Fluconazole

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications: 

• Cryptococcal meningitis in mentally alert patients without localising neurological signs and as a follow-up therapy after amphotericin B therapy
• Maintenance therapy to prevent relapse of cryptococcal disease in patients with acquired immunodeficiency syndrome (AIDS)
• Systemic candidiasis
• Oropharyngeal and oesophageal candidiasis
• Prevention of fungal infections in patients with malignancy who are predisposed to such infections such as a result of cytotoxic chemotherapy and radiotherapy
• Vaginal candidiasis - acute or recurrent infections and as prophylaxis to reduce the incidence of recurrent infections
• Candidial balanitis
• Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis) and dermal candida infections

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to related azole substances
• Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400mg/day or higher based upon results of a multiple dose interaction study
• Coadministration of other medicines known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to related azole substances
• Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400mg/day or higher based upon results of a multiple dose interaction study
• Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine, and erythromycin

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment (multiple doses) 
• Hepatic impairment
• Elderly
• Newborns (up to 4 weeks old) (sus)
• Congenital QT prolongation
• Risk factors for QT prolongation
  - Structural heart disease
  - Electrolyte abnormalities
  - Hypokalaemia
  - Advanced cardiac failure
• Tinea capitis in children (see additional prescribing points)
• Pulmonary and cutaneous cryptococcosis
• Deep endemic mycoses
  - Paracoccidioidomycosis, lymphocutaneous, sporotrichosis and histoplasmosis
• Potentially proarrhythmic conditions
• AIDS patients
• Diabetic patients (sus)
• Continued use for >14 days (sus)
• Sodium benzoate hypersensitivity (sus)
• Sodium controlled/restricted patients (IV)
• Fluid restricted patients (IV)
• Galactose intolerance (cap)
• Lapp lactase deficiency (cap)
• Glucose-galactose malabsorption (cap)
• Fructose intolerance (sus)
• Glucose/galactose malabsorption (sus)
• Sucrase-isomaltase insufficiency (sus)

Forms avail. in SA and covered in this monograph: cap, sus, inj, inf

Dosages below include:

• South African Standard Treatment Guideline indications and dosages
• South African registered indications and dosages

Infections caused by: Candida albicans, Candida tropicalis, C. glabrata, C. neoformans, B. dermatitidis, H. capsulatum, C. immitis, Paracoccidioides brasiliensis, and ringworm fungi (dermatophytes)

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guideline indications and dosages

Scalp infections
- Tinea capitis

• Oral (cap): 200mg, weekly; Treatment duration: 6 weeks
  (STG, PHC 2020)

Fungal skin infections
- Dermatophyte hair and nail infections
- Immunocompromised individuals with extensive skin infection
- Recurrent infections where repeat exposure is not prevented

• Oral (cap): 200mg, weekly; Treatment duration: 6 weeks
  (STG, Adult 2019)

Onychomycosis

• Oral (cap): 200mg, weekly; Treatment duration: 6 months
  (STG, Adult 2019)

Intravascular catheter infections (Additional agent required)
- For candidaemia, if susceptible, as follow up therapy after IV amphotericin B, OR if there is intolerance to amphotericin B

• Oral (cap): 800mg, dly
  (STG, Adult 2019)

Oesophageal/ tracheal/ bronchial candidiasis

• IV/Oral (cap): 200mg, dly; Treatment duration: 14 days
  (STG, Adult 2023; PHC 2023)

- Early relapse

• IV/Oral (cap): 200mg, dly; Treatment duration: 4 weeks  
  (STG, Adult 2023)

Asymptomatic cryptococcosis in HIV-infected patients
- If there is any delay in performing lumbar puncture

• Oral (cap): 1200mg, immediately
  (STG, PHC 2023)

- With cryptococcal meningitis excluded by negative cryptococcal antigen on CSF

• Oral (cap): Induction phase: 1200mg, dly; Treatment duration: 14 days; Consolidation phase: 800mg, dly; Treatment duration: 8 weeks; Maintenance phase: 200mg, dly; Treatment duration: At least 1 year, provided that the CD4 count increases to >200 cells/mm³ on ART; If the CD4 count does not increase continue treatment indefinitely
  (STG, Adult 2023; PHC 2023)

Cryptococcal meningitis in HIV-infected patients (Additional agent required)
- If flucytosine is available

• Oral (cap): Days 8-14 of induction phase: 1200mg, dly; Treatment duration: 7 days; Consolidation phase: 800mg, dly; Treatment duration: 8 weeks; Maintenance phase: 200mg, dly; Treatment duration: At least 1 year provided that the CD4 count increases to >200 cells/mm³ on ART. If the CD4 count does not increase continue treatment indefinitely
  (STG, Adult 2023)

- If flucytosine is not available

• Oral (cap): Induction phase: 1200mg, dly; Treatment duration: 14 days; Consolidation phase: 800mg, dly; Treatment duration: 8 weeks; Maintenance phase: 200mg, dly; Treatment duration: At least 1 year, provided that the CD4 count increases to >200 cells/mm³ on ART; If the CD4 count does not increase continue treatment indefinitely
  (STG, Adult 2023)

Cryptococcal meningitis in HIV-uninfected patients (Additional agent required)

• Oral (cap): 800mg, dly; Treatment duration: 2 weeks; Followed by: 400mg, dly; Treatment duration: 2 months; Maintenance: 200mg, dly: Treatment duration: For a minimum of 1 year
  (STG, Adult 2019)

---

South African registered indications and dosages

Cryptococcal meningitis in mentally alert patients without localising neurological signs and as a follow up therapy after amphotericin B therapy (Additional agent required)

• IV/Oral (cap, sus): Initial: 400mg, on first day; Then: 200mg, once dly; Depending on the clinical response: Increase to 400mg, once dly if required; Treatment duration: 6-8 weeks

- Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with AIDS after the patient receives a full course of primary therapy

• IV/Oral (cap, sus): 100-200mg, dly; Treatment duration: Until the CD4 count has stabilised at >250 cells/mm³

Systemic candidiasis

• IV/Oral (cap, sus): Initial: 400mg, on first day; Then: 200mg, once dly; Depending on the clinical response: Increase to 400mg, once dly, if required; Treatment duration: Based on clinical response

Oropharyngeal candidiasis

• IV/Oral (cap, sus): Usual dose: 50-100mg, once dly; Treatment duration: 7-14 days; Treatment can be continued for longer periods in severely immunocompromised patients if needed

- To prevent oropharyngeal candidiasis relapse in AIDS patients, after the patient receives a full course of primary therapy

• IV/Oral (cap, sus): 150mg, weekly

---

Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse

---

Oesophageal candidiasis

• IV/Oral (cap, sus): Initial: 200mg on first day; Then 100-200mg, once dly; Doses up to 400mg/day may be used based on medical judgement of the patient's response to therapy; Treatment duration: Minimum of 3 weeks and for at least 2 weeks after symptoms have resolved

Prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy and radiotherapy

• IV/Oral (cap, sus): 50-400mg, once dly, based on the patient’s risk for developing fungal infection

---

For patients at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia, a dose of 400mg once daily has been used. Fluconazole administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells/mm³

---

See additional prescribing points for administration directions

---

Vaginal candidiasis
Candida balanitis

• Oral (cap): 150mg as a single dose

Recurring vaginal candidiasis

• Oral (cap): 150mg as a single dose, monthly; Treatment duration: Ranges from 4-12 months, duration should be individualised, some patients may require more frequent dosing

Dermal infection including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis) and dermal candida infections

• Oral (cap): 150mg as a single dose, weekly; Treatment duration: 2-4 weeks, tinea pedis may require up to 6 weeks

---

For tinea unguium, treatment should be continued until the infected nail grows out and is replaced with the uninfected nail. Fingernails generally require 3-6 months to regrow and toenails 6-12 months. However, growth rates may vary widely in individuals and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured

---

All indications: Once the results of cultures and other laboratory studies become available, anti-infective therapy should
be adjusted accordingly. The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection

Paed. forms avail. in SA and covered in this monograph: cap, sus, inj, inf

Paed. dosages below include:

• South African Standard Treatment Guideline indications and dosages
• South African registered indications and dosages

Infections caused by: Candida albicans, Candida tropicalis, C. glabrata, C. neoformans, B. dermatitidis, H. capsulatum, C. immitis, Paracoccidioides brasiliensis, and ringworm fungi (dermatophytes)

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guideline indications and dosages

Scalp infections
- Tinea capitis

• Oral (cap, sus): 6mg/kg, dly; Treatment duration: 28 days
  (STG, PHC 2020)

Fungal skin infections - candidiasis
- Unresponsive to imidazole cream

• Oral (cap, sus): 3-6mg/kg, dly; Treatment duration: 14 days
  (STG, Paed. 2023) 

Oesophageal candidiasis

• IV/Oral (cap, sus): 6mg/kg, immediately as a single dose; Then: 3mg/kg, dly; Treatment duration: 3 weeks
  (STG, Paed. 2023)

- In patients with HIV/AIDS

• Oral (cap, sus): 6mg/kg, dly; Treatment duration: 21 days
  (STG, PHC 2023)

Vulvovaginitis

• Oral (cap, sus): 12mg/kg, as a single dose; Max dose: 150mg
  (STG, Paed. 2023)

Cryptococcal meningitis (Additional agent required)

• IV/Oral (cap, sus): 2nd week: 12mg/kg, dly; Treatment duration: 7 days; Max dose: 800mg
  OR
  IV/Oral (cap, sus): Initial: 12mg/kg, dly; Treatment duration: 14 days; Max dose: 800mg
• Oral (cap, sus): Consolidation: 12mg/kg, dly; Treatment duration: 8 weeks; Max dose: 800mg
  (STG, Paed. 2023)

Cryptococcal meningitis secondary prophylaxis (Maintenance treatment)

• Oral (cap, sus): 6mg/kg, dly; Max dose: 400mg
  (STG, Paed. 2023) 

Suspected or confirmed fungal pneumonia (other than PJP) in HIV exposed or infected children

• IV/Oral (cap, sus): 10mg/kg, dly; Treatment duration: At least 14 days
  (STG, Paed. 2023)

---

South African registered indications and dosages

Oropharyngeal candidiasis

• IV/Oral (cap, sus): Recommended dose: 6mg/kg on first day; Then: 3mg/kg, once dly; Treatment duration: For at least 2 weeks to decrease the likelihood of relapse 

Oesophageal candidiasis

• IV/Oral (cap, sus): Recommended dose: 6mg/kg on first day; Then: 3mg/kg, once dly; Doses up to 12mg/kg/day may be used based on medical judgement of the patient's response to therapy; Treatment duration: Minimum 3 weeks and for at least 2 weeks following the resolution of symptoms

Systemic candidiasis
Cryptococcal infection

• IV/Oral (cap, sus): 6-12mg/kg, dly depending on disease severity

Prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy

• IV/Oral (cap, sus): 3-12mg/kg, dly depending on the extent and duration of the induced neutropenia

---

Once the results of cultures and other laboratory studies become available, anti-infective therapy should
be adjusted accordingly. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children. Fluconazole is administered as a single daily dose

---

Use in children 4 weeks of age and younger
Neonates excrete fluconazole slowly. In the first 2 weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life the same dose should be given every 48 hours

---

See additional prescribing points for administration directions

Pregnancy

South African recommendations

• Contraindicated
• Fluconazole is contraindicated for use during pregnancy
• There have been reports of congenital abnormalities in infants whose mothers were treated with fluconazole
• There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800mg/day) fluconazole therapy for coccidioidomycosis
• A few published case reports describe a distinctive and a rare pattern of birth defects among infants whose mothers received high-dose (400-800mg/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
• Women of childbearing potential/contraception in males and females: Effective contraceptive measures must be used in women of childbearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose

Recommendations in other jurisdictions

• Caution; positive evidence of risk
• An observational study has suggested an increased risk of spontaneous abortion in women treated with fluconazole during the first trimester
• Data from several thousand pregnant women treated with a cumulative dose of ≤150mg of fluconazole in the first trimester show no increase in the overall risk of malformations in the foetus
• In one large observational cohort study, first trimester exposure to oral fluconazole was associated with a small increased risk of musculoskeletal malformations. This corresponds to approximately 1 additional case per 1000 women treated with cumulative doses ≤450mg compared with women treated with topical azoles and to approximately 4 additional cases per 1000 women treated with cumulative doses over 450mg
• The adjusted relative risk was 1.29 (95% CI 1.05 to 1.58) for 150 mg oral fluconazole and 1.98 (95% CI 1.23 to 3.17) for doses over 450mg fluconazole
• There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing, and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear
• Studies in animals have shown reproductive toxicity
• Fluconazole in standard doses and short-term treatment should not be used during pregnancy unless clearly necessary
• Fluconazole in high doses and/or in prolonged regimens should not be used during pregnancy except for life-threatening infections
• In women of child bearing potential appropriate contraceptive measures should be considered in case long-term treatment is indicated

Breastfeeding

South African recommendations

• Contraindicated
• Fluconazole is found in breast milk at concentrations similar to plasma
• Fluconazole should not be used in mothers breastfeeding their infants

Recommendations in other jurisdictions

• Caution
• Fluconazole passes into breast milk in concentrations lower than those in plasma
• Breastfeeding may be maintained after a single use of a standard dose of fluconazole (150mg or 200mg or less). Breastfeeding is not recommended after repeated use or after high dose fluconazole
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for fluconazole and any potential adverse effects on the breastfed child from fluconazole or from the underlying maternal condition

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Fluconazole did not affect the fertility of male or female rats

Recommendations below are applicable to South Africa and other jurisdictions

• Single dose: No dose adjustment recommended
• Multiple-doses: Caution; dose adjustment recommended
  Adults and children: An initial dose of 50-400mg should be given, based on the recommended daily dose for the indication
  After this initial loading dose, the daily dose (according to indication) should be based on the following table

CrCl (ml/min)	Dose
>50	100% of recommended dose
≤50 (no haemodialysis)	50% of recommended dose
Haemodialysis	100% of recommended dose after haemodialysis

Patients on haemodialysis should receive 100% of the recommended dose after each haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance
These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended 
  Dosage should be adjusted based on the renal function

Central Nervous System Disorders

• Somnolence
• Insomnia
• Headache
• Seizures
• Paraesthesia  
• Dizziness
• Tremor
• Fatigue

Cardiovascular Disorders

• Torsade de Pointes
• QT prolongation

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Diarrhoea
• Constipation
• Dyspepsia
• Flatulence
• Dry mouth

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Cholestasis
• Jaundice
• Increased bilirubin
• Hepatic failure
• Hepatocellular necrosis
• Hepatitis
• Hepatocellular damage

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypercholesterolaemia
• Hypertriglyceridaemia
• Hypokalemia

Musculoskeletal Disorders

• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Drug eruption
• Urticaria
• Pruritus
• Increased sweating
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Acute generalised exanthematous-pustulosis
• Exfoliative dermatitis
• Angioedema
• Face oedema
• Alopecia
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Anaphylaxis
• Anaemia
• Agranulocytosis
• Leukopenia
• Thrombocytopenia
• Neutropenia
• Fever

Sensory Disorders

• Vertigo
• Taste perversion

• Halofantrine
• QT-prolonging agents
• Terfenadine
• Cisapride
• Astemizole
• Pimozide
• Quinidine
• Erythromycin
• Amiodarone
• Rifampicin
• Hydrochlorothiazide
• Alfentanil
• Amitriptyline
• Nortriptyline
• Amphotericin B
• Coumarin-type anticoagulants
• Warfarin
• Indanedione anticoagulants
• Benzodiazepines (short-acting)
• Midazolam
• Triazolam
• Carbamazepine
• Calcium channel blockers
• Nifedipine
• Isradipine
• Amlodipine
• Verapamil
• Felodipine
• Celecoxib
• Cyclophosphamide
• Fentanyl
• HMG-CoA reductase inhibitors
• Simvastatin
• Atorvastatin
• Fluvastatin
• Ibrutinib
• Ivacaftor
• Olaparib
• Immunosuppressors
• Ciclosporin
• Everolimus
• Sirolimus
• Tacrolimus
• Losartan
• Methadone
• Non-steroidal anti-inflammatory drugs
• Flurbiprofen
• Ibuprofen
• Naproxen
• Lornoxicam
• Meloxicam
• Diclofenac
• Phenytoin
• Prednisone
• Rifabutin
• Saquinavir
• Sulfonylureas
• Chlorpropamide
• Glibenclamide
• Glipizide
• Tolbutamide
• Theophylline
• Tofacitinib
• Vinca alkaloids
• Vincristine
• Vinblastine
• Vitamin A
• All-trans-retinoid acid
• Voriconazole
• Zidovudine
• Azithromycin
• Oral contraceptives

None routine. Specific cases may require

• Hepatic function
• Renal function
• Serum potassium

Administration directions

• To reconstitute powder for oral suspension: Tap the bottle to loosen powder, add 24ml water and shake well
• Intravenous fluconazole may be infused at a maximum rate of approximately 200mg/hour through an existing line with one of the following suitable diluents include: 20% dextrose, ringer's solution, normal saline, potassium chloride in dextrose and 4.2% sodium bicarbonate
• Fluconazole IV infusion is formulated in 0.9% sodium chloride solution, each 200mg (100ml bottle) containing 15mmol each of Na+ and Cl-. Because Fluconazole IV infusion is available as a dilute saline solution, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration
• Although no specific incompatibilities have been noted, mixing with any other medicine prior to infusion is not recommended

Fluconazole is a triazole antifungal agent. The primary mode of action of fluconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Spectrum of activity: Candida spp.; Cryptococcus neoformans; Cryptococcus gatti; Coccidioides immitis ; Blastomyces dermatiditis; Histoplasma caspulatum; Paracoccidioides brasiliensis

Capsule 50mg

• Aricon (Actavis)
• Aspen fluconazole (Pharmacare)
• Austell fluconazole (Austell)
• Bio Fluconazole 50mg (Biotech Laboratories)
• Cipla fluconazole (Cipla Medpro)
• Diflucan (Pfizer) originator
• Flucoric (Ranbaxy)
• Fluzol (Sandoz)
• Gulf fluconazole (Gulf Drug)

Capsule 100mg

• Gulf fluconazole (Gulf Drug)

Capsule 150mg

• Aspen fluconazole (Pharmacare)
• Auro fluconazole (Aurobindo)
• Austell fluconazole (Austell)
• Bio Fluconazole 150mg (Biotech Laboratories)
• Diflucan (Pfizer) originator
• Difluzol (Cipla Medpro)
• Fluconazole 150 Strides (Strides)
• Fluconazole Unicorn (Sandoz)
• Flucoric (Ranbaxy)
• Fluzol (Sandoz)
• Gulf Fluconazole 150 (Gulf Drug)
• Insep 150 (Novagen)
• Mycorest (Zydus)
• Mylan fluconazole (Mylan)
• Simayla fluconazole (Ranbaxy)

Capsule 200mg

• Aricon (Actavis)
• Aspen fluconazole (Pharmacare)
• Auro fluconazole (Aurobindo)
• Austell fluconazole (Austell)
• Bio Fluconazole 200mg (Biotech Laboratories)
• Cipla fluconazole (Cipla Medpro)
• Diflucan (Pfizer) originator
• Fluconazole 200 Strides (Strides)
• Flucoric (Ranbaxy)
• Fluzol (Sandoz)
• Gulf fluconazole (Gulf Drug)
• Insep 200 (Novagen)
• Mycorest (Zydus)
• Mylan fluconazole (Mylan)
• Simayla fluconazole (Ranbaxy)
• Zydus fluconazole (Zydus)

Suspension (per 5ml) 50mg

• Diflucan (Pfizer) originator

Suspension (per 5ml) 200mg

• Diflucan (Pfizer) originator

Injection (per ml) 2mg

• Aspen Fluconazole (Pharmacare)
• Bio Fluconazole (Biotech)
• Diflucan IV (Pfizer) originator
• Exomax (Dezzo)
• Fluzol (Sandoz)
• Zucan (Pharma Dynamics)
• Fluconazole Fresenius (Fresenius Kabi)