Drugs List

Therapeutic Indications

Uses

Autoimmune disease
Immunomodulatory effect in bone marrow transplantation
Malignant neoplasms

Cyclophosphamide may be used as a single agent or in combination with other cytotoxic drugs for the treatment of:
Chronic lymphocytic leukaemia (CLL).
Acute lymphocytic leukaemia (ALL).
As conditioning for a bone marrow transplantation, in the treatment of acute lymphoblastic leukaemia, chronic myelogenous leukaemia and acute myelogenous leukaemia, in combination with whole body irritation or busulfan.
Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma.
Metastatic ovarian and breast carcinoma.
Ewing's sarcoma.
Small cell lung cancer.
Advanced or metastatic neuroblastoma.
Life-threatening autoimmune diseases such as severe progressive forms of lupus nephritis and Wegener's granulomatosis.

Unlicensed Uses

Idiopathic thrombocytopenic purpura
Nephrotic syndrome - steroid sensitive
Severe systemic rheumatoid arthritis

Treatment of severe systemic rheumatoid arthritis and other connective tissue diseases.
Treatment of steroid sensitive nephrotic syndrome in children.
Treatment of idiopathic thrombocytopenic purpura (ITP).

Administration

For intravenous injection or infusion.

To be administered very slowly. Infusions should range from 30 minutes to 2 hours depending on volume and carrier fluid.

Some products are also licensed for oral administration.

Contraindications

Infection
Bone marrow aplasia
Breastfeeding
Haemorrhagic cystitis
Porphyria
Pregnancy
Urinary obstruction
Urinary tract infection

Precautions and Warnings

Concurrent radiotherapy
Elderly
Leucocyte count below 2.5 x 10 to the power of 9 / L
Platelet count below 50 x 10 to the power of 9 / L
Recent radiotherapy
Recent surgery
Adrenal insufficiency
Cardiac disorder
Diabetes mellitus
Myelosuppression
Severe hepatic impairment
Severe renal impairment

Advise ability to drive/operate machinery may be affected by side effects
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
Not all available brands are licensed for all routes of administration
Prophylactic G-CSF should be considered
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by breastfeeding staff
Staff: Not to be handled by pregnant staff
Perform urine analysis before and after each course of treatment
Monitor closely patient at risk of cardiovascular disorders
Monitor patient for signs of haematuria throughout treatment
Monitor platelets and leucocytes frequently
Monitor urine output
Advise patient to report any new or worsening respiratory symptoms
Advise patient to report signs or symptoms of cystitis
Advise patient to report symptoms of infection immediately
Advise patient to report unexplained fever, sore throat, bruising, bleeding
Antimicrobial prophylaxis recommended if severe neutropenia occurs
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider the use of anti-emetics before and during therapy
Treatment may adversely affect wound healing
Discontinue if severe haemorrhagic cystitis occurs
Interrupt treatment if platelet count <50 x 10 to the power of 9/L
Reduce dose if leukocyte count less than 4 x 10 to the power 9/L
Reduce dose if platelet count below 100 X 10 to power 9/L
Suspend treatment if leukocyte count less than 2.5 x 10 to the power 9/L
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

Cyclophosphamide should be given early in the day and the bladder voided frequently. The patient should be well hydrated and maintained in fluid balance. Urotoxic effects may be reduced with concurrent administration of mesna.

Urinary sediment should be checked regularly for the presence of erythrocytes.

Use of haematopoiesis stimulating agents (colony stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to cytostatics, including cyclophosphamide.

Cyclophosphamide should not be administered to patients who had a surgery less than 10 days ago.

In some patients, alcohol may increase cyclophosphamide-induced vomiting and nausea.

When the leukocyte count drops below 3000 cells per microlitre, more frequent monitoring may be required in addition to the dose adjustment.
The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. The bone marrow recovers relatively quickly, and the levels of peripheral blood cell counts normalize, as a rule, after approximately 20 days.

Cases of veno-occlusive liver disease have been reported in patients receiving cyclophosphamide, ensuring a time interval of at least 24 hours between the last busulfan dose and the first cyclophosphamide reduces the risk.

Cases of pulmonary toxicity including fatal cases have been observed in patients receiving cyclophosphamide. Pneumonitis may develop even years after treatment.

Pregnancy and Lactation

Pregnancy

Cyclophosphamide is contraindicated in pregnancy.

There are very limited data from the use of cyclophosphamide in pregnant women. There are reports of serious multiple congenital aberrations after use during the first trimester. Animal studies have shown teratogenicity and other reproduction toxicity. Considering the data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended.

The effect of concurrent therapies must also be considered.
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

Cyclophosphamide is contraindicated in breastfeeding.

Cyclophosphamide passes into breast milk in large quantities. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially alkylating agents such as cyclophosphamide. Neutropenia has been reported in 2 infants whose mothers breastfed them while receiving cyclophosphamide. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk.

The effect of concurrent therapies must also be considered.

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

Alopecia
Amenorrhoea
Anaphylaxis
Anorexia
Azoospermia
Bladder contracture
Bladder fibrosis
Cardiac failure
Cardiac tamponade
Cardiotoxicity
Change in carbohydrate metabolism
Creatine phosphokinase increased
Depression of the reticulo-endothelial system
ECG changes
Febrile neutropenia
Fluid retention
Haematuria
Haemolytic uraemic syndrome
Haemorrhagic cystitis
Hepatic impairment
Hyperglycaemia
Hypoglycaemia
Hyponatraemia
Inappropriate secretion of antidiuretic hormone
Increase in AST level
Increase in lactate dehydrogenase
Increase in mean corpuscular volume (MCV)
Intravascular coagulation (disseminated)
Jaundice
Leukopenia
Malignancies
Myelodysplastic syndrome
Myocarditis
Myopericarditis
Nausea
Nephrotoxicity
Pancreatitis
Pericardial effusion
Pigmentation of nails
Pneumonitis
Pulmonary fibrosis
Pulmonary toxicity
Renal impairment
Renal tubular necrosis
Skin pigmentation changes
Sterility
Stomatitis
Supraventricular arrhythmias
Thromboembolism
Ulceration of mucous membrane
Urethritis
Veno-occlusive disease
Ventricular arrhythmias
Vomiting
Water intoxication

Presentation

Injection containing cyclophosphamide

Drugs List

Therapeutic Indications

Uses

Autoimmune disease
Immunomodulatory effect in bone marrow transplantation
Malignant neoplasms

Cyclophosphamide may be used as a single agent or in combination with other cytotoxic drugs for the treatment of:
Chronic lymphocytic leukaemia (CLL).
Acute lymphocytic leukaemia (ALL).
As conditioning for a bone marrow transplantation, in the treatment of acute lymphoblastic leukaemia, chronic myelogenous leukaemia and acute myelogenous leukaemia, in combination with whole body irritation or busulfan.
Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma.
Metastatic ovarian and breast carcinoma.
Ewing's sarcoma.
Small cell lung cancer.
Advanced or metastatic neuroblastoma.
Life-threatening autoimmune diseases such as severe progressive forms of lupus nephritis and Wegener's granulomatosis.

Unlicensed Uses

Idiopathic thrombocytopenic purpura
Nephrotic syndrome - steroid sensitive
Severe systemic rheumatoid arthritis

Treatment of severe systemic rheumatoid arthritis and other connective tissue diseases.
Treatment of steroid sensitive nephrotic syndrome in children.
Treatment of idiopathic thrombocytopenic purpura (ITP).

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.

Adults

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For intravenous injection or infusion.

To be administered very slowly. Infusions should range from 30 minutes to 2 hours depending on volume and carrier fluid.

Some products are also licensed for oral administration.

Contraindications

Infection
Bone marrow aplasia
Breastfeeding
Haemorrhagic cystitis
Porphyria
Pregnancy
Urinary obstruction
Urinary tract infection

Precautions and Warnings

Concurrent radiotherapy
Elderly
Leucocyte count below 2.5 x 10 to the power of 9 / L
Platelet count below 50 x 10 to the power of 9 / L
Recent radiotherapy
Recent surgery
Adrenal insufficiency
Cardiac disorder
Diabetes mellitus
Myelosuppression
Severe hepatic impairment
Severe renal impairment

Advise ability to drive/operate machinery may be affected by side effects
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
Not all available brands are licensed for all routes of administration
Prophylactic G-CSF should be considered
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by breastfeeding staff
Staff: Not to be handled by pregnant staff
Perform urine analysis before and after each course of treatment
Monitor closely patient at risk of cardiovascular disorders
Monitor patient for signs of haematuria throughout treatment
Monitor platelets and leucocytes frequently
Monitor urine output
Advise patient to report any new or worsening respiratory symptoms
Advise patient to report signs or symptoms of cystitis
Advise patient to report symptoms of infection immediately
Advise patient to report unexplained fever, sore throat, bruising, bleeding
Antimicrobial prophylaxis recommended if severe neutropenia occurs
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider the use of anti-emetics before and during therapy
Treatment may adversely affect wound healing
Discontinue if severe haemorrhagic cystitis occurs
Interrupt treatment if platelet count <50 x 10 to the power of 9/L
Reduce dose if leukocyte count less than 4 x 10 to the power 9/L
Reduce dose if platelet count below 100 X 10 to power 9/L
Suspend treatment if leukocyte count less than 2.5 x 10 to the power 9/L
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

Cyclophosphamide should be given early in the day and the bladder voided frequently. The patient should be well hydrated and maintained in fluid balance. Urotoxic effects may be reduced with concurrent administration of mesna.

Urinary sediment should be checked regularly for the presence of erythrocytes.

Use of haematopoiesis stimulating agents (colony stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to cytostatics, including cyclophosphamide.

Cyclophosphamide should not be administered to patients who had a surgery less than 10 days ago.

In some patients, alcohol may increase cyclophosphamide-induced vomiting and nausea.

When the leukocyte count drops below 3000 cells per microlitre, more frequent monitoring may be required in addition to the dose adjustment.
The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. The bone marrow recovers relatively quickly, and the levels of peripheral blood cell counts normalize, as a rule, after approximately 20 days.

Cases of veno-occlusive liver disease have been reported in patients receiving cyclophosphamide, ensuring a time interval of at least 24 hours between the last busulfan dose and the first cyclophosphamide reduces the risk.

Cases of pulmonary toxicity including fatal cases have been observed in patients receiving cyclophosphamide. Pneumonitis may develop even years after treatment.

Pregnancy and Lactation

Pregnancy

Cyclophosphamide is contraindicated in pregnancy.

There are very limited data from the use of cyclophosphamide in pregnant women. There are reports of serious multiple congenital aberrations after use during the first trimester. Animal studies have shown teratogenicity and other reproduction toxicity. Considering the data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended.

The effect of concurrent therapies must also be considered.
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

Cyclophosphamide is contraindicated in breastfeeding.

Cyclophosphamide passes into breast milk in large quantities. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially alkylating agents such as cyclophosphamide. Neutropenia has been reported in 2 infants whose mothers breastfed them while receiving cyclophosphamide. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk.

The effect of concurrent therapies must also be considered.

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

Alopecia
Amenorrhoea
Anaphylaxis
Anorexia
Azoospermia
Bladder contracture
Bladder fibrosis
Cardiac failure
Cardiac tamponade
Cardiotoxicity
Change in carbohydrate metabolism
Creatine phosphokinase increased
Depression of the reticulo-endothelial system
ECG changes
Febrile neutropenia
Fluid retention
Haematuria
Haemolytic uraemic syndrome
Haemorrhagic cystitis
Hepatic impairment
Hyperglycaemia
Hypoglycaemia
Hyponatraemia
Inappropriate secretion of antidiuretic hormone
Increase in AST level
Increase in lactate dehydrogenase
Increase in mean corpuscular volume (MCV)
Intravascular coagulation (disseminated)
Jaundice
Leukopenia
Malignancies
Myelodysplastic syndrome
Myocarditis
Myopericarditis
Nausea
Nephrotoxicity
Pancreatitis
Pericardial effusion
Pigmentation of nails
Pneumonitis
Pulmonary fibrosis
Pulmonary toxicity
Renal impairment
Renal tubular necrosis
Skin pigmentation changes
Sterility
Stomatitis
Supraventricular arrhythmias
Thromboembolism
Ulceration of mucous membrane
Urethritis
Veno-occlusive disease
Ventricular arrhythmias
Vomiting
Water intoxication

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: August 2015

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.

Martindale: The Complete Drug Reference (online) London: Brayfield A (ed). Pharmaceutical Press. Accessed on 17 August 2015.

Summary of Product Characteristics: Cyclophosphamide injection 1g. Baxter Healthcare Ltd. Revised December 2014.

Summary of Product Characteristics: Cyclophosphamide injection 500mg. Baxter Healthcare Ltd. Revised December 2014.

Summary of Product Characteristics: Cyclophosphamide injection 1g. Sandoz Limited. Revised August 2014.

Summary of Product Characteristics: Cyclophosphamide injection 2g. Sandoz Limited. Revised August 2014.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Cyclophosphamide. Last revised: 03 October 2014
Last accessed: 7 August 2015.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 18 August 2017