Voriconazole

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:

• Invasive aspergillosis
• Serious invasive infections caused by Candida spp. (including C. krusei)
• Serious fungal infections caused by Scedosporium spp. and Fusarium spp.
• Prevention of breakthrough of fungal infections in febrile high-risk patients (allogentic bone marrow transplants, relapsed leukaemia patients) where liposomal amphotericin B cannot be used

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Prolonged QT syndrome
• Pregnancy
• Breastfeeding
• Severe impairment of hepatic function (Child-Pugh Class C)
• Coadministration with the CYP3A4 substrates
  • Terfenadine, astemizole, cisapride, pimozide, quinidine or ivabradine
  • Ergot alkaloids (ergotamine, dihydroergotamine)
  • Naloxegol
• Coadministration with
  • Rifampicin, carbamazepine, phenobarbital and St John’s Wort
  • Sirolimus
  • Rifabutin
  • Tolvaptan
  • Lurasidone
• Coadministration of standard doses of voriconazole with efavirenz doses of 400mg once daily or higher
• Coadministration of voriconazole with high dose ritonavir (400mg and above twice daily)
• Coadministration with venetoclax at initiation and during the venetoclax dose titration phase

Cautions

• Moderate to severe renal impairment (CrCl<50 ml/min)(inj)
• Hepatic impairment (Child-Pugh Class A and B)
• Patients with hypersensitivity to other azoles
• Prolonged duration (> 6 months)
• QT prolongation or risk factors thereof
• Cardiomyopathy
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Exposure to direct sunlight
• Sodium controlled diet (inj)
• Galactose intolerance (tab)
• Lapp lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)

Forms avail. in SA and covered in this monograph: tab, inj

Infections caused by: Candida Spp., Aspergillus spp., Scedosporium spp. and Fusarium spp.

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

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant recipients
Invasive aspergillosis 
Candidaemia in non-neutropaenic patients
Fluconazle-resistant serious invasive Candida infections
Serious fungal infections caused by Scedosporium spp. and Fusarium spp.

• IV: Loading dose: 6mg/kg, 12hrly for first 24hrs; Maintenance: 3-4mg/kg, 12hrly

< 40kg

• Oral (tab): Loading dose: 200mg, 12hrly for first 24hrs; Maintenance: 100mg, 12hrly; Max: 150mg, 12hrly

> 40kg

• Oral (tab): Loading dose: 400mg, 12hrly for first 24hrs; Maintenance: 200mg, 12hrly; Max: 300mg, 12hrly

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Initiate on the day of transplant, Treatment duration: 100-180 days

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Correct any electrolyte disturbances prior to initiating therapy

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IV: Max rate: 3mg/kg/hr over 1-3hrs

---

See additional prescribing points for dosage adjustment recommendations

Paed. forms avail. in SA and covered in this monograph: tab, inj

Infections caused by: Candida Spp., Aspergillus spp., Scedosporium spp. and Fusarium spp.

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

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant recipients
Invasive aspergillosis 
Candidaemia in non-neutropaenic patients
Fluconazle-resistant serious invasive Candida infections
Serious fungal infections caused by Scedosporium spp. and Fusarium spp.

Younger than 2 years

• Not established for use

Between 2-12 years

• IV: Loading dose: 6-9mg/kg, 12hrly for first 24hrs; Maintenance: 4-8mg/kg, 12hrly
• Oral (tab): Loading dose: Not recommended; Maintenance: 9mg/kg, 12hrly; Max: 350mg, 12hrly

Older than 12 years

• See adult dosage

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Children between 12-14 years who weigh < 50kg should receive paediatric dosages 

---

Initiate on the day of transplant; Treatment duration: 100-180 days

---

Correct any electrolyte disturbances prior to initiating therapy

---

IV: Max rate: 3mg/kg/hr over 1-3hrs

---

See additional prescribing points for dosage adjustment recommendations

 Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Renal Impairment

• Oral (tab): No dose adjustment recommended
• IV: CrCl ≥50 ml/min: No dose adjustment recommended
• IV: CrCl <50 ml/min: Caution; no dose adjustment recommended
  Accumulation of the intravenous vehicle usually occurs
  Serum creatinine levels should be closely monitored and, if increases occur, consideration should be given to changing to oral voriconazole therapy
  Haemodialysis: Poorly dialysable; No adjustment necessary

Hepatic Impairment

• Child-Pugh Class A and B: Caution; dose adjustment recommended
  Loading dose: No adjustment necessary; Maintenance: Reduce dose by 50%
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Hallucination
• Anxiety
• Insomnia
• Agitation
• Confusion
• Headache
• Seizures
• Syncope
• Tremor
• Hypertonia
• Paraesthesia
• Somnolence
• Dizziness
• Brain oedema
• Encephalopathy
• Extrapyramidal disorder
• Neuropathy peripheral
• Ataxia
• Hypoaesthesia
• Dysgeusia
• Hepatic encephalopathy
• Guillain-Barre syndrome
• Nystagmus
• Asthenia

Cardiovascular Disorders

• Supraventricular arrhythmia
• Tachycardia
• Bradycardia
• Ventricular fibrillation 
• Ventricular extrasystoles
• Ventricular tachycardia
• QT prolongation
• Supraventricular tachycardia
• Torsades de pointes
• Atrioventricular block complete
• Bundle branch block
• Nodal rhythm
• Hypotension
• Phlebitis
• Thrombophlebitis
• Lymphangitis
• Chest pain

Respiratory Disorders

• Respiratory distress
• Acute respiratory distress syndrome
• Pulmonary oedema
• Sinusitis 

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Cheilitis
• Dyspepsia
• Constipation
• Gingivitis
• Peritonitis
• Pancreatitis
• Swollen tongue
• Duodenitis
• Gastroenteritis
• Glossitis

Hepatobiliary Disorders

• Abnormal hepatic function tests
• Jaundice
• Cholestatic jaundice
• Hepatitis
• Hepatic failure
• Hepatomegaly
• Cholecystitis
• Cholelithiasis

Genitourinary Disorders

• Renal failure
• Haematuria
• Renal tubular necrosis
• Proteinuria
• Nephritis
• Increased blood creatinine
• Increased blood urea 

Endocrine and Metabolic Disorders

• Adrenal insufficiency
• Hypothyroidism
• Hyperthyroidism
• Peripheral oedema 
• Hypoglycaemia
• Hypokalaemia
• Hyponatraemia
• Increased blood cholesterol 

Musculoskeletal Disorders

• Back pain
• Arthritis
• Periostitis

Skin and Subcutaneous Tissue Disorders

• Rash
• Exfoliative dermatitis
• Alopecia
• Maculo-papular rash
• Pruritus
• Erythema
• Stevens-Johnson syndrome
• Phototoxicity
• Purpura
• Urticaria
• Allergic dermatitis
• Papular rash
• Macular rash
• Eczema
• Toxic epidermal necrolysis
• Angioedema
• Actinic keratosis
• Pseudoporphyria erythema multiforme
• Psoriasis
• Drug eruption
• Cutaneous lupus erythematosus
• Ephelides
• Lentigo
• Infusion site reaction

Immune, Blood and Lymphatic System Disorders

• Pseudomembranous colitis
• Benign, malignant and unspecified neoplasms
• Squamous cell carcinoma
• Agranulocytosis
• Pancytopenia
• Thrombocytopenia
• Leukopenia
• Anaemia
• Bone marrow failure
• Lymphadenopathy
• Eosinophilia
• Disseminated intravascular coagulation
• Immune system disorders
• Hypersensitivity
• Anaphylactoid reaction
• Pyrexia

Sensory Disorders

• Visual impairment
• Retinal haemorrhage
• Optic nerve disorder
• Papilloedema
• Oculogyric crisis
• Diplopia
• Scleritis
• Blepharitis
• Optic atrophy
• Corneal opacity
• Hypoacusis
• Vertigo
• Tinnitus

• CYP3A4 substrates
• Terfenadine
• Astemizole
• Cisapride
• Pimozide
• Quinidine
• Ivabradine
• Rifampicin
• Carbamazepine
• Phenobarbital
• Efavirenz (400mg once daily or higher)
• Ritonavir (400mg and above twice daily)
• Ergot alkaloids (ergotamine, dihydroergotamine)
• Sirolimus
• Rifabutin
• Naloxegol
• Tolvaptan
• Lurasidone
• Venetoclax
• CYP450 inducers
• CYP3A4 inhibitors
• CYP2C19 inhibitors 
• CYP2C19 inducers 
• CYP2C9 inhibitors 
• CYP2C9 inducers 
• Anticoagulants
• Non-steroidal anti-inflammatory drugs
• Sulfonylureas 
• Digoxin 
• UDP-glucuronyl transferase substrate
• Ranitidine 
• QT prolonging agents

Other interactions

• St John’s Wort

• Hepatic function
• Renal function
• Electrolytes
• Ophthalmic examination

Specific cases may require

• Pancreatic function

Dosage adjustment

Adults

• IV: If patient unable to tolerate 4mg/kg, 12hrly; reduce to 3mg/kg, 12hrly
• Oral: if patient unable to tolerate higher doses, reduce oral dose increments of 50mg to 200mg, 12hrly (or 100mg, 12hrly if patient <40kg)

Children

• If response to treatment is inadequate, increase dose in increments of 1mg/kg (OR in 50mg increments if max of 350mg used initially) 
• If patient unable to tolerate treatment, reduce in increments of 1mg/kg steps (OR in increments of 50mg if initial of 350mg used)

Coadministration with phenytoin

• Maintenance dose of voriconazole must be increased from 200mg to 400mg orally, 12hrly (100mg to 200mg orally, 12hrly in patients < 40kg)

Coadministration with rifabutin

• Avoid if posssible
• Maintenance dose of voriconazole must be increased from 200mg to 350mg orally, 12hrly (100mg to 200mg orally, 12hrly in patients <40kg)

Coadministration with efavirenz

• Maintenance dose of voriconazole must be increased to 400mg, 12hrly and the efavirenz dose must be reduced by 50%. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored

Voriconazole is a broad spectrum triazole antifungal agent. Its mode of action is inhibition of fungal cytochrome P450-mediated 14-sterol demethylation, an essential step in ergosterol biosynthesis.

Spectrum of activity: Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp.

Tablet 50mg

• Vfend (Pfizer) originator

Tablet 200mg

• Vfend (Pfizer) originator

Injection (per vial) 200mg

• Vcide 200 IV (Abex Pharmaceutica)
• Vfend (Pfizer) originator
• Vondip IV 200mg (Pharma Dynamics)
• Vorifend IV (Activo Health)
• Vorzol IV (Sandoz SA)