Drugs List

Therapeutic Indications

Uses

Autoimmune disease
Crohn's disease
Transplant rejection - prevention of
Ulcerative colitis

Adjunctive treatment with corticosteroids and/or other immunosuppressive agents and procedures to enhance the survival of organ transplants such as renal, cardiac and hepatic transplants.

Adjunctive treatment to reduce the corticosteroid requirements of renal transplant recipients.

Either alone or as adjunctive treatment with corticosteroids and/or other drugs and procedures in a proportion of patients with the following conditions:
-Severe rheumatoid arthritis
-Systemic lupus erythematous
-Dermatomyositis and polymyositis
-Auto-immune chronic active hepatitis
-Pemphigus vulgaris
-Polyarteritis nodosa
-Auto-immune haemolytic anaemia
-Chronic refractory idiopathic thrombocytopenia purpura
-Pyoderma gangrenosa

-Severe or moderately severe inflammatory intestinal disease (Crohn's disease or ulcerative colitis)

Unlicensed Uses

Severe refractory eczema

Treatment of severe refractory eczema.

Contraindications

None known

Precautions and Warnings

Elderly
Inherited NUDT15 gene mutation
Inherited thiopurine methyltransferase deficiency
Recent exposure or co-existing varicella or herpes zoster
Severe infection
Breastfeeding
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Inflammatory bowel disease
Lactose intolerance
Lesch-Nyhan syndrome
Pancreatitis
Pregnancy
Renal impairment

Administration of live vaccines is not recommended
Consider prophylactic immunoglobulin if exposure to varicella virus
Live virus vaccine should not be given for 3 months after treatment
Not all formulations are licensed for all uses
Passive immunisation of chicken pox / herpes zoster may be required
Some formulations contain lactose
Take at the same time in respect to food as absorption may be affected
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
Advise patient to report symptoms of infection immediately
Advise patient to report unexplained fever, sore throat, bruising, bleeding
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
Reduce dose in patients with haematological toxicity
Withdraw treatment gradually under supervision of a specialist
Discontinue if Macrophage Activation Syndrome is suspected
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Consider dose reduction in hepatic impairment
Consider dose reduction in renal impairment
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 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 (more frequently at higher doses and in severe renal and/or hepatic impairment). The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly and at least every 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.

Pregnancy and Lactation

Pregnancy

Use azathioprine with caution in pregnancy.

Does not appear to cause structural abnormalities when used during organogenesis.

Exposure during the 3rd trimester has been linked to immunosuppression. Dose modifications appear to reduce the risk of toxicity.

Briggs suggests that maternal treatment benefit outweighs potential risk to infant.

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

Schaefer suggests a detailed ultrasound should be offered to confirm normal morphologic development in cases of first trimester exposure. If leucopenia occurs in the mother during the third trimester, dose should be reduced to avoid leucopenia in the neonate.

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

6-mercaptopurine (a metabolite of azathioprine) has been identified in the colostrum and breast milk of women receiving azathioprine treatment.

Some sources recommend avoiding breastfeeding for 2 to 6 hours after dose to further reduce the risk to infant.

Studies of women taking azathioprine while breastfeeding have shown no adverse effects in nursing infants. However, long-term follow ups for effects have not been performed.

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
Interstitial nephritis
Kaposi's Sarcoma
Leucopenia
Lymphoproliferative disorders
Macrophage-activation syndrome
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

Oral formulations of azathioprine

Drugs List

Therapeutic Indications

Uses

Autoimmune disease
Crohn's disease
Transplant rejection - prevention of
Ulcerative colitis

Adjunctive treatment with corticosteroids and/or other immunosuppressive agents and procedures to enhance the survival of organ transplants such as renal, cardiac and hepatic transplants.

Adjunctive treatment to reduce the corticosteroid requirements of renal transplant recipients.

Either alone or as adjunctive treatment with corticosteroids and/or other drugs and procedures in a proportion of patients with the following conditions:
-Severe rheumatoid arthritis
-Systemic lupus erythematous
-Dermatomyositis and polymyositis
-Auto-immune chronic active hepatitis
-Pemphigus vulgaris
-Polyarteritis nodosa
-Auto-immune haemolytic anaemia
-Chronic refractory idiopathic thrombocytopenia purpura
-Pyoderma gangrenosa

-Severe or moderately severe inflammatory intestinal disease (Crohn's disease or ulcerative colitis)

Unlicensed Uses

Severe refractory eczema

Treatment of severe refractory eczema.

Dosage

Adults

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Contraindications

None known

Precautions and Warnings

Elderly
Inherited NUDT15 gene mutation
Inherited thiopurine methyltransferase deficiency
Recent exposure or co-existing varicella or herpes zoster
Severe infection
Breastfeeding
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Inflammatory bowel disease
Lactose intolerance
Lesch-Nyhan syndrome
Pancreatitis
Pregnancy
Renal impairment

Administration of live vaccines is not recommended
Consider prophylactic immunoglobulin if exposure to varicella virus
Live virus vaccine should not be given for 3 months after treatment
Not all formulations are licensed for all uses
Passive immunisation of chicken pox / herpes zoster may be required
Some formulations contain lactose
Take at the same time in respect to food as absorption may be affected
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
Advise patient to report symptoms of infection immediately
Advise patient to report unexplained fever, sore throat, bruising, bleeding
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
Reduce dose in patients with haematological toxicity
Withdraw treatment gradually under supervision of a specialist
Discontinue if Macrophage Activation Syndrome is suspected
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Consider dose reduction in hepatic impairment
Consider dose reduction in renal impairment
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 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 (more frequently at higher doses and in severe renal and/or hepatic impairment). The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly and at least every 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.

Pregnancy and Lactation

Pregnancy

Use azathioprine with caution in pregnancy.

Does not appear to cause structural abnormalities when used during organogenesis.

Exposure during the 3rd trimester has been linked to immunosuppression. Dose modifications appear to reduce the risk of toxicity.

Briggs suggests that maternal treatment benefit outweighs potential risk to infant.

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

Schaefer suggests a detailed ultrasound should be offered to confirm normal morphologic development in cases of first trimester exposure. If leucopenia occurs in the mother during the third trimester, dose should be reduced to avoid leucopenia in the neonate.

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

6-mercaptopurine (a metabolite of azathioprine) has been identified in the colostrum and breast milk of women receiving azathioprine treatment.

Some sources recommend avoiding breastfeeding for 2 to 6 hours after dose to further reduce the risk to infant.

Studies of women taking azathioprine while breastfeeding have shown no adverse effects in nursing infants. However, long-term follow ups for effects have not been performed.

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. Administration with food may help relieve nausea however administration with food may reduce absorption. Patients are advised to standardise the method of administration.
Advise patient not to take at least 1 hour before or 2 hours after 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
Interstitial nephritis
Kaposi's Sarcoma
Leucopenia
Lymphoproliferative disorders
Macrophage-activation syndrome
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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: September 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

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, 36th edition (2009) ed. Sweetman, S. Pharmaceutical Press, London.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

Summary of Product Characteristics: Azapress 50mg tablets. Ennogen Pharma Ltd. Revised February 2012.

Summary of Product Characteristics: Azathioprine 50mg tablets. Actavis UK Ltd. Revised January 2014.
Summary of Product Characteristics: Azathioprine 50mg tablets. Arrow generics Ltd. Revised March 2012.
Summary of Product Characteristics: Azathioprine 50mg Tablets. Co-pharma Ltd. Revised January 2010.

Summary of Product Characteristics: Azathioprine 25mg tablets. Generics UK. Revised November 2013.
Summary of Product Characteristics: Azathioprine 50mg tablets. Generics UK. Revised November 2013.

Summary of Product Characteristics: Azathioprine 25mg tablets. Norton healthcare Ltd. Revised January 2013.
Summary of Product Characteristics: Azathioprine 50mg tablets. Norton healthcare Ltd. Revised January 2013.

Summary of Product Characteristics: Azathioprine 25mg tablets. Sandoz Ltd. Revised May 2013.
Summary of Product Characteristics: Azathioprine 50mg tablets. Sandoz Ltd. Revised March 2014.

Summary of Product Characteristics: Azathioprine 25mg tablets. Tillomed Ltd. Revised October 2012.
Summary of Product Characteristics: Azathioprine 50mg tablets. Tillomed Ltd. Revised October 2012.

Summary of Product Characteristics: Imuran 25mg Tablets. Aspen Europe. Revised October 2019.
Summary of Product Characteristics: Imuran 50mg Tablets. Aspen Europe. Revised October 2019.

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

UK Drugs in Lactation Advisory Service.
Available at: https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Last accessed: 12 September, 2014.

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: 8 July 2014
Last accessed: 12 September 2014.