Drugs List

Therapeutic Indications

Uses

Oropharyngeal candidiasis: treatment
Prophylaxis of fungal infection in haematopoietic stem cell transplant pts
Prophylaxis of invasive fungal infection in patients receiving chemotherapy
Treatment of aspergillosis when other treatment unsuitable/ineffective
Treatment of chromoblastomycosis when itraconazole unsuitable/ineffective
Treatment of coccidioidomycosis when other treatment unsuitable/ineffective
Treatment of fusariosis when amphotericin unsuitable/ineffective
Treatment of mycetoma when itraconazole unsuitable/ineffective

Treatment of the following invasive fungal infections in adults:
Invasive aspergillosis in patients who are unresponsive or intolerant to amphotericin B or itraconazole.

Fusariosis in patients who are unresponsive or intolerant to amphotericin B.

Chromoblastomycosis and mycetoma in patients who are unresponsive or intolerant to itraconazole.

Coccidioidomycosis in patients who are unresponsive or intolerant to amphotericin B, itraconazole or fluconazole.

'Unresponsive' is defined as the progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.

Oral suspension only
Oropharyngeal candidiasis: as first line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor.

Prophylaxis of invasive fungal infections in the following patients:
Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections.

Haematopoietic stem cell transplant recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.

Contraindications

Children under 18 years
Acute porphyria
Breastfeeding

Precautions and Warnings

Family history of long QT syndrome
Cardiac arrhythmias
Cardiac failure
Cardiomyopathy
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of torsade de pointes
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Long QT syndrome
Pregnancy
Sinus bradycardia

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Not all formulations are licensed for all uses
Treatment to be initiated and supervised by a specialist
Some formulations contain glucose
Adjust dose if switching between solid oral formulations & oral solution
Different oral formulations are not interchangeable (not bioequivalent)
Perform ECG before treatment
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
Monitor ECG in patients at risk of QT prolongation
Monitor electrolytes, esp potassium, magnesium and calcium during therapy
Monitor hepatic function
Monitor pts with severe GI dysfunction for breakthrough fungal infections
Female: Ensure adequate contraception during treatment

The limited data available show that people with hepatic impairment have an increase in plasma exposure compared with those of a normal hepatic function. There have been reports of hepatic reactions during treatment with posaconazole. These reactions included increases in ALT, AST, alkaline phosphatase, and total bilirubin levels and clinical hepatitis. Rarely more severe hepatic reactions with fatal outcomes have been reported, which may be more likely in patients with serious underlying medical conditions. Elevated liver function tests were generally reversible following discontinuation of therapy, and sometimes normalised without interrupting treatment.

Hepatic function (including liver function tests and bilirubin) should be monitored during treatment. Patients who develop abnormal liver functions tests during treatment, should be routinely monitored for the development of more severe hepatic effects. If symptoms of hepatic impairment occur during therapy, consider the discontinuation of posaconazole.

Pregnancy and Lactation

Pregnancy

Use posaconazole with caution during pregnancy.

Briggs suggests, due to the limited human data, posaconazole should be avoided during pregnancy, especially during the first trimester. If the condition requires posaconazole and the benefit is considered to outweigh the potential risk, posaconazole may be given at the lowest possible dose. The manufacturer suggests there are insufficient data on the use of posaconazole in pregnant women. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Due to the molecular weight (about 701), low metabolism and long half-life of posaconazole, it is considered likely that posaconazole will cross the placenta to the foetus.

Animal studies have shown reproductive toxicity, but due to the absence of human clinical experience the risk of toxicity during human pregnancy is unknown.

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 to 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

Posaconazole is contraindicated in breastfeeding.

Briggs suggests the effect of potential exposure to the infant via breast milk is unknown but severe treatment toxicity has been reported in adults. The manufacturer suggests breastfeeding must be stopped on initiation of treatment with posaconazole.

At the time of writing, there are no data on the use of posaconazole during human breastfeeding. Animal studies have shown that posaconazole is excreted in rat milk.

Due to its low molecular weight (about 701), low metabolism (about 17%) and long half-life (range 20 to 66 hours), it is considered likely that posaconazole will be excreted in human breast milk. The effects of posaconazole on a nursing infant are unknown.

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

Adrenal suppression
Alopecia
Altered liver function tests
Anaemia
Anorexia
Arrhythmias
Asterixis
Asthenia
Cardiac disorders
Cerebrovascular accident
Changes of blood pressure
Chills
Cholestasis
Cholestatic hepatitis
Coagulation disorders
Confusion
Convulsions
Decreased gonadotrophins
Depression
Diplopia
Dizziness
Drowsiness
Dry mouth
Electrolyte disturbances
Encephalopathy
Eosinophilia
Facial oedema
Fatigue
Fever
Gastro-intestinal disturbances
Gastro-intestinal haemorrhage
Haemolytic uraemic syndrome
Haemorrhage
Headache
Hearing disturbances
Hepatic damage
Hepatic failure
Hepatic tenderness
Hepatitis
Hepatomegaly
Hepatosplenomegaly
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Hypotension
Ileus
Interstitial nephritis
Interstitial pneumonia
Jaundice
Leucopenia
Lymphadenopathy
Malaise
Menstrual disturbances
Mouth ulcers
Nausea
Neuropathy
Neutropenia
Oedema
Pain
Pancreatitis
Pancytopenia
Paraesthesia
Peripheral neuropathy
Pneumonitis
Psychosis
Pulmonary embolism
Rash
Renal failure
Renal tubular acidosis
Scotoma
Serum creatinine increased
Somnolence
Stevens-Johnson syndrome
Stroke
Syncope
Thrombocytopenia
Thrombosis
Thrombotic thrombocytopenic purpura
Tongue oedema
Torsades de pointes
Tremor
Visual disturbances
Vomiting

Presentation

Oral formulations containing posaconazole

Drugs List

Therapeutic Indications

Uses

Oropharyngeal candidiasis: treatment
Prophylaxis of fungal infection in haematopoietic stem cell transplant pts
Prophylaxis of invasive fungal infection in patients receiving chemotherapy
Treatment of aspergillosis when other treatment unsuitable/ineffective
Treatment of chromoblastomycosis when itraconazole unsuitable/ineffective
Treatment of coccidioidomycosis when other treatment unsuitable/ineffective
Treatment of fusariosis when amphotericin unsuitable/ineffective
Treatment of mycetoma when itraconazole unsuitable/ineffective

Treatment of the following invasive fungal infections in adults:
Invasive aspergillosis in patients who are unresponsive or intolerant to amphotericin B or itraconazole.

Fusariosis in patients who are unresponsive or intolerant to amphotericin B.

Chromoblastomycosis and mycetoma in patients who are unresponsive or intolerant to itraconazole.

Coccidioidomycosis in patients who are unresponsive or intolerant to amphotericin B, itraconazole or fluconazole.

'Unresponsive' is defined as the progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.

Oral suspension only
Oropharyngeal candidiasis: as first line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor.

Prophylaxis of invasive fungal infections in the following patients:
Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections.

Haematopoietic stem cell transplant recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.

Dosage

Adults

Elderly

Contraindications

Children under 18 years
Acute porphyria
Breastfeeding

Precautions and Warnings

Family history of long QT syndrome
Cardiac arrhythmias
Cardiac failure
Cardiomyopathy
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of torsade de pointes
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Long QT syndrome
Pregnancy
Sinus bradycardia

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Not all formulations are licensed for all uses
Treatment to be initiated and supervised by a specialist
Some formulations contain glucose
Adjust dose if switching between solid oral formulations & oral solution
Different oral formulations are not interchangeable (not bioequivalent)
Perform ECG before treatment
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
Monitor ECG in patients at risk of QT prolongation
Monitor electrolytes, esp potassium, magnesium and calcium during therapy
Monitor hepatic function
Monitor pts with severe GI dysfunction for breakthrough fungal infections
Female: Ensure adequate contraception during treatment

The limited data available show that people with hepatic impairment have an increase in plasma exposure compared with those of a normal hepatic function. There have been reports of hepatic reactions during treatment with posaconazole. These reactions included increases in ALT, AST, alkaline phosphatase, and total bilirubin levels and clinical hepatitis. Rarely more severe hepatic reactions with fatal outcomes have been reported, which may be more likely in patients with serious underlying medical conditions. Elevated liver function tests were generally reversible following discontinuation of therapy, and sometimes normalised without interrupting treatment.

Hepatic function (including liver function tests and bilirubin) should be monitored during treatment. Patients who develop abnormal liver functions tests during treatment, should be routinely monitored for the development of more severe hepatic effects. If symptoms of hepatic impairment occur during therapy, consider the discontinuation of posaconazole.

Pregnancy and Lactation

Pregnancy

Use posaconazole with caution during pregnancy.

Briggs suggests, due to the limited human data, posaconazole should be avoided during pregnancy, especially during the first trimester. If the condition requires posaconazole and the benefit is considered to outweigh the potential risk, posaconazole may be given at the lowest possible dose. The manufacturer suggests there are insufficient data on the use of posaconazole in pregnant women. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Due to the molecular weight (about 701), low metabolism and long half-life of posaconazole, it is considered likely that posaconazole will cross the placenta to the foetus.

Animal studies have shown reproductive toxicity, but due to the absence of human clinical experience the risk of toxicity during human pregnancy is unknown.

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 to 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

Posaconazole is contraindicated in breastfeeding.

Briggs suggests the effect of potential exposure to the infant via breast milk is unknown but severe treatment toxicity has been reported in adults. The manufacturer suggests breastfeeding must be stopped on initiation of treatment with posaconazole.

At the time of writing, there are no data on the use of posaconazole during human breastfeeding. Animal studies have shown that posaconazole is excreted in rat milk.

Due to its low molecular weight (about 701), low metabolism (about 17%) and long half-life (range 20 to 66 hours), it is considered likely that posaconazole will be excreted in human breast milk. The effects of posaconazole on a nursing infant are unknown.

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

Adrenal suppression
Alopecia
Altered liver function tests
Anaemia
Anorexia
Arrhythmias
Asterixis
Asthenia
Cardiac disorders
Cerebrovascular accident
Changes of blood pressure
Chills
Cholestasis
Cholestatic hepatitis
Coagulation disorders
Confusion
Convulsions
Decreased gonadotrophins
Depression
Diplopia
Dizziness
Drowsiness
Dry mouth
Electrolyte disturbances
Encephalopathy
Eosinophilia
Facial oedema
Fatigue
Fever
Gastro-intestinal disturbances
Gastro-intestinal haemorrhage
Haemolytic uraemic syndrome
Haemorrhage
Headache
Hearing disturbances
Hepatic damage
Hepatic failure
Hepatic tenderness
Hepatitis
Hepatomegaly
Hepatosplenomegaly
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Hypotension
Ileus
Interstitial nephritis
Interstitial pneumonia
Jaundice
Leucopenia
Lymphadenopathy
Malaise
Menstrual disturbances
Mouth ulcers
Nausea
Neuropathy
Neutropenia
Oedema
Pain
Pancreatitis
Pancytopenia
Paraesthesia
Peripheral neuropathy
Pneumonitis
Psychosis
Pulmonary embolism
Rash
Renal failure
Renal tubular acidosis
Scotoma
Serum creatinine increased
Somnolence
Stevens-Johnson syndrome
Stroke
Syncope
Thrombocytopenia
Thrombosis
Thrombotic thrombocytopenic purpura
Tongue oedema
Torsades de pointes
Tremor
Visual disturbances
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: May 2014

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on April 23, 2014].

Summary of Product Characteristics: Noxafil 100 mg gastro-resistant tablets. Merck Sharp and Dohme. Revised April 2014.
Summary of Product Characteristics: Noxafil 40mg/ml oral suspension. Merck Sharp and Dohme. Revised April 2014.