Drugs List

Therapeutic Indications

Uses

Cushing's syndrome

Treatment of endogenous Cushing's syndrome in adults and adolescents above the age of 12 years.

Contraindications

Children under 12 years
Acute porphyria
Breastfeeding
Galactosaemia
Hepatic disorder
Hepatic enzymes above 2 times the upper limit of normal
Long QT syndrome
Pregnancy
Torsade de pointes

Precautions and Warnings

Family history of long QT syndrome
Females of childbearing potential
Achlorhydria
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
History of hepatic impairment
History of torsade de pointes
Lactose intolerance

Correct electrolyte disorders before treatment
Inflammatory/autoimmune disorder may occur after Cushing's remission
Advise ability to drive/operate machinery may be affected by side effects
Treatment to be initiated and supervised by a specialist
Contains lactose
Monitor hepatic function prior to treatment
Perform ECG before treatment
Adrenal insufficiency suspected: Monitor cortisol and reduce/suspend dose
If adrenal insufficiency occurs, consider corticosteroid cover
Monitor cortisol levels every few days/weeks during treatment initiation
Monitor ECG within 1 week of initiation and then as clinically indicated
Monitor hepatic function every 4 weeks for 6 months, or as indicated
Monitor hepatic function weekly for 1 month after initiation
Monitor LFTs at same frequency as when initiating with any dose increase
Monitor serum electrolytes
Once effective dose is established, monitor cortisol every 3 to 6 months
Advise patient to report signs of hypocortisolism
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Discontinue if hepatitis develops
Discontinue immediately following signs of acute hepatotoxicity
Potentially hepatotoxic
Discontinue if hepatic enzymes are equal to or greater than 3 x ULN
Advise patient not to take paracetamol during treatment
Advise patient not to take St John's wort concurrently
Advise patient to avoid antacids for at least 2 hours after dose
Advise patient to avoid alcohol during treatment
Female: Ensure adequate contraception during treatment
Block and replace regimen: Consider emergency card/glucocorticoid set

Hepatic function

It is required before starting the treatment to measure liver enzymes (AST, ALAT, gammaGT and alkaline phosphatase) and bilirubin.

Patients should be informed about the risk of hepatotoxicity, including to stop treatment and to contact their doctor immediately if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice. abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function tests should be performed.

In the case of an increase in liver enzymes of less than 3 times the upper limit of normal , more frequent monitoring of liver function tests should be performed and the daily dose should be decreased by at least 200mg.

Adrenal function

Adrenal insufficiency can occur:

Under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. in case of stress, surgery, or infection).

In case of ketoconazole overtreatment in patients treated with a block-only regime.

In insufficient glucocorticoid replacement therapy in patients treated with a block-and-replace regimen.

Block and replace regimen

Patients treated with a block-and-replace regime should be taught to adjust their glucocorticoid replacement therapy dose under conditions of stress.

Gastric acidity

Absorption of ketoconazole is impaired with decreased gastric acidity.

In patients with achlorhydria, e.g. certain AIDS patients and those on acid secretion suppressors (such as H2-antagonists, proton pump inhibitors), it is advisable to administer ketoconazole with an acidic beverage e.g. cola, orange juice.

If acid secretion suppressors are added to or removed from the concomitant medication then ketoconazole dose should be adjusted according to cortisol levels.

Treatment of Infections

The CHMP has recommended that the use of oral ketoconazole to treat fungal infections should be suspended. The CHMP concluded that the risk of hepatotoxicity associated with oral ketoconazole is greater than the benefit in treating fungal infections. An alternative available treatment should be used.

Pregnancy and Lactation

Pregnancy

Ketoconazole is contraindicated during pregnancy.

Use of ketoconazole during pregnancy is contraindicated by the manufacturer. Pre-clinical data show that ketoconazole crosses the placenta and is teratogenic.

Animal studies have shown teratogenic effects. There are insufficient data regarding the use of ketoconazole in pregnant women and as such a potential risk cannot be ruled out.

Schaefer reports the use of ketoconazole in several occasions in pregnancy with good maternal and fetal outcome (Schaefer 2015). Also, Schaefer reports some studies showing no evidence of an increased risk of malformation (Schaefer 2015).

Lactation

Ketoconazole is contraindicated during breastfeeding.

The manufacturer suggests because ketoconazole is excreted in breast milk, patients should not breastfeed whilst being treated.

Briggs reports a case where the exposure to ketoconazole on a breastfeed infant did not appear to be clinically significant (Briggs 2015).

LactMed (2018) indicates that if oral ketoconazole is required by the mother, it may not be a reason to discontinue breastfeeding. Taking the dose just before the infant's longest sleep period or avoiding breastfeeding from 2 to 5 hours after the dose might decrease the infant's exposure to ketoconazole.

Side Effects

Abdominal pain
Abnormal liver function tests
Adrenal insufficiency
Alcohol intolerance
Alopecia
Anaphylactic reaction
Anaphylactic shock
Anaphylactoid reaction
Angioedema
Anorexia
Arthralgia
Asthenia
Azoospermia
Bulging fontanelles in infants
Cirrhosis
Decrease in plasma testosterone (transient)
Dermatitis
Diarrhoea
Dizziness
Dry mouth
Dry skin
Dysgeusia
Dyspepsia
Epistaxis
Erectile dysfunction
Erythema
Erythema multiforme
Flatulence
Gynaecomastia
Headache
Hepatic failure
Hepatic impairment
Hepatic necrosis
Hepatitis
Hepatotoxicity
Hot flushes
Hypersensitivity reactions
Increased appetite
Increases in hepatic enzymes
Insomnia
Jaundice
Malaise
Menstrual disturbances
Myalgia
Nausea
Nervousness
Papilloedema
Paraesthesia
Peripheral oedema
Photophobia
Photosensitivity
Pruritus
Pyrexia
Raised intracranial pressure
Rash
Reduced platelet count
Somnolence
Thrombocytopenia
Tongue discolouration
Transient adrenocortical insufficiency
Urticaria
Vomiting

Presentation

Oral formulation of ketoconazole.

Drugs List

Therapeutic Indications

Uses

Cushing's syndrome

Treatment of endogenous Cushing's syndrome in adults and adolescents above the age of 12 years.

Dosage

Ketoconazole daily dose should be periodically adjusted on an individual basis with the aim to normalise urinary free cortisol and/or plasma cortisol levels.

Adults

Children

Additional Dosage Information

Contraindications

Children under 12 years
Acute porphyria
Breastfeeding
Galactosaemia
Hepatic disorder
Hepatic enzymes above 2 times the upper limit of normal
Long QT syndrome
Pregnancy
Torsade de pointes

Precautions and Warnings

Family history of long QT syndrome
Females of childbearing potential
Achlorhydria
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
History of hepatic impairment
History of torsade de pointes
Lactose intolerance

Correct electrolyte disorders before treatment
Inflammatory/autoimmune disorder may occur after Cushing's remission
Advise ability to drive/operate machinery may be affected by side effects
Treatment to be initiated and supervised by a specialist
Contains lactose
Monitor hepatic function prior to treatment
Perform ECG before treatment
Adrenal insufficiency suspected: Monitor cortisol and reduce/suspend dose
If adrenal insufficiency occurs, consider corticosteroid cover
Monitor cortisol levels every few days/weeks during treatment initiation
Monitor ECG within 1 week of initiation and then as clinically indicated
Monitor hepatic function every 4 weeks for 6 months, or as indicated
Monitor hepatic function weekly for 1 month after initiation
Monitor LFTs at same frequency as when initiating with any dose increase
Monitor serum electrolytes
Once effective dose is established, monitor cortisol every 3 to 6 months
Advise patient to report signs of hypocortisolism
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Discontinue if hepatitis develops
Discontinue immediately following signs of acute hepatotoxicity
Potentially hepatotoxic
Discontinue if hepatic enzymes are equal to or greater than 3 x ULN
Advise patient not to take paracetamol during treatment
Advise patient not to take St John's wort concurrently
Advise patient to avoid antacids for at least 2 hours after dose
Advise patient to avoid alcohol during treatment
Female: Ensure adequate contraception during treatment
Block and replace regimen: Consider emergency card/glucocorticoid set

Hepatic function

It is required before starting the treatment to measure liver enzymes (AST, ALAT, gammaGT and alkaline phosphatase) and bilirubin.

Patients should be informed about the risk of hepatotoxicity, including to stop treatment and to contact their doctor immediately if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice. abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function tests should be performed.

In the case of an increase in liver enzymes of less than 3 times the upper limit of normal , more frequent monitoring of liver function tests should be performed and the daily dose should be decreased by at least 200mg.

Adrenal function

Adrenal insufficiency can occur:

Under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. in case of stress, surgery, or infection).

In case of ketoconazole overtreatment in patients treated with a block-only regime.

In insufficient glucocorticoid replacement therapy in patients treated with a block-and-replace regimen.

Block and replace regimen

Patients treated with a block-and-replace regime should be taught to adjust their glucocorticoid replacement therapy dose under conditions of stress.

Gastric acidity

Absorption of ketoconazole is impaired with decreased gastric acidity.

In patients with achlorhydria, e.g. certain AIDS patients and those on acid secretion suppressors (such as H2-antagonists, proton pump inhibitors), it is advisable to administer ketoconazole with an acidic beverage e.g. cola, orange juice.

If acid secretion suppressors are added to or removed from the concomitant medication then ketoconazole dose should be adjusted according to cortisol levels.

Treatment of Infections

The CHMP has recommended that the use of oral ketoconazole to treat fungal infections should be suspended. The CHMP concluded that the risk of hepatotoxicity associated with oral ketoconazole is greater than the benefit in treating fungal infections. An alternative available treatment should be used.

Pregnancy and Lactation

Pregnancy

Ketoconazole is contraindicated during pregnancy.

Use of ketoconazole during pregnancy is contraindicated by the manufacturer. Pre-clinical data show that ketoconazole crosses the placenta and is teratogenic.

Animal studies have shown teratogenic effects. There are insufficient data regarding the use of ketoconazole in pregnant women and as such a potential risk cannot be ruled out.

Schaefer reports the use of ketoconazole in several occasions in pregnancy with good maternal and fetal outcome (Schaefer 2015). Also, Schaefer reports some studies showing no evidence of an increased risk of malformation (Schaefer 2015).

Lactation

Ketoconazole is contraindicated during breastfeeding.

The manufacturer suggests because ketoconazole is excreted in breast milk, patients should not breastfeed whilst being treated.

Briggs reports a case where the exposure to ketoconazole on a breastfeed infant did not appear to be clinically significant (Briggs 2015).

LactMed (2018) indicates that if oral ketoconazole is required by the mother, it may not be a reason to discontinue breastfeeding. Taking the dose just before the infant's longest sleep period or avoiding breastfeeding from 2 to 5 hours after the dose might decrease the infant's exposure to ketoconazole.

Side Effects

Abdominal pain
Abnormal liver function tests
Adrenal insufficiency
Alcohol intolerance
Alopecia
Anaphylactic reaction
Anaphylactic shock
Anaphylactoid reaction
Angioedema
Anorexia
Arthralgia
Asthenia
Azoospermia
Bulging fontanelles in infants
Cirrhosis
Decrease in plasma testosterone (transient)
Dermatitis
Diarrhoea
Dizziness
Dry mouth
Dry skin
Dysgeusia
Dyspepsia
Epistaxis
Erectile dysfunction
Erythema
Erythema multiforme
Flatulence
Gynaecomastia
Headache
Hepatic failure
Hepatic impairment
Hepatic necrosis
Hepatitis
Hepatotoxicity
Hot flushes
Hypersensitivity reactions
Increased appetite
Increases in hepatic enzymes
Insomnia
Jaundice
Malaise
Menstrual disturbances
Myalgia
Nausea
Nervousness
Papilloedema
Paraesthesia
Peripheral oedema
Photophobia
Photosensitivity
Pruritus
Pyrexia
Raised intracranial pressure
Rash
Reduced platelet count
Somnolence
Thrombocytopenia
Tongue discolouration
Transient adrenocortical insufficiency
Urticaria
Vomiting

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 ).

Further Information

Last Full Review Date: April 2020.

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

Summary of Product Characteristics: Ketoconazole HRA 200mg tablets. Laboratoire HRA Pharma. Revised August 2017.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Ketoconazole Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/
Last revised: 03 December 2018.
Last accessed: 25 February 2020.

European Medicines Agency (EMA).
Committee for Medicinal Products for Human Use (CHMP).
Available at: www.ema.europa.eu/en/medicines/human/referrals/ketoconazole-containing-medicines
Last accessed: 06 April 2020.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 25 February 2020.

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last revised: October 2018
Last accessed: 25 February 2020.