Drugs List

Therapeutic Indications

Uses

Treatment of oral and/or oesophageal candidosis in HIV-positive or immunocompromised patients.

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 (<500 cells/microlitre). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

Administration

For oral administration.

For optimal absorption, itraconazole oral solution should be taken without food. Patients should be advised not to consume any food for at least one hour after taking itraconazole oral solution.

Treatment of oral and/or oesophageal candidosis

Swish the oral solution around the oral cavity for approximately 20 seconds and then swallow. The mouth should NOT be rinsed after the solution is swallowed.

Contraindications

Breastfeeding - see Lactation section

Acute porphyria

Hereditary fructose intolerance

Precautions and Warnings

Pregnancy - see Pregnancy section.

Women of childbearing potential should use adequate contraception throughout itraconazole treatment and until the next menstrual period following the end of itraconazole therapy.

A transient asymptomatic decrease of the left ventricular ejection fraction was observed during a healthy volunteer study with intravenous itraconazole.

Itraconazole has been shown to have a negative inotropic effect and it has been associated with reports of congestive heart failure. Itraconazole should not be used in patients with current or a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual risk/benefit assessment should take into consideration factors such as the severity of the infection, the dose, duration of treatment, and individual risk factors for congestive heart failure.
Risk factors for congestive heart failure include:
Cardiac disease
Ischaemic disease
Valvular disease
Significant pulmonary disease such as chronic obstructive pulmonary disease
Renal failure
Other oedematous disorders
These patients should be informed of the signs and symptoms of congestive heart failure. They should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment - see CSM Warnings.
Itraconazole should be discontinued if signs or symptoms of congestive heart failure occur during treatment.
Clinical reports suggest that the risk of congestive heart failure may increase with the total daily dose of itraconazole.

Blood level monitoring should be considered in neutropenic patients particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of itraconazole oral solution.

When itraconazole is used for the prophylaxis of deep fungal infections in neutropenic patients, gastrointestinal tract disturbances (commonly involving diarrhoea) may occur and result in impaired absorption and altered microbiological flora which can favour fungal colonisation. If gastrointestinal disturbances occur, the discontinuation of itraconazole oral solution should be considered.

Itraconazole for the treatment of oral and/or oesophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties, itraconazole oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Itraconazole should be discontinued if neuropathy, which may be due to itraconazole therapy, occurs.

Hepatic impairment - see Dosage; Hepatic Impairment.
Hepatic function should be monitored during treatment.
Serious hepatotoxicity and some cases of fatal acute hepatic failure have occurred rarely with itraconazole use. Some of these cases have involved patients with no pre-existing hepatic impairment. Some cases were observed within the first month of treatment, including some within the first week.
Anorexia, nausea, vomiting, fatigue, abdominal pain, dark urine or other symptoms suggestive of hepatitis should be reported to a physician immediately. If these symptoms occur, itraconazole should be discontinued and hepatic function tested.
Most cases of serious hepatotoxicity involved the following patients:
Patients with pre-existing hepatic impairment
Patients treated for systemic indications
Patients with significant other medical conditions
Patients taking concurrent hepatotoxic drugs

Patients with raised hepatic enzymes, active hepatic impairment or a history of hepatotoxicity due to other drugs should not be treated with itraconazole unless the expected benefits outweigh the risk of hepatic injury. If these patients are treated, hepatic enzymes must be monitored.

Renal impairment - see Dosage; Renal Impairment.

There are inadequate data on the use of itraconazole in elderly patients. Itraconazole should not be used in these patients unless the potential benefits outweigh the risks.

Itraconazole for the treatment of oral and/or oesophageal candidosis in children is not recommended unless the benefits outweigh the risks. Clinical data on the use of itraconazole oral solution in paediatric patients is limited.
For the prophylaxis of deep fungal infections, the efficacy of itraconazole oral solution in neutropenic children has not been established. There is limited safety experience and the incidence of adverse events such as diarrhoea, abdominal pain, vomiting, fever, rash and mucositis was higher than in adults.

Cross hypersensitivity between itraconazole and other azole antifungal agents has not been established. Therefore, patients with hypersensitivity to other azoles should be treated with caution.

Side effects, such as dizziness, visual disturbances and hearing loss may affect the patients ability to drive and operate machinery.

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

St John's wort should not be administered during treatment with itraconazole. A reduction in efficacy is expected up to 2 weeks after discontinuation.

Oral solution contains sorbitol. Should not be taken by patients with hereditary fructose intolerance.

CSM Warnings

Heart Failure
Following rare reports of heart failure, the CSM has advised caution when prescribing itraconazole to patients at high risk of heart failure. Those at risk include:

- patients receiving high doses and longer treatment courses;

- older patients and those with cardiac disease;

- patients receiving treatment with negative inotropic drugs, e.g. calcium channel blockers.

Itraconazole should be avoided in patients with ventricular dysfunction or a history of heart failure unless the infection is serious.

Pregnancy and Lactation

Pregnancy

Due to insufficient human data, the use of itraconazole during pregnancy is not recommended unless the disease is life-threatening and involves systemic fungal infection, and when the potential benefit outweighs the potential harm to the foetus.

The little available human data suggests that there is a low risk of harm to the foetus if itraconazole therapy is inadvertently exposed or require during the first trimester of pregnancy. A detailed ultrasound should be considered after treatment with itraconazole is completed.

Animal studies with itraconazole have demonstrated an increased incidence of foetal abnormalities and adverse effects on the foetus. Human studies do not suggest that itraconazole presents a significant risk for major anomalies of the foetus, however, there is little experience in this area and no studies have been conducted which observe the risk of minor abnormalities or late-appearing major defects. It is unknown whether itraconazole crosses the human placenta, however, due to its low molecular weight passage to the foetus should be expected.

Women of childbearing potential should use adequate contraception throughout itraconazole treatment and until the next menstrual period following the end of itraconazole therapy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Itraconazole is excreted in human milk. Treatment of breastfeeding mothers with itraconazole is not recommended.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Nausea
Vomiting
Abdominal pain
Dyspepsia
Diarrhoea
Constipation
Headache
Dizziness
Hypersensitivity reactions
Peripheral neuropathy
Pruritus
Rash
Urticaria
Alopecia
Angioedema
Stevens-Johnson syndrome
Menstrual disturbances
Oedema
Congestive cardiac failure
Pulmonary oedema
Hypokalaemia
Acute hepatic failure
Hepatotoxicity
Hepatitis
Increases in hepatic enzymes (reversible)
Anaphylaxis
Leukopenia
Neutropenia
Thrombocytopenia
Serum sickness
Hypertriglyceridaemia
Paraesthesia
Hypoaesthesia
Visual disturbances
Blurred vision
Diplopia
Tinnitus
Dysgeusia
Hyperbilirubinaemia
Toxic epidermal necrolysis
Erythema multiforme
Exfoliative dermatitis
Leukocytoclastic vasculitis
Photosensitivity
Myalgia
Arthralgia
Pollakiuria
Urinary incontinence
Erectile dysfunction
Hearing loss
Pyrexia
Pancreatitis
Dyspnoea
Acute generalised exanthematous pustulosis

Presentation

Oral solution containing itraconazole 10mg/ml

Drugs List

Therapeutic Indications

Uses

Treatment of oral and/or oesophageal candidosis in HIV-positive or immunocompromised patients.

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 (<500 cells/microlitre). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

Dosage

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Administration

For oral administration.

For optimal absorption, itraconazole oral solution should be taken without food. Patients should be advised not to consume any food for at least one hour after taking itraconazole oral solution.

Treatment of oral and/or oesophageal candidosis

Swish the oral solution around the oral cavity for approximately 20 seconds and then swallow. The mouth should NOT be rinsed after the solution is swallowed.

Contraindications

Breastfeeding - see Lactation section

Acute porphyria

Hereditary fructose intolerance

Precautions and Warnings

Pregnancy - see Pregnancy section.

Women of childbearing potential should use adequate contraception throughout itraconazole treatment and until the next menstrual period following the end of itraconazole therapy.

A transient asymptomatic decrease of the left ventricular ejection fraction was observed during a healthy volunteer study with intravenous itraconazole.

Itraconazole has been shown to have a negative inotropic effect and it has been associated with reports of congestive heart failure. Itraconazole should not be used in patients with current or a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual risk/benefit assessment should take into consideration factors such as the severity of the infection, the dose, duration of treatment, and individual risk factors for congestive heart failure.
Risk factors for congestive heart failure include:
Cardiac disease
Ischaemic disease
Valvular disease
Significant pulmonary disease such as chronic obstructive pulmonary disease
Renal failure
Other oedematous disorders
These patients should be informed of the signs and symptoms of congestive heart failure. They should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment - see CSM Warnings.
Itraconazole should be discontinued if signs or symptoms of congestive heart failure occur during treatment.
Clinical reports suggest that the risk of congestive heart failure may increase with the total daily dose of itraconazole.

Blood level monitoring should be considered in neutropenic patients particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of itraconazole oral solution.

When itraconazole is used for the prophylaxis of deep fungal infections in neutropenic patients, gastrointestinal tract disturbances (commonly involving diarrhoea) may occur and result in impaired absorption and altered microbiological flora which can favour fungal colonisation. If gastrointestinal disturbances occur, the discontinuation of itraconazole oral solution should be considered.

Itraconazole for the treatment of oral and/or oesophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties, itraconazole oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Itraconazole should be discontinued if neuropathy, which may be due to itraconazole therapy, occurs.

Hepatic impairment - see Dosage; Hepatic Impairment.
Hepatic function should be monitored during treatment.
Serious hepatotoxicity and some cases of fatal acute hepatic failure have occurred rarely with itraconazole use. Some of these cases have involved patients with no pre-existing hepatic impairment. Some cases were observed within the first month of treatment, including some within the first week.
Anorexia, nausea, vomiting, fatigue, abdominal pain, dark urine or other symptoms suggestive of hepatitis should be reported to a physician immediately. If these symptoms occur, itraconazole should be discontinued and hepatic function tested.
Most cases of serious hepatotoxicity involved the following patients:
Patients with pre-existing hepatic impairment
Patients treated for systemic indications
Patients with significant other medical conditions
Patients taking concurrent hepatotoxic drugs

Patients with raised hepatic enzymes, active hepatic impairment or a history of hepatotoxicity due to other drugs should not be treated with itraconazole unless the expected benefits outweigh the risk of hepatic injury. If these patients are treated, hepatic enzymes must be monitored.

Renal impairment - see Dosage; Renal Impairment.

There are inadequate data on the use of itraconazole in elderly patients. Itraconazole should not be used in these patients unless the potential benefits outweigh the risks.

Itraconazole for the treatment of oral and/or oesophageal candidosis in children is not recommended unless the benefits outweigh the risks. Clinical data on the use of itraconazole oral solution in paediatric patients is limited.
For the prophylaxis of deep fungal infections, the efficacy of itraconazole oral solution in neutropenic children has not been established. There is limited safety experience and the incidence of adverse events such as diarrhoea, abdominal pain, vomiting, fever, rash and mucositis was higher than in adults.

Cross hypersensitivity between itraconazole and other azole antifungal agents has not been established. Therefore, patients with hypersensitivity to other azoles should be treated with caution.

Side effects, such as dizziness, visual disturbances and hearing loss may affect the patients ability to drive and operate machinery.

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

St John's wort should not be administered during treatment with itraconazole. A reduction in efficacy is expected up to 2 weeks after discontinuation.

Oral solution contains sorbitol. Should not be taken by patients with hereditary fructose intolerance.

CSM Warnings

Heart Failure
Following rare reports of heart failure, the CSM has advised caution when prescribing itraconazole to patients at high risk of heart failure. Those at risk include:

- patients receiving high doses and longer treatment courses;

- older patients and those with cardiac disease;

- patients receiving treatment with negative inotropic drugs, e.g. calcium channel blockers.

Itraconazole should be avoided in patients with ventricular dysfunction or a history of heart failure unless the infection is serious.

Pregnancy and Lactation

Pregnancy

Due to insufficient human data, the use of itraconazole during pregnancy is not recommended unless the disease is life-threatening and involves systemic fungal infection, and when the potential benefit outweighs the potential harm to the foetus.

The little available human data suggests that there is a low risk of harm to the foetus if itraconazole therapy is inadvertently exposed or require during the first trimester of pregnancy. A detailed ultrasound should be considered after treatment with itraconazole is completed.

Animal studies with itraconazole have demonstrated an increased incidence of foetal abnormalities and adverse effects on the foetus. Human studies do not suggest that itraconazole presents a significant risk for major anomalies of the foetus, however, there is little experience in this area and no studies have been conducted which observe the risk of minor abnormalities or late-appearing major defects. It is unknown whether itraconazole crosses the human placenta, however, due to its low molecular weight passage to the foetus should be expected.

Women of childbearing potential should use adequate contraception throughout itraconazole treatment and until the next menstrual period following the end of itraconazole therapy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Itraconazole is excreted in human milk. Treatment of breastfeeding mothers with itraconazole is not recommended.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

No studies are available on the effect of itraconazole on driving or operating machinery. However, dizziness, hearing loss, and visual disturbances have been reported as adverse events and patients suffering from these events should avoid driving or operating machinery.

Counselling

Advise patients to report anorexia, nausea, vomiting, fatigue, abdominal pain, dark urine or other symptoms suggestive of hepatitis to a physician immediately.

Patients should be advised that side effects such as dizziness and visual disturbances may affect their ability to drive or operate machinery.

Advise patients not to take St John's wort concurrently with this medicine.

Side Effects

Nausea
Vomiting
Abdominal pain
Dyspepsia
Diarrhoea
Constipation
Headache
Dizziness
Hypersensitivity reactions
Peripheral neuropathy
Pruritus
Rash
Urticaria
Alopecia
Angioedema
Stevens-Johnson syndrome
Menstrual disturbances
Oedema
Congestive cardiac failure
Pulmonary oedema
Hypokalaemia
Acute hepatic failure
Hepatotoxicity
Hepatitis
Increases in hepatic enzymes (reversible)
Anaphylaxis
Leukopenia
Neutropenia
Thrombocytopenia
Serum sickness
Hypertriglyceridaemia
Paraesthesia
Hypoaesthesia
Visual disturbances
Blurred vision
Diplopia
Tinnitus
Dysgeusia
Hyperbilirubinaemia
Toxic epidermal necrolysis
Erythema multiforme
Exfoliative dermatitis
Leukocytoclastic vasculitis
Photosensitivity
Myalgia
Arthralgia
Pollakiuria
Urinary incontinence
Erectile dysfunction
Hearing loss
Pyrexia
Pancreatitis
Dyspnoea
Acute generalised exanthematous pustulosis

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

Store at or below 25 degrees C

Further Information

Last Full Review Date: November 2011

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8th edition (2008) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Sporanox 10mg/ml oral solution. Janssen-Cilag Ltd. Revised Decmeber 2017
Summary of Product Characteristics: Itraconazole 10mg/ml oral solution. Beacon Pharmaceuticals. Revised November 2016.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

NICE Evidence Services Available at: www.nice.org.uk Last accessed:11 September 2017

The Drug Database for acute Porphyria (NAPOS)
Available at: https://www.drugs-porphyria.com/languages/UnitedKingdom/index2.php?l=gbr
Itraconazole Last revised: October 1, 2004
Last accessed: November 10, 2011