Itraconazole

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:

• Persistant vulvovaginal candidiasis (cap)
• Dermatomycosis (cap)
• Fungal keratitis (cap)
• Systemic aspergillosis and candidiasis, histoplasmosis, sporotrichosis, paracoccidioidomycosis and blastomycosis (cap)
• Onychomycosis, caused by dermatophytes and/or yeasts (cap)
• Oral and/or oesophageal candidiasis in HIV seropositive or AIDS or other immunocompromised patients (sol)
• Prophylaxis of deep fungal infections when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant and who are expected to become neutropenic (sol)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy in non-life-threatening cases
  - Women of childbearing potential (except if on contraception)
• Porphyria
• Evidence of ventricular dysfunction
  - Congestive heart failure or a history thereof except for the treatment of life-threatening or other serious infections
• Coadministration with CYP3A4 substrates (see Interactions)

Cautions

• Hypersensitivity to other azole antifungal agents
• Pregnancy in life-threatening cases
• Breastfeeding
• Severe renal impairment (eGFR ≤10ml/min)
• Hepatic impairment
  - Pre-existing hepatic function abnormalities
• Elderly
• High doses
• Risk factors for congestive heart failure
  - Cardiac disease such as ischaemic and valvular disease
  - Significant pulmonary disease such as chronic obstructive pulmonary disease
  - Renal failure
  - Other oedematous disorders
• Pre-existing liver disease
• History of hepatotoxicity with other medications
• Abnormal gastro-intestinal motility
• Conditions resulting in reduced gastric acidity
  - Achlorhydria
  - Medications reducing gastric acidity
• Children
• Immunocompromised patients
  - Neutropenic patients
  - AIDS patients, specifically those at risk of relapse of systemic fungal infection
  - Organ transplant patients
• Initiation of treatment in patients with immediately life-threatening systemic fungal infections (cap)
• Initiation of treatment in patients at immediate risk of systemic candidosis (sol)
• Fluconazole-resistant strains of Candida species
• Interchanging between oral solution and capsules
• Coadministration with calcium channel blockers
• Coadministration with hepatotoxic agents
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: cap, sol

Dosages below include:

• General dosing range
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by Candida albicans; Candida dubliniensis; Candida tropicalis; Candida parapsilosis; Candida guilliermondii; Blastomyces dermatitidis; Histoplasma capsulatum; Aspergillus spp.; Blastomyces dermatitidis; Cladosporium spp.; Coccidioides immitis; Cryptococcus neoformans; Epidermophyton floccosum; Fonsecaea spp.; Geotrichum spp.; Histoplasma spp.; Malassezia (formerly Pityrosporum) spp.; Microsporum spp.; Paracoccidioides brasiliensis; Penicillium marneffei; Pseudallescheria boydii; Sporothrix schenckii; Trichophyton spp.; Trichosporon spp.

General dosing range

• Oral (cap): 200mg, dly; Max: 600mg/24hrs

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

International manufacturer recommendations

Capsule

Vulvovaginal candidosis

• Oral (cap): 200mg, 12hrly; Treatment duration: 1 day

Pityriasis versicolor

• Oral (cap): 200mg, dly; Treatment duration: 7 days

Tinea corporis
Tinea cruris 

• Oral (cap): 100mg, dly; Treatment duration: 15 days

OR

• Oral (cap): 200mg, dly; Treatment duration: 7 days

Tinea pedis
Tinea manuum 

• Oral (cap): 100mg, dly; Treatment duration: 30 days

Oropharyngeal Candidosis

• Oral (cap): 100mg, dly; Treatment duration: 15 days

- In AIDS or neutropenic patients

• Oral (cap): 200mg, dly; Treatment duration: 15 days

Onychomycosis
- Toenails with or without fingernail involvement

• Oral (cap): 200mg, dly; Treatment duration: 3 months

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For skin, vulvovaginal and oropharyngeal infections, optimal clinical and mycological effects are reached 1-4 weeks after cessation of treatment and for nail infections, 6-9 months after the cessation of treatment. This is because the elimination of itraconazole from skin, nails and mucous membranes is slower than from plasma

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Aspergillosis

• Oral (cap): 200mg, dly

- Invasive or disseminated disease

• Oral (cap): 200mg, 12hrly

Candidosis

• Oral (cap): 100-200mg, dly

- Invasive or disseminated disease

• Oral (cap): 200mg, 12hrly

Non-meningeal cryptococcosis 

• Oral (cap): 200mg, dly

Cryptococcal meningitis

• Oral (cap): 200mg, dly

Histoplasmosis

• Oral (cap): 200mg, 12-24hrly

Maintenance therapy for penicilliosis and histoplasmosis in AIDS patients

• Oral (cap): 200mg, 12-24hrly; Treatment duration: Based upon status of the immune recovery

Maintenance therapy of cryptococcal meningitis in AIDS patients

• Oral (cap): 200mg, 12hrly; Treatment duration: Based upon status of the immune recovery

Prophylaxis of fungal infections in immunocompromised patients with severe neutropenia

• Oral (cap): 200mg, 12hrly, initiated 1-3 days prior to or at the start of chemotherapy; Treatment duration: Based upon status of the immune recovery

Solution

Oral and/or oesophageal candidosis

• Oral (sol): 200mg, dly, in two intakes or alternatively one intake; Treatment duration: 7 days

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If there is no response after 1 week, treatment should be continued for another week

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Itraconazole sol should be swished around the oral cavity for approximately 20secs and swallowed. There should be no rinsing after swallowing

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Treatment of fluconazole-resistant oral and/or oesophageal candidosis

• Oral (sol): 100-200mg, 12hrly; Treatment duration: 2 weeks

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If there is no response after 2 weeks, continue treatment for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement

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Prophylaxis of fungal infections
- In patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e. <500 cells/µl)

• Oral (sol): 5mg/kg/day, in two intakes, administered immediately prior to cytostatic treatment and generally 1 week before transplant procedure; Treatment duration: Until recovery of neutrophils (>1000 cells/μl)

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Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Itraconazole oral solution

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Treatment duration for systemic fungal infections should be dictated by the mycological and clinical response to therapy

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Itraconazole sol should be taken without food and patients are advised to refrain from eating for at least 1 hour after administration

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It is not recommended that itraconazole capsules and oral solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given

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South African manufacturer recommendations

Capsule

Vulvovaginal candidiasis
- Acute and recurrent

• Oral (cap): 200mg, 12hrly; Treatment duration: 1 day

OR

• Oral (cap): 200mg, dly; Treatment duration: 3 days

- To reduce the incidence of recurrent vulvovaginal candidiasis

• Oral (cap): 200mg, on first day of menstrual cycle; Treatment duration: 6 months

Dermatomycosis

• Oral (cap): 200mg, dly; Treatment duration: 7 days

OR

• Oral (cap): 100mg, dly; Treatment duration: 15 days

Plantar tinea pedis
Palmar tinea manus 

• Oral (cap): 100mg, dly; Treatment duration: 30 days

OR

• Oral (cap): 200mg, 12hrly; Treatment duration: 7 days

Fungal keratitis

• Oral (cap): 200mg, dly; Treatment duration: 21 days, adjusted as per clinical response

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Onychomycosis 
- Continuous treatment

• Oral (cap): 200mg, dly; Treatment duration: 3 months

- Pulse treatment

• Oral (cap): 200mg, 12hrly; Treatment duration: 7 days

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Fingernail infections: 2 pulse treatments
Toenail infections: 3 pulse treatments

Pulse treatments are always separated by a 3-week drug-free interval

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Elimination of itraconazole from skin and nail is slower than from plasma. Optimal clinical mycological effects are thus reached 1 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after cessation of treatment for nail infections

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Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis

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Aspergillosis

• Oral (cap): 200mg, dly; Treatment duration: 2-5 months

- Invasive/disseminated disease

• Oral (cap): 200mg, 12hrly; Treatment duration: 2-5 months

Candidiasis (excluding vulvovaginal)

• Oral (cap): 100-200mg, dly; Treatment duration: 3 weeks - 7 months

- Invasive/disseminated disease

• Oral (cap): 200mg, 12hrly; Treatment duration: 3 weeks - 7 months

Histoplasmosis (excluding meningeal histoplasmosis)

• Oral (cap): 200mg, dly; Treatment duration: 8 months

OR

• Oral (cap): 200mg, 12hrly; Treatment duration: 8 months

OR

• Oral (cap): 400mg, dly; Treatment duration: 8 months

Sporotrichosis (lymphocutaneous and cutaneous)

• Oral (cap): 100mg, dly; Treatment duration 3 months

Paracoccidioidomycosis

• Oral (cap): 100mg, dly; Treatment duration: 6 months

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Data on the efficacy of itraconazole caps at this dosage for treatment of paracoccidioidomycosis in patients with AIDS is not available

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Chromomycosis

• Oral (cap): 100-200mg, dly; Treatment duration: 6 months

Blastomycosis

• Oral (cap): 100mg, dly; Treatment duration: 6 months

OR 

• Oral (cap): 200mg, 12hrly; Treatment duration: 6 months

OR

• Oral (cap): 400mg, dly; Treatment duration: 6 months

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All indications: Duration of treatment should be adjusted depending on clinical response

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Solution

Oral and/or oesophageal candidiasis

• Oral (sol): 200mg, dly, in two intakes or alternatively one intake; Treatment duration: 1 weeks

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If there is no response after 1 week, treatment should be continued for another week

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Prophylaxis of fungal infections
- In patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e. <500 cells/µl)

• Oral (sol): 5mg/kg/day, in two in two intakes, administered immediately prior to cytostatic treatment and generally 1 week before transplant procedure; Treatment duration: Until recovery of neutrophils (>1000 cells/μl)

Forms avail. in SA and covered in this monograph: cap, sol

Paed. dosages below include:

• General dosing range
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by Candida albicans; Candida dubliniensis; Candida tropicalis; Candida parapsilosis; Candida guilliermondii; Blastomyces dermatitidis; Histoplasma capsulatum; Aspergillus spp.; Blastomyces dermatitidis; Cladosporium spp.; Coccidioides immitis; Cryptococcus neoformans; Epidermophyton floccosum; Fonsecaea spp.; Geotrichum spp.; Histoplasma spp.; Malassezia (formerly Pityrosporum) spp.; Microsporum spp.; Paracoccidioides brasiliensis; Penicillium marneffei; Pseudallescheria boydii; Sporothrix schenckii; Trichophyton spp.; Trichosporon spp.

General dosing range

Oral (sol, cap): 5-10mg/kg, 12-24hrly; Max 600mg/24hrs

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

International manufacturer recommendations

• Oral (cap, sol): Not recommended for use

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Clinical data on the use of itraconazole in paediatric patients are limited. The use of itraconazole in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks

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Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes

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South African manufacturer recommendations

Younger than 12 years

• Not recommended for use

12 years and older

• No information available

Pregnancy

• Contraindicated; non-life threatening cases
• Caution; life-threatening cases
• Itraconazole must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus
• In animal studies itraconazole has shown reproduction toxicity
• There is limited information on the use of itraconazole during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with itraconazole has not been established
• Epidemiological data on exposure to itraconazole during the first trimester of pregnancy - mostly in patients receiving short-term treatment for vulvovaginal candidosis - did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens
• Women of childbearing potential taking itraconazole should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of itraconazole therapy

Breastfeeding

• Caution; not recommended
• A very small amount of itraconazole is excreted in human milk. The expected benefits of itraconazole therapy should be weighed against the risks of breastfeeding. In case of doubt, the patient should not breastfeed

Fertility

• In the rat, itraconazole had no effect on male or female fertility at doses which exhibited signs of general toxicity. The effect in humans is unknown

Renal Impairment

• eGFR ≥11-89ml/min: No dose adjustment recommended
• eGFR ≤10ml/min: Caution; dose adjustment recommended
  Avoid multiple doses protocol
  Reduced recommended dose by 50% in patients with concomitant hepatic impairment or on CYP3A4 inhibitors

Hepatic Impairment

• Caution; no dose adjustment recommended
  In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications

Elderly

• Caution; no dose adjustment recommended
  Clinical data on the use of itraconazole in elderly patients are limited. It is advised to use itraconazole in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Peripheral neuropathy
• Paraesthesia
• Hypoaesthesia
• Confusional state
• Somnolence
• Tremor
• Fatigue

Cardiovascular Disorders

• Congestive cardiac failure
• Cardiac failure
• Left ventricular failure
• Tachycardia
• Hypertension
• Hypotension
• Chest pain

Respiratory Disorders

• Dyspnoea
• Cough
• Sinusitis
• Upper respiratory tract infection
• Rhinitis
• Pulmonary oedema
• Dysphonia
• Chest pain

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Dyspepsia
• Constipation
• Flatulence
• Pancreatitis

Hepatobiliary Disorders

• Abnormal hepatic function
• Fatal acute hepatic failure
• Hyperbilirubinaemia
• Serious hepatotoxicity
• Jaundice
• Increased hepatic enzymes
  - Increased alanine aminotransferase
  - Increased aspartate aminotransferase
  - Increased gamma-glutamyltransferase

Genitourinary Disorders

• Menstrual disorder
• Pollakiuria
• Erectile dysfunction
• Renal impairment
• Urinary incontinence
• Abnormal urine analysis
• Increased blood urea

Endocrine and Metabolic Disorders

• Hypertriglyceridaemia
• Hypokalaemia
• Hyperglycaemia
• Hyperkalaemia
• Hypomagnesaemia

Musculoskeletal Disorders

• Myalgia
• Arthralgia
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Pruritus
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Acute generalised exanthematous pustulosis
• Erythema multiforme
• Exfoliative dermatitis
• Leukocytoclastic vasculitis
• Alopecia
• Photosensitivity
• Erythematous rash
• Hyperhidrosis
• Face oedema

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reaction
• Anaphylactoid reaction
• Leukopenia
• Serum sickness
• Angioneurotic oedema
• Oedema
• Fever
• Granulocytopenia
• Thrombocytopenia
• Chills
• Generalised oedema
• Increased blood lactate dehydrogenase

Sensory Disorders

• Dysgeusia
• Visual disturbance
  - Diplopia
  - Blurred vision
• Tinnitus
• Hearing loss (transient or permanent)

Others

• Pain

• CYP3A4 inducers
• Levacetylmethadol (levomethadyl)
• Methadone
• Antiarrhythmics
• Disopyramide
• Dofetilide
• Dronedarone
• Quinidine
• Halofantrine
• Antihistamines
• Astemizole
• Mizolastine
• Terfenadine
• Antimigraine agents
• Ergot alkaloids
• Dihydroergotamine
• Ergometrine (ergonovine)
• Ergotamine
• Methylergometrine (methylergonovine)
• Irinotecan
• Antipsychotics
• Anxiolytics
• Hypnotics
• Lurasidone
• Oral midazolam
• Pimozide
• Sertindole
• Triazolam
• Bepridil
• Felodipine
• Lercanidipine
• Nisoldipine
• Cardiovascular agents
• Ivabradine
• Ranolazine
• Diuretics
• Eplerenone
• Gastrointestinal agents
• Cisapride
• Aprepitant
• Domperidone
• Colchicine
• Isoniazid
• Rifabutin
• Rifampicin
• Carbamazepine
• Phenobarbital
• Phenytoin
• Antivirals
• Efavirenz
• Nevirapine
• CYP3A4 inhibitors
• Ciprofloxacin
• Clarithromycin
• Erythromycin
• Ritonavir-boosted darunavir
• Ritonavir-boosted fosamprenavir
• Indinavir
• Ritonavir
• P-glycoprotein substrates
• Agents that reduce gastric acidity
• Aluminium hydroxide
• H2-receptor antagonists
• Proton-pump inhibitors
• Antibacterials
• Anticonvulsants
• Alpha blockers
• Tamsulosin
• Fentanyl
• Rivaroxaban
• Antineoplastics
• Dasatinib
• Nilotinib
• Trabectedin
• Aliskiren
• Everolimus
• Salmeterol
• Vardenafil
• Alfentanil
• Buprenorphine IV and sublingual
• Oxycodone
• Digoxin
• Anticoagulants
• Antiplatelets
• Coumarins
• Cilostazol
• Dabigatran
• Antidiabetics
• Repaglinide
• Saxagliptin
• Antihelmintics
• Antiprotozoals
• Praziquantel
• Ebastine
• Eletriptan
• Bortezomib
• Busulphan
• Docetaxel
• Erlotinib
• Ixabepilone
• Lapatinib
• Trimetrexate
• Vinca alkaloids
• Alprazolam
• Aripiprazole
• Brotizolam
• Buspirone
• Haloperidol
• Midazolam IV
• Persopirone
• Quetiapine
• Ramelteon
• Risperidone
• Antivirals
• Maraviroc
• Saquinavir
• Nadolol
• Other dihydropyridines
• Calcium channel blockers
• Verapamil
• Immunosuppressants
• Budesonide
• Ciclesonide
• Dexamethasone
• Rapamycin (sirolimus)
• Tacrolimus
• Temsirolimus
• Lipid regulating agents
• Lovastatin
• Simvastatin
• Atorvastation
• Respiratory agents
• Selective serotonin reuptake inhibitors
• Tricyclics and related antidepressants
• Reboxetine
• Urological agents
• Fesoterodine
• Imidafenacin
• Sildenafil
• Solifenacin
• Tadalafil
• Tolterodine
• Alitretinoin (oral formulation)
• Cinacalcet
• Mozavaptan
• Tolvaptan

Other interactions

• St. John's Wort

None routine. Specific cases may require

• Hepatic function
• Renal function
• Serum trough concentrations

Additional observations

• Signs and symptoms of heart failure

Itraconazole, a triazole derivative, has a broad spectrum of activity. Itraconazole inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi. In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

Spectrum of activity: Candida albicans; Candida dubliniensis; Candida tropicalis; Candida parapsilosis; Candida guilliermondii; Blastomyces dermatitidis; Histoplasma capsulatum; Aspergillus spp.; Blastomyces dermatitidis; Cladosporium spp.; Coccidioides immitis; Cryptococcus neoformans; Epidermophyton floccosum; Fonsecaea spp.; Geotrichum spp.; Histoplasma spp.; Malassezia (formerly Pityrosporum) spp.; Microsporum spp.; Paracoccidioides brasiliensis; Penicillium marneffei; Pseudallescheria boydii; Sporothrix schenckii; Trichophyton spp.; Trichosporon spp.

Capsule 100mg

• Adco-Sporozole (Adcock Ingram)
• Mylan Itraconazole (Mylan) 
• Sporanox (Janssen) originator
• Trisporal (Janssen) 

Solution (per ml) 10mg

• Sporanox oral solution (Janssen) originator