, Lotrimin, or Mycelex. Studies have shown that HIV-negative women may only have to take the drug Fluconazole one time to treat this condition. Always consult with your doctor before beginning treatment.

• Cryptococcal meningitis is a very serious fungal infection. It is caused by a fungus found mainly in dirt and bird droppings. Meningitis means swelling of the meninges. The meninges cover the brain and spinal cord.
• istoplasmosis is a fungal infection caused by inhaling dust from spore-infected bird droppings. Histoplasmosis can be a life-threatening fungal infection and commonly occurs in the Southwestern U.S. The acute form is treated with antifungal medication.
• Blastomycosis is a fungal infection involving the lungs and occasionally spreading to the skin. The fungus is of unknown natural source. Most reported cases are from the southeastern states and the Mississippi River valley, and occur in men ages 20 to 40. When infection occurs in the lungs, a dry hacking or productive cough, chest pain, fever, chills, drenching sweats, and shortness of breath are initial symptoms. If untreated, the disease slowly causes death. Amphotericin B is highly effective. Improvement begins within a week, with rapid disappearance of organisms.  

What are Antifungals?

Antifungals are drugs that are used to treat fungal infections . Like antibiotics, antifungals stop the fungus from functioning normally. But there are not as many different groups of antifungals as there are antibiotics.

Antifungal Agents include

Polyene antibiotics (macrolides)

Amphotericin B - binds to ergosterol moiety in the plasma membrane causing derangement of the membrane integrity and leakage of cytoplasmic contents. Administered systemically.

Nystatin - binds to ergosterol and disrupts plasma membrane. Highly insoluble and toxic and therefore used topically only.

Azoles
Block ergosterol synthesis at one or more sites with the accumulation of 14 -methyl sterol (which replaces ergosterol in the plasma membrane causing selective leakage and increased osmotic sensitivity). They also disrupt chitin synthesis. All effects are due to the binding to cytochrome P-450.

• Butoconazole
• Clotrimazole
• Econazole
• Fluconazole
• Itraconazole
• Ketoconazole
• Miconazole
• Oxiconazole
• Sulconazole
• Terconazole

Allylamines

Naftifine - Binds to and inhibits squalene epoxidase which blocks ergosterol synthesis.

Terbinafine - Binds to and inhibits squalene epoxidase which blocks ergosterol synthesis.

Pyrimidine analogs

Flucytosine - It is deaminated to fluracil where it is either (1) incorporated into RNA in place of uracil where it inhibits protein synthesis or (2) metabolized to 5-fluorodeoxy-uridylic acid where it inhibits thymidylate synthetase, thus blocking DNA synthesis.

Miscellaneous types

Griseofulvin - causes disruption of the mitotic spindle by interacting with polymerized microtubules through binding to microtubule protein. Administered systemically for dermatophytic infections.

Haloprogin - a halogenated phenolic ether administered topically for dermatophytic infections.

Ciclopirox olamine - a topical for the treatment of dermatophytic infections and Candida albicans.

Tolnaftate - a thiocarbonate used to treat dermatophytic infections.

Potassium iodide - Given orally for sporotrichosis

How does Fluconazole work?

Fluconazole is a type of medicine called a triazole antifungal. Fluconazole is used to treat infections with fungi and yeasts.

Fluconazole works by preventing fungi from producing a substance called ergosterol, which is a component of fungal cell membranes. The cell membranes of fungi are vital for their survival. They keep unwanted substances from entering the cells and stop the contents of the cells from leaking out. Without ergosterol as part of the cell membrane, the membrane is weakened and damaged, and essential constituents of the fungal cells can leak out. This kills the fungi.

It can be explained as follows-

 

 

4.FLUCONAZOLE EFFECTIVENESS
(When is Fluconazole best taken?)

The pharmacokinetic properties of Fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered Fluconazole is over 90% compared with intravenous administration.

Peak plasma concentrations in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of Fluconazole leads to a mean plasma concentration of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50-400 mg, Fluconazole plasma concentrations becomes dose proportional.

Administration of a single oral 150 mg tablet of Fluconazole to ten lactating women resulted in a mean plasma concentration of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL).

5.FLUCONAZOLE EFFECTS ON SPECIAL POPULATION
How do different people react to Fluconazole?

Pregnancy
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of Fluconazole in nursing mothers is not recommended.

Pediatric Use
An open-label, randomized, controlled trial has shown Fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age.

The use of Fluconazole 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 non-comparative pediatric clinical studies. In addition, pharmacokinetic studies in children have established dose proportionality between children and adults.

In a non-comparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of Fluconazole 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 valuable 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 Fluconazole 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 Fluconazole 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.

Efficacy of Fluconazole has not been established in infants less than 6 months of age. A small number of patients ranging in age from 1 day to 6 months have been treated safely with Fluconazole.

6.FLUCONAZOLE EFFECTS ON MEDICAL CONDITIONS
(How does Fluconazole affect your existing condition/ailment?)

Hepatic injury: Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of Fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed.

Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during Fluconazole therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to Fluconazole .

(2)Anaphylaxis : In rare cases, anaphylaxis has been reported.

(3) Dermatologic : Patients have rarely developed exfoliative skin disorders during treatment with Fluconazole. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with Fluconazole should be monitored closely and the drug discontinued if lesions progress.

7.OTHER/ALTERNATE USES OF FLUCONAZOLE
(What else does Fluconazole treat?)

Oral, esophageal, urinary, vaginal and possibly other organ infections caused by the fungus Candida. Fluconazole has also been used in the fungal infection Cryptococcus.

8.ADVERSE/SIDE EFFECTS of FLUCONAZOLE
What are the side effects of Fluconazole?

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 Fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to Fluconazole 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 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 Fluconazole 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%.

The following adverse events have occurred under conditions where a causal association is probable:

Hepatobiliary : In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with Fluconazole . 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 Fluconazole .

Immunologic : In rare cases, anaphylaxis has been reported.

The following adverse events have occurred under conditions where a causal association is uncertain:

Central Nervous System : Seizures.

Dermatologic : Exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia.

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

Metabolic : Hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Adverse Reactions in Children:

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 Fluconazole 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
	Fluconazole (N=577)	Comparative Agents (N=451)
With any side effect	13.0	9.3
Vomiting	5.4	5.1
Abdominal pain	2.8	1.6
Nausea	2.3	1.6
Diarrhea	2.1	2.2

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