Drugs List

Therapeutic Indications

Uses

Anaemia - due to autoimmune haemolysis
Dermatomyositis
Hepatitis - autoimmune chronic active
Immunosuppressant in rheumatoid arthritis
Immunosuppression in transplant patients
Lupus erythematosus - systemic
Pemphigus vulgaris
Polyarteritis nodosa
Polymyositis
Thrombocytopenia - chronic refractory idiopathic

Unlicensed Uses

Crohn's disease
Ulcerative colitis

Administration

Azathioprine injection must only be administered by the intravenous route.

Azathioprine injection should only be used when the oral route is impractical, and should be discontinued as soon as the oral route is tolerated.

Contraindications

None known

Precautions and Warnings

Elderly
Inherited NUDT15 gene mutation
Inherited thiopurine methyltransferase deficiency
Recent exposure or co-existing varicella or herpes zoster
Breastfeeding
Hepatic impairment
Lesch-Nyhan syndrome
Pregnancy
Renal impairment

Consider prophylactic immunoglobulin if exposure to varicella virus
Live virus vaccine should not be given for 3 months after treatment
Passive immunisation of chicken pox / herpes zoster may be required
Monitor blood counts weekly for first 8 weeks and then monthly thereafter
Monitor for signs of bone marrow depression
Monitor for signs of Macrophage Activation Syndrome (MAS)
Monitor hepatic function
Perform regular blood counts especially if renal or hepatic impairment
Advise patient to report immediately signs/symptoms bone marrow suppression
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Potentially mutagenic and carcinogenic
Reactivation of hepatitis B may occur in chronic carriers
Discontinue if Macrophage Activation Syndrome is suspected
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Maintain treatment at the lowest effective dose
Therapy should be maintained indefinitely in transplant patients
Advise patient not to take with milk
Dairy products may impair absorption
Male & female: Ensure adequate contraception during treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to sunlight and UV rays during treatment
If exposed to chickenpox or Herpes zoster seek urgent medical attention

It is suggested that during the first 8 weeks of therapy, complete blood counts, including platelets should be performed weekly or more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly, or at least at intervals of not longer than 3 months.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co-administration of drugs that inhibit TMPT, such as olsalazine, mesalazine and sulfasalazine.

Limited evidence suggests that azathioprine is not beneficial to patients with Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase deficiency). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive azathioprine.

Relief of chronic renal insufficiency by renal transplantation involving the administration of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.

Patients receiving immunosuppressive therapy are at an increased risk of developing Non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcoma (Kaposi's and non-Kaposi's) and uterine cervical cancer. The risk appears to be related to the intensity and duration of immunosuppression, rather than the use of any specific agent. Reduction or discontinuation of immunosuppression may cause lymphomas and sarcomas to regress.

Infection with varicella zoster virus (VZV, chickenpox and herpes zoster) may become severe during treatment with immunosuppressants. Patient history of VZV should be checked before starting immunosuppressant regime; serologic testing may be useful for confirming previous exposure. Patients with no history of exposure should be advised to avoid contact with individuals with chickenpox or herpes zoster and to report any exposure as soon as possible. If exposure does occur special care should be taken to avoid development of chickenpox or herpes zoster, passive immunisation with varicella-zoster immunoglobulin may be considered.

Azathioprine should be maintained indefinitely in transplant patients, even if only low doses are necessary, as cessation of azathioprine therapy may result in graft rejection.

Pregnancy and Lactation

Pregnancy

Use azathioprine with caution in pregnancy.

Azathioprine should not be given to patients who are pregnant or who are likely to become pregnant without careful assessment of the risk/benefit ratio. Additional haematological monitoring is advised if used during pregnancy.

There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly when used in combination with corticosteroids. There have also been reports of spontaneous abortion following maternal and paternal exposure to azathioprine.

Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after maternal administration of azathioprine. Additionally, leucopenia and/or thrombocytopenia have been reported in neonates whose mothers took azathioprine throughout their pregnancies.

Briggs (2015) indicates that azathioprine does not seem to cause structural anomalies in humans when used during organogenesis. Use of azathioprine during the third trimester may be linked to immunosuppression and bone marrow suppression. Dose modification in the third trimester may limit this risk of toxicity. Overall, the benefit of treatment to the mother outweighs the potential risk to the foetus.

Schaefer (2015) indicates that the teratogenic potential of azathioprine has not been recognised and that the drug can be prescribed during pregnancy. A detailed ultrasound is recommended to confirm normal foetal development. As the success of a transplant is most important for a successful and uncomplicated pregnancy, immunosuppressant therapy should not be changed during a pregnancy.

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

Use azathioprine with caution in breastfeeding.

Metabolites of azathioprine have been identified in the colostrum and breast milk of women receiving azathioprine treatment.

LactMed indicates that the use of azathioprine during breastfeeding has limited adverse effects in nursing infants. To keep the exposure of the infant to a minimum, it is suggested to avoid breastfeeding for 4 hours after receiving a dose of azathioprine. It is suggested that monitoring blood count, differential and liver function tests in exclusively breastfed infants might be desirable (Hale, 2014). Schaefer (2015) recommends monitoring for signs of immunosuppression in the child at the age of around 4 weeks.

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 myeloid leukaemia
Agranulocytosis
Alopecia
Anaemia
Aplastic anaemia
Arthralgia
Bone marrow depression
Bowel perforation
Cholestatic jaundice
Colitis
Diarrhoea
Diverticulitis
Dizziness
Exanthema
Fever
Hepatic impairment
Hypersensitivity reactions
Hypotension
Increased risk of cervical cancer
Increased risk of skin cancer
Increased susceptibility to infection
Injection site reactions
Interstitial nephritis
Kaposi's Sarcoma
Leucopenia
Lymphoma
Malaise
Malignant melanoma
Megaloblastic anaemia
Myalgia
Myelodysplastic syndrome
Nausea
Nodular regenerative hyperplasia
Non Hodgkin's lymphoma
Non Kaposi's sarcoma
Non melanoma skin cancer
Pancreatitis
Pancytopenia
Peliosis hepatis
Photosensitivity
Pneumonitis
Rash
Red cell hypoplasia
Renal impairment
Rigors
Sinusoidal dilation
Stevens-Johnson syndrome
Thrombocytopenia
Toxic epidermal necrolysis
Vasculitis
Veno-occlusive disease
Vomiting

Presentation

Powder for solution for injection or infusion containing azathioprine

Drugs List

Therapeutic Indications

Uses

Anaemia - due to autoimmune haemolysis
Dermatomyositis
Hepatitis - autoimmune chronic active
Immunosuppressant in rheumatoid arthritis
Immunosuppression in transplant patients
Lupus erythematosus - systemic
Pemphigus vulgaris
Polyarteritis nodosa
Polymyositis
Thrombocytopenia - chronic refractory idiopathic

Unlicensed Uses

Crohn's disease
Ulcerative colitis

Dosage

Adults

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Administration

Azathioprine injection must only be administered by the intravenous route.

Azathioprine injection should only be used when the oral route is impractical, and should be discontinued as soon as the oral route is tolerated.

Contraindications

None known

Precautions and Warnings

Elderly
Inherited NUDT15 gene mutation
Inherited thiopurine methyltransferase deficiency
Recent exposure or co-existing varicella or herpes zoster
Breastfeeding
Hepatic impairment
Lesch-Nyhan syndrome
Pregnancy
Renal impairment

Consider prophylactic immunoglobulin if exposure to varicella virus
Live virus vaccine should not be given for 3 months after treatment
Passive immunisation of chicken pox / herpes zoster may be required
Monitor blood counts weekly for first 8 weeks and then monthly thereafter
Monitor for signs of bone marrow depression
Monitor for signs of Macrophage Activation Syndrome (MAS)
Monitor hepatic function
Perform regular blood counts especially if renal or hepatic impairment
Advise patient to report immediately signs/symptoms bone marrow suppression
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Potentially mutagenic and carcinogenic
Reactivation of hepatitis B may occur in chronic carriers
Discontinue if Macrophage Activation Syndrome is suspected
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Maintain treatment at the lowest effective dose
Therapy should be maintained indefinitely in transplant patients
Advise patient not to take with milk
Dairy products may impair absorption
Male & female: Ensure adequate contraception during treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to sunlight and UV rays during treatment
If exposed to chickenpox or Herpes zoster seek urgent medical attention

It is suggested that during the first 8 weeks of therapy, complete blood counts, including platelets should be performed weekly or more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly, or at least at intervals of not longer than 3 months.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co-administration of drugs that inhibit TMPT, such as olsalazine, mesalazine and sulfasalazine.

Limited evidence suggests that azathioprine is not beneficial to patients with Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase deficiency). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive azathioprine.

Relief of chronic renal insufficiency by renal transplantation involving the administration of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.

Patients receiving immunosuppressive therapy are at an increased risk of developing Non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcoma (Kaposi's and non-Kaposi's) and uterine cervical cancer. The risk appears to be related to the intensity and duration of immunosuppression, rather than the use of any specific agent. Reduction or discontinuation of immunosuppression may cause lymphomas and sarcomas to regress.

Infection with varicella zoster virus (VZV, chickenpox and herpes zoster) may become severe during treatment with immunosuppressants. Patient history of VZV should be checked before starting immunosuppressant regime; serologic testing may be useful for confirming previous exposure. Patients with no history of exposure should be advised to avoid contact with individuals with chickenpox or herpes zoster and to report any exposure as soon as possible. If exposure does occur special care should be taken to avoid development of chickenpox or herpes zoster, passive immunisation with varicella-zoster immunoglobulin may be considered.

Azathioprine should be maintained indefinitely in transplant patients, even if only low doses are necessary, as cessation of azathioprine therapy may result in graft rejection.

Pregnancy and Lactation

Pregnancy

Use azathioprine with caution in pregnancy.

Azathioprine should not be given to patients who are pregnant or who are likely to become pregnant without careful assessment of the risk/benefit ratio. Additional haematological monitoring is advised if used during pregnancy.

There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly when used in combination with corticosteroids. There have also been reports of spontaneous abortion following maternal and paternal exposure to azathioprine.

Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after maternal administration of azathioprine. Additionally, leucopenia and/or thrombocytopenia have been reported in neonates whose mothers took azathioprine throughout their pregnancies.

Briggs (2015) indicates that azathioprine does not seem to cause structural anomalies in humans when used during organogenesis. Use of azathioprine during the third trimester may be linked to immunosuppression and bone marrow suppression. Dose modification in the third trimester may limit this risk of toxicity. Overall, the benefit of treatment to the mother outweighs the potential risk to the foetus.

Schaefer (2015) indicates that the teratogenic potential of azathioprine has not been recognised and that the drug can be prescribed during pregnancy. A detailed ultrasound is recommended to confirm normal foetal development. As the success of a transplant is most important for a successful and uncomplicated pregnancy, immunosuppressant therapy should not be changed during a pregnancy.

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

Use azathioprine with caution in breastfeeding.

Metabolites of azathioprine have been identified in the colostrum and breast milk of women receiving azathioprine treatment.

LactMed indicates that the use of azathioprine during breastfeeding has limited adverse effects in nursing infants. To keep the exposure of the infant to a minimum, it is suggested to avoid breastfeeding for 4 hours after receiving a dose of azathioprine. It is suggested that monitoring blood count, differential and liver function tests in exclusively breastfed infants might be desirable (Hale, 2014). Schaefer (2015) recommends monitoring for signs of immunosuppression in the child at the age of around 4 weeks.

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

Counselling

May be taken with food or on an empty stomach. Patients are advised to standardise the method of administration.
Advise patient not to take with milk or dairy products.
Advise patient to report symptoms of bone marrow depression.
Advise patient to report symptoms of infection immediately.
Advise patient to avoid exposure to sunlight and UV rays during treatment, wear protective clothing and use sunscreen with a high protection factor.
Advise patient to inform anaesthesiologist of their treatment with azathioprine prior to surgery.

Side Effects

Acute myeloid leukaemia
Agranulocytosis
Alopecia
Anaemia
Aplastic anaemia
Arthralgia
Bone marrow depression
Bowel perforation
Cholestatic jaundice
Colitis
Diarrhoea
Diverticulitis
Dizziness
Exanthema
Fever
Hepatic impairment
Hypersensitivity reactions
Hypotension
Increased risk of cervical cancer
Increased risk of skin cancer
Increased susceptibility to infection
Injection site reactions
Interstitial nephritis
Kaposi's Sarcoma
Leucopenia
Lymphoma
Malaise
Malignant melanoma
Megaloblastic anaemia
Myalgia
Myelodysplastic syndrome
Nausea
Nodular regenerative hyperplasia
Non Hodgkin's lymphoma
Non Kaposi's sarcoma
Non melanoma skin cancer
Pancreatitis
Pancytopenia
Peliosis hepatis
Photosensitivity
Pneumonitis
Rash
Red cell hypoplasia
Renal impairment
Rigors
Sinusoidal dilation
Stevens-Johnson syndrome
Thrombocytopenia
Toxic epidermal necrolysis
Vasculitis
Veno-occlusive disease
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 ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Further Information

Last Full Review Date: October 2016

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

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.

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

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

Summary of Product Characteristics: Imuran Injection. Aspen. Revised October 2019

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 21 June 2017

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
Azathioprine Last revised: 31 October 2018
Last accessed: 23 January 2019