Drugs List

Therapeutic Indications

Uses

Malignant conditions

Administration

To be administered by intravenous injection or infusion.

Ifosfamide should only be used with the concurrent administration of mesna to protect against urothelial toxicity. Where intravenous injection of ifosfamide is used (rather than infusion) additional doses of mesna may be required. This is particularly the case in children, those with previous urothelial damage and those who are not adequately protected by standard mesna doses.

Contraindications

Acute infection
Leucocyte count below 4 x 10 to the power of 9 / L
Platelet count below 100 x 10 to the power of 9/ L
Breastfeeding
Dehydration
Haemorrhagic cystitis
Hepatic impairment
Myelosuppression
Porphyria
Pregnancy
Renal impairment - serum creatinine above 120micromol/l
Urinary obstruction
Urinary tract infection

Precautions and Warnings

Children under 18 years
Elderly
History of platin treatment
Obesity
Cardiac disorder
Diabetes mellitus
Electrolyte imbalance
Renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Consider diuretic if inadequate urinary output
Consider risk factors for CNS toxicity prior to initiating
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Prophylactic G-CSF should be considered
Treatment to be prescribed under the supervision of a specialist
Staff: Not to be handled by breastfeeding staff
Staff: Not to be handled by pregnant staff
Monitor haematological parameters before and during treatment
Urinalysis required pre and post treatment
Monitor for haematuria 4 hourly during treatment
Monitor for proteinuria 4 hourly during treatment
Advise patient to report signs or symptoms of cystitis
Concurrent mesna required to limit urothelial toxicity
May affect immune response to live vaccines
Prophylactic antiemetic recommended before each dose
Reactivation of latent chronic infections may occur
Secondary tumours may occur as long-term sequelae
Stop treatment if CNS toxicity suspected and provide supportive therapy
Discontinue if hypertensive encephalopathy occurs
Interrupt therapy if urinary tract infection occurs
Suspend treatment if leucocytes fall below 4,000/cubic mm
Suspend treatment if platelets fall below 100,000/cubic mm
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Male & female: May cause infertility
Female: Contraception required during and for 1 year after treatment
Male: Contraception required during and for 6 months after treatment
Advise increased fluid intake for 24-48 hours post treatment
Advise patient of need for high oral hygiene standards

Dose selection for elderly patients should be cautious due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease and/or other drug therapy.

Patients should maintain adequate hydration prior to and during treatment. Fluid intake of patients on intermittent regimens should be at least 2 litres in 24 hours.

Concurrent mesna is required to limit urothelial toxicity. Where ifosfamide is used as an intravenous bolus, increased doses of mesna are recommended in children, patients whose urothelium may be damaged from previous therapies and those who are not adequately protected by the standard dose of mesna.

The risk of myelosuppression is dose dependent; a single high dose carries a greater risk than fractionated administration. The risk of myelosuppression is also higher in patients with renal impairment. Administration of ifosfamide is associated with a reduction in the leukocyte count. The leukocyte nadir is usually seen during the second week after administration, after which, the leukocyte count rises again. Close haematological monitoring is advised; including white blood cell count, platelet count and haemoglobin levels. These should be obtained prior to each administration of ifosfamide and at regular intervals during therapy.

Ifosfamide may cause CNS toxicity and other neurotoxic effects. This may become evident within a few hours to a few days after the initial administration and usually resolves within 48 to 72 hours of ifosfamide discontinuation. In addition to dose dependant CNS toxicity, other supplementary risk factors may increase a patients possibility of CNS toxicity. These risk factors include electrolyte imbalances, presence of brain metastases, previous CNS disease, brain irradiation, cerebral sclerosis and peripheral vasculopathy. Also, a lower abdomen tumour, bulky abdomen disease, poor performance status, advanced age, obesity and female gender may affect an individuals potential to experience CNS toxicity.

The risk of developing cardiotoxic effects is dose dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

The risk of haemorrhagic cystitis is dose dependent; a single high dose carries a greater risk than fractionated administration.

Girls who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Some degree of testicular atrophy may occur. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Pregnancy and Lactation

Pregnancy

Ifosfamide is contraindicated in pregnancy.

There is limited data available on the use of ifosfamide during pregnancy. Foetal growth retardation and neonatal anaemia have been reported in infants of mothers who received ifosfamide-containing chemotherapy regimes. Congenital deviations in infants have been reported in cases where the mother received ifosfamide during the first trimester of pregnancy.

Based on animal studies, human case reports and ifosfamide's mechanism of action, it is advised not to use ifosfamide during pregnancy, particularly during the first trimester. The benefit for the mother will need to be assessed against the risk for the foetus. The pregnant patient should be counselled on the potential risk to the foetus.

Animal data generated with cyclophosphamide, another oxazaphosphorine cytotoxic agent, suggests that an increased risk of failed pregnancy and malformations may remain even after treatment with the agent has ceased as long as the oocytes/follicles exist that were in any maturation phase when exposed to the agent.

Ifosfamide has been shown to be teratogenic in three species of animal and also to be both mutagenic and carcinogenic. Due to this and the similarity with cyclophosphamide, a known human teratogen, ifosfamide should be considered to have a high potential for human teratogenicity and embryo/foetal toxicity (Briggs, 2015).

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

Ifosfamide is contraindicated in breastfeeding.

Ifosfamide is excreted in breast milk and may cause neutropenia, thrombocytopenia, low haemoglobin concentrations and diarrhoea in the nursing infant.

Hale (2014) suggests withholding breastfeeding for at least 72 hours.

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

Acute respiratory distress syndrome
Alopecia
Amenorrhoea
Anaemia
Angina pectoris
Angioedema
Arthralgia
Asterixis
Blood pressure changes
Capillary leak syndrome
Cardiac arrest
Cardiomyopathy
Cardiovascular disturbances
Cardiovascular toxicity
Chills
CNS toxicity
Confusion
Conjunctivitis
Convulsions
Cough
Cytolytic hepatitis
Deafness
Decreased appetite
Deep vein thrombosis (DVT)
Dermatitis
Diabetes insipidus
Disorientation
Drowsiness
Dyspnoea
ECG changes
Echolalia
Enuresis
Erythema
Eye irritation
Facial swelling
Flushing
Gastrointestinal disorder
Growth retardation (children)
Haematological disorders
Haematuria
Haemolytic uraemic syndrome
Haemorrhagic cystitis
Hepatic veno-occlusive disease
Hepatotoxicity
Hyperhidrosis
Hyperpigmentation of skin
Hypersensitivity reactions
Hypoxia
Immunosuppression
Impaired gonadal function
Impaired vision
Inappropriate secretion of antidiuretic hormone
Infections
Infertility
Interstitial lung disease
Jaundice
Local reaction at injection site
Malaise
Mental status changes
Metabolic acidosis
Multiorgan failure
Muscle twitch
Myalgia
Myelosuppression
Myocardial infarction
Neuralgia
Oedema
Osteomalacia
Palmar-plantar erythrodysaesthesia
Peripheral neuropathy
Perseveration
Phlebitis
Pleural effusion
Pneumonitis
Polydipsia
Polyuria
Portal vein thrombosis
Premature menopause
Pulmonary embolism
Pulmonary hypertension
Pulmonary oedema
Pyrexia
Radiation recall dermatitis
Rash
Renal disorders
Renal structural changes
Respiratory failure
Restlessness
Rhabdomyolysis
Rickets
Risk of secondary tumours as late sequelae
Skin necrosis
Stevens-Johnson syndrome
Tinnitus
Toxic epidermal necrolysis
Tumour lysis syndrome
Urothelial toxicity
Urticaria
Vasculitis
Vertigo

Presentation

Ifosfamide for parenteral use

Drugs List

Therapeutic Indications

Uses

Malignant conditions

Dosage

Due to the complexity and specialist nature of dosage regimens for the treatment of malignant disease, specific dosing information on this agent is not included.
Doses may vary significantly if this agent is used as monotherapy or different combinations.
When using this agent, specialist literature, national guidelines, cancer network protocols and Trust chemotherapy protocols should be consulted.

Patients with Renal Impairment

Patients with Hepatic Impairment

Administration

To be administered by intravenous injection or infusion.

Ifosfamide should only be used with the concurrent administration of mesna to protect against urothelial toxicity. Where intravenous injection of ifosfamide is used (rather than infusion) additional doses of mesna may be required. This is particularly the case in children, those with previous urothelial damage and those who are not adequately protected by standard mesna doses.

Contraindications

Acute infection
Leucocyte count below 4 x 10 to the power of 9 / L
Platelet count below 100 x 10 to the power of 9/ L
Breastfeeding
Dehydration
Haemorrhagic cystitis
Hepatic impairment
Myelosuppression
Porphyria
Pregnancy
Renal impairment - serum creatinine above 120micromol/l
Urinary obstruction
Urinary tract infection

Precautions and Warnings

Children under 18 years
Elderly
History of platin treatment
Obesity
Cardiac disorder
Diabetes mellitus
Electrolyte imbalance
Renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Consider diuretic if inadequate urinary output
Consider risk factors for CNS toxicity prior to initiating
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Prophylactic G-CSF should be considered
Treatment to be prescribed under the supervision of a specialist
Staff: Not to be handled by breastfeeding staff
Staff: Not to be handled by pregnant staff
Monitor haematological parameters before and during treatment
Urinalysis required pre and post treatment
Monitor for haematuria 4 hourly during treatment
Monitor for proteinuria 4 hourly during treatment
Advise patient to report signs or symptoms of cystitis
Concurrent mesna required to limit urothelial toxicity
May affect immune response to live vaccines
Prophylactic antiemetic recommended before each dose
Reactivation of latent chronic infections may occur
Secondary tumours may occur as long-term sequelae
Stop treatment if CNS toxicity suspected and provide supportive therapy
Discontinue if hypertensive encephalopathy occurs
Interrupt therapy if urinary tract infection occurs
Suspend treatment if leucocytes fall below 4,000/cubic mm
Suspend treatment if platelets fall below 100,000/cubic mm
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Male & female: May cause infertility
Female: Contraception required during and for 1 year after treatment
Male: Contraception required during and for 6 months after treatment
Advise increased fluid intake for 24-48 hours post treatment
Advise patient of need for high oral hygiene standards

Dose selection for elderly patients should be cautious due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease and/or other drug therapy.

Patients should maintain adequate hydration prior to and during treatment. Fluid intake of patients on intermittent regimens should be at least 2 litres in 24 hours.

Concurrent mesna is required to limit urothelial toxicity. Where ifosfamide is used as an intravenous bolus, increased doses of mesna are recommended in children, patients whose urothelium may be damaged from previous therapies and those who are not adequately protected by the standard dose of mesna.

The risk of myelosuppression is dose dependent; a single high dose carries a greater risk than fractionated administration. The risk of myelosuppression is also higher in patients with renal impairment. Administration of ifosfamide is associated with a reduction in the leukocyte count. The leukocyte nadir is usually seen during the second week after administration, after which, the leukocyte count rises again. Close haematological monitoring is advised; including white blood cell count, platelet count and haemoglobin levels. These should be obtained prior to each administration of ifosfamide and at regular intervals during therapy.

Ifosfamide may cause CNS toxicity and other neurotoxic effects. This may become evident within a few hours to a few days after the initial administration and usually resolves within 48 to 72 hours of ifosfamide discontinuation. In addition to dose dependant CNS toxicity, other supplementary risk factors may increase a patients possibility of CNS toxicity. These risk factors include electrolyte imbalances, presence of brain metastases, previous CNS disease, brain irradiation, cerebral sclerosis and peripheral vasculopathy. Also, a lower abdomen tumour, bulky abdomen disease, poor performance status, advanced age, obesity and female gender may affect an individuals potential to experience CNS toxicity.

The risk of developing cardiotoxic effects is dose dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

The risk of haemorrhagic cystitis is dose dependent; a single high dose carries a greater risk than fractionated administration.

Girls who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Some degree of testicular atrophy may occur. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Pregnancy and Lactation

Pregnancy

Ifosfamide is contraindicated in pregnancy.

There is limited data available on the use of ifosfamide during pregnancy. Foetal growth retardation and neonatal anaemia have been reported in infants of mothers who received ifosfamide-containing chemotherapy regimes. Congenital deviations in infants have been reported in cases where the mother received ifosfamide during the first trimester of pregnancy.

Based on animal studies, human case reports and ifosfamide's mechanism of action, it is advised not to use ifosfamide during pregnancy, particularly during the first trimester. The benefit for the mother will need to be assessed against the risk for the foetus. The pregnant patient should be counselled on the potential risk to the foetus.

Animal data generated with cyclophosphamide, another oxazaphosphorine cytotoxic agent, suggests that an increased risk of failed pregnancy and malformations may remain even after treatment with the agent has ceased as long as the oocytes/follicles exist that were in any maturation phase when exposed to the agent.

Ifosfamide has been shown to be teratogenic in three species of animal and also to be both mutagenic and carcinogenic. Due to this and the similarity with cyclophosphamide, a known human teratogen, ifosfamide should be considered to have a high potential for human teratogenicity and embryo/foetal toxicity (Briggs, 2015).

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

Ifosfamide is contraindicated in breastfeeding.

Ifosfamide is excreted in breast milk and may cause neutropenia, thrombocytopenia, low haemoglobin concentrations and diarrhoea in the nursing infant.

Hale (2014) suggests withholding breastfeeding for at least 72 hours.

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

Acute respiratory distress syndrome
Alopecia
Amenorrhoea
Anaemia
Angina pectoris
Angioedema
Arthralgia
Asterixis
Blood pressure changes
Capillary leak syndrome
Cardiac arrest
Cardiomyopathy
Cardiovascular disturbances
Cardiovascular toxicity
Chills
CNS toxicity
Confusion
Conjunctivitis
Convulsions
Cough
Cytolytic hepatitis
Deafness
Decreased appetite
Deep vein thrombosis (DVT)
Dermatitis
Diabetes insipidus
Disorientation
Drowsiness
Dyspnoea
ECG changes
Echolalia
Enuresis
Erythema
Eye irritation
Facial swelling
Flushing
Gastrointestinal disorder
Growth retardation (children)
Haematological disorders
Haematuria
Haemolytic uraemic syndrome
Haemorrhagic cystitis
Hepatic veno-occlusive disease
Hepatotoxicity
Hyperhidrosis
Hyperpigmentation of skin
Hypersensitivity reactions
Hypoxia
Immunosuppression
Impaired gonadal function
Impaired vision
Inappropriate secretion of antidiuretic hormone
Infections
Infertility
Interstitial lung disease
Jaundice
Local reaction at injection site
Malaise
Mental status changes
Metabolic acidosis
Multiorgan failure
Muscle twitch
Myalgia
Myelosuppression
Myocardial infarction
Neuralgia
Oedema
Osteomalacia
Palmar-plantar erythrodysaesthesia
Peripheral neuropathy
Perseveration
Phlebitis
Pleural effusion
Pneumonitis
Polydipsia
Polyuria
Portal vein thrombosis
Premature menopause
Pulmonary embolism
Pulmonary hypertension
Pulmonary oedema
Pyrexia
Radiation recall dermatitis
Rash
Renal disorders
Renal structural changes
Respiratory failure
Restlessness
Rhabdomyolysis
Rickets
Risk of secondary tumours as late sequelae
Skin necrosis
Stevens-Johnson syndrome
Tinnitus
Toxic epidermal necrolysis
Tumour lysis syndrome
Urothelial toxicity
Urticaria
Vasculitis
Vertigo

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: November 2016

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.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed on 30 September 2016.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications. Accessed on 30 September 2016.

Summary of Product Characteristics: Ifosfamide injection 1g. Baxter Healthcare Ltd. Revised February 2014.

Summary of Product Characteristics: Ifosfamide injection 2g. Baxter Healthcare Ltd. Revised February 2014.