Fluconazole

Overview

Fluconazole (Diflucan®) is a triazole antifungal agent commonly used in dogs and cats for the treatment of systemic and localized fungal infections. It is almost completely absorbed after oral administration, with or without food and regardless of gastric pH, and is widely distributed throughout the body.

A key advantage of fluconazole is its ability to reach therapeutic concentrations in the central nervous system and respiratory tract, as well as high urinary concentrations due to renal excretion. This makes it the preferred azole for infections involving the CNS, the eye and the urinary tract.

Mechanism of Action (MOA): Fluconazole is fungistatic: it inhibits a fungal cytochrome P450-dependent demethylation enzyme that produces ergosterol, an essential component of fungal cell membranes. The resulting accumulation of methylated sterols weakens the fungal cell membrane, increasing its permeability and allowing leakage of cellular contents while impairing uptake of purine and pyrimidine precursors.

Indications

Fluconazole is used in dogs and cats for the treatment of a wide range of fungal infections, particularly those requiring good tissue penetration such as CNS, respiratory, and urinary infections.

• Systemic fungal infections: Effective against organisms such as Blastomyces, Histoplasma and Coccidioides, although coccidioidomycosis may need the higher end of the dose range.
• Cryptococcosis: Preferred for ocular and CNS cryptococcosis – water soluble, and it penetrates the central nervous system better than the alternatives; also used for nasal cryptococcosis.
• Candidiasis: Used for systemic or urinary Candida infections, with high urinary drug concentrations improving efficacy; Candida albicans is usually susceptible, but non-albicans species are more often resistant and warrant susceptibility testing.
• Dermatophytosis (e.g., Microsporum canis): A less effective but less expensive alternative for dermatophytosis; for Malassezia dermatitis, ketoconazole or itraconazole are preferred.
• Urinary fungal infections: The initial treatment of choice for Candida albicans urinary infection; it is excreted into urine in an active form, whereas itraconazole, ketoconazole, posaconazole and voriconazole are not recommended for this site.
• Limited activity against moulds: activity against Aspergillus is inconsistent and it is not a first-choice agent for aspergillosis, with only variable activity against Penicillium and weak activity against Zygomycetes.

Dosage (Reference)

Dog

In dogs, fluconazole is used for systemic and urinary fungal infections, with dosing depending on the type and severity of infection.

Cat

In cats, fluconazole dosing varies depending on infection type and location, with higher doses often used for systemic or CNS infections.

Warnings & Precautions

Fluconazole is generally well tolerated in dogs and cats, but careful use and monitoring are required, particularly during prolonged therapy or in patients with underlying disease.

• Pregnancy and lactation: Avoid in pregnancy and lactation: azoles are teratogenic at high doses. Use in a pregnant animal only where the infection is severe or life-threatening and the benefit to the mother outweighs the risk to the fetus. The drug reaches milk at concentrations similar to plasma, so consider a milk replacer for nursing animals.
• Hypersensitivity: Do not use in patients that are hypersensitive to fluconazole or to other azole antifungal agents.
• Hepatic effects: Hepatotoxicity is possible: 15 to 20% of dogs on long-term treatment develop increased ALT activity, and in one study every elevation was mild. With continued monitoring most dogs complete treatment without a dose reduction. Check ALT monthly, and whenever the patient goes off food; stop temporarily if the patient is anorexic or ALT exceeds 300 U/L, then restart at half the previous dose.
• Renal impairment: Dose adjustment is required as the drug is primarily excreted by the kidneys.
• Prolonged therapy: Treatment duration may be extended; continue therapy until clinical resolution and confirmed elimination of infection.
• Systemic disease monitoring: Patients with severe or disseminated infections require regular reassessment of clinical response and organ function.
• Severe hepatic disease: Avoid in severe hepatic disease, and reduce the dose in milder liver impairment; use in a patient with existing hepatic disease only when the benefit clearly outweighs the risk.
• Compounded formulations: Use a manufactured product wherever possible. Compounded fluconazole suspensions have been measured at 74 to 95% of their labelled concentration and shown poor accuracy and precision, and treatment failures have been reported with chemical-grade compounded formulations. Do not add other drugs or additives to the injection.
• Cardiac effects: May prolong the QT interval. Use with caution in patients at increased risk of arrhythmia – structural heart disease, heart failure or electrolyte imbalance – and be cautious about combining it with other QT-prolonging drugs.
• Off-licence use: All use in dogs and cats is off-licence – there is no veterinary-licensed fluconazole product.
• Handling precautions: Classified as a hazardous drug for occupational exposure; use appropriate personal protective equipment when handling it.
• Name confusion: Take care not to confuse fluconazole with flecainide, fluoxetine or furosemide when prescribing or dispensing.

Drug Interactions

In humans, fluconazole is a potent CYP2C and a moderate CYP3A inhibitor; in veterinary patients it can raise plasma concentrations of many concurrently administered drugs. Careful monitoring and dose adjustments may be required.

• Theophylline: Plasma concentrations may increase, raising the risk of toxicity.
• Ciclosporin: In dogs, fluconazole raises ciclosporin concentrations: ciclosporin doses were reduced by 33 to 50% to hold comparable trough concentrations. Monitor trough concentrations and adjust the ciclosporin dose during concurrent treatment.
• QT prolonging Agents (eg amiodarone, disopyramide, ondansetron, procainamide, sotalol) : May increase the risk of arrhythmia, and several of these combinations are contraindicated in people.
• Tramadol: In dogs, fluconazole increased tramadol exposure about 31-fold and exposure to its M1 metabolite about 39-fold.
• Anaesthetics and sedatives: In dogs, fluconazole decreased midazolam and ketamine clearance by about 50%, and ketamine’s clinical effects were prolonged.
• Methadone: Fluconazole significantly increases methadone exposure in dogs.
• NSAIDs and corticosteroids: Fluconazole may increase concentrations of some NSAIDs, including carprofen, meloxicam and robenacoxib, and may inhibit corticosteroid metabolism; monitor for increased adverse effects.
• Amphotericin B: Laboratory-animal studies suggest concurrent amphotericin B may be antagonistic against Aspergillus or Candida; the clinical importance of this is unclear.
• Drugs that reduce fluconazole exposure: Rifampin may decrease fluconazole exposure and efficacy, while fluconazole may increase rifampin concentrations; cimetidine may also reduce fluconazole concentrations.

Side Effects & Overdose

Side Effects

Fluconazole is generally well tolerated in dogs and cats, but adverse effects may occur, particularly with prolonged use.

• Gastrointestinal effects: Inappetence, vomiting, soft stools or diarrhoea may occur; these may be mild and transient and not require treatment to be stopped. If the patient vomits or seems unwell after a dose on an empty stomach, give it with food or a small treat.
• Hepatotoxicity: Increased ALT activity is reported in 15 to 20% of dogs on long-term treatment Most dogs complete treatment without a dose reduction. Going off food is the most common sign and should prompt a liver check.
• Ulcerative dermatitis: Dose-related ulcerative skin lesions due to vasculitis occur in some dogs. Stop treatment until the ulcers resolve, then restart at half the previous dose.
• Less common effects: Other reported effects include focal alopecia, hypoadrenocorticism, ocular discharge, dry skin and malaise. Unlike ketoconazole, fluconazole has no appreciable effect on steroid hormone synthesis.

Overdose

Published information on the acute toxicity of fluconazole is limited.

• Reported signs at high doses : In laboratory rodents given 1 to 2 g/kg, reported signs were respiratory depression, salivation, lacrimation, urinary incontinence and cyanosis; comparable dog and cat data are not published.
• Evidence limitation : The only published acute-toxicity data come from laboratory rodents, in which death followed doses of 1 to 2 g/kg.
• Management: Provide supportive therapy as required.
• Decontamination and dialysis: After a massive ingestion consider gastric decontamination. Fluconazole is removed by haemodialysis or peritoneal dialysis – a 3-hour haemodialysis session halves plasma concentrations in people – and a 24-hour poison control centre with veterinary expertise should be contacted.

Key Notes

Practical clinical insights to optimize the use of fluconazole in dogs and cats:

• Excellent CNS penetration: The only azole with reliable CNS penetration – it reaches roughly 50 to 90% of plasma concentrations in cerebrospinal fluid, measured at a CSF-to-serum ratio of 0.88 in cats – which is why it is preferred for brain, spinal and ocular infection.
• High urinary excretion: About 70% of a dose is excreted unchanged in urine in dogs, giving high urinary concentrations of active drug – the reason it works for fungal cystitis where itraconazole, ketoconazole, posaconazole and voriconazole do not.
• Flexible dosing regimens: Can be administered once or twice daily depending on infection type and severity.
• Good oral bioavailability: Oral bioavailability is essentially complete – 100% in dogs, peaking at about 4 hours, and complete in cats peaking at 2.6 hours – and, unlike itraconazole and ketoconazole, is unaffected by food or gastric pH, so it can be given to an inappetent patient or one receiving antacids.
• Clinical response monitoring: For cryptococcosis, monitor antigen titres every 1 to 2 months; titres should decline by 2 to 3 months if treatment is working. On long-term therapy, take a baseline chemistry panel and check liver enzymes monthly at first.
• Fungistatic activity: Fluconazole is fungistatic and inhibits fungal growth, with fungistatic activity shown against some strains of Candida, Coccidioides, Cryptococcus, Histoplasma and Blastomyces.
• Half-life and steady state: Elimination half-life is about 13 to 15 hours in dogs and 13 to 25 hours in cats. Human data, based on a 30-hour half-life, indicate that steady state is not reached for 6 to 14 days unless a loading dose is given.
• Comparison with itraconazole: In canine blastomycosis it had similar efficacy to itraconazole and cost less, though median treatment was longer at 183 versus 138 days. In canine histoplasmosis no difference in efficacy, survival, remission or relapse was reported. For cryptococcosis it is the most economical choice.
• Resistance: Cryptococcal organisms may become resistant during treatment; if antigen titres fail to decline after 2 to 3 months, consider another agent. Non-albicans Candida are more commonly resistant and warrant susceptibility testing.
• Storage and handling: Store tablets and powder below 30 degrees C in a tight container, and store the injection and reconstituted oral suspension at 5 to 30 degrees C without freezing, following the injection manufacturer’s label. Discard reconstituted oral suspension 2 weeks after mixing. Tablets may be crushed.