Drugs List

Therapeutic Indications

Uses

Prevention of rejection following bone marrow and stem cell transplantation
Prevention of rejection following solid organ transplant
Prophylaxis of graft-versus-host disease (GVHD)
Treatment of graft-versus-host disease (GVHD)
Treatment of transplant rejection after use of other immunosuppressants

Prevention of transplant rejection following solid organ transplants.
Treatment of organ transplant rejection in patients who previously received other immunosuppressive agents.
Prevention of transplant rejection following allogeneic bone marrow and stem cell transplantation.
Prophylaxis of graft-versus-host disease (GVHD) following allogeneic bone marrow transplant.
Treatment of established graft-versus-host disease (GVHD) following allogeneic bone marrow transplant.

Unlicensed Uses

Ulcerative colitis

Ulcerative colitis

Administration

The concentrate for infusion is for intravenous administration over a period of 2 to 6 hours after dilution.

Contraindications

Neonates under 1 month
Breastfeeding

Precautions and Warnings

Allergic disposition
Children under 3 months
Alcoholism
Electrolyte imbalance
Epileptic disorder
Hepatic impairment
Hyperkalaemia
Hyperuricaemia
Pregnancy
Renal impairment

Administration of live vaccines is not recommended
Correct serum magnesium levels before commencing treatment
Premedication with antihistamine recommended
Treatment to be initiated and supervised by a specialist
Contains alcohol
Infusion concentrate contains polyoxyethylene hydrogenated castor oil
Resuscitation facilities must be immediately available
Monitor blood lipids before and during treatment
Consider immunosuppressant adjustment in the event of PML
Elderly: Monitor renal function and consider dose modification
Monitor and control serum magnesium levels in the peri-transplant period
Monitor blood pressure
Monitor for hypersensitivity reactions during infusion
Monitor hepatic function
Monitor renal function
Monitor serum potassium regularly
Advise patient to report headaches, seizures, confusion, visual disturbance
Consider immunosuppressant adjustment if BK virus nephropathy develops
Consider immunosuppressant adjustment if polyomavirus nephropathy develops
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Monitor for hypersensitivity reactions for at least 30 mins after admin
Oversuppression of immune system may increase susceptibility to infection
Discontinue if anaphylactoid reaction occurs
Discontinue if benign intracranial hypertension develops
Advise patient not to take echinacea products concurrently
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Avoid high dietary potassium intake
Advise patient to avoid exposure to sunlight and UV rays during treatment

During long-term therapy, some patients may develop structural changes in the kidney which in renal transplant recipients must be distinguished from chronic rejection.
In renal transplant patients, acute tubular necrosis is more likely if the machine perfusion time is more than 24 hours and the reanastomosis time more than 45 minutes.
In elderly patients, renal function should be regularly monitored. Hyperuricaemia may be aggravated by ciclosporin treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) also known as Reversible Posterior Leucoencephalopathy Syndrome (RPLS)
Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with this agent. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed, treatment should be discontinued and adequate blood pressure and seizure control administration is advisable. The safety of reinstating treatment in patients previously experiencing PRES is unknown.

Ciclosporin can cause gingival hyperplasia therefore routine dental check-ups (e.g. every three months) are recommended. In order to preclude or reduce gingival hyperplasia, teeth should be cleaned professionally and the patient should be instructed about measures necessary for personal dental hygiene.

Ciclosporin should be withdrawn immediately if benign intracranial hypertension is suspected due to risk of permanent visual loss.

Pregnancy and Lactation

Pregnancy

Use ciclosporin with caution in pregnancy.

Ciclosporin should only be used when the benefits outweigh the risks.

Data available from organ transplant recipients indicate that, compared with other immunosuppressive agents, ciclosporin treatment imposes no increased risk of adverse effects on the course or outcome of pregnancy, however there is an increased risk of premature birth.

Exposure to ciclosporin does not justify termination of pregnancy. A detailed foetal ultrasound examination should be offered to confirm normal morphologic development in the case of first-trimester exposure.

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

Ciclosporin is contraindicated in breastfeeding.

Ciclosporin is excreted into breast milk, although the concentrations are relatively low. A risk to neonates cannot be excluded.

Schaefer considers that this drug should pose no obstacle to breastfeeding, as long as breastfeeding did not take place for at least four hours after ciclosporin administration so as to avoid peak ciclosporin levels in milk.

LactMed states that limited information indicates that ciclosporin produces low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than two months.

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

Abdominal pain
Acne
Acute respiratory distress
Acute tubular necrosis
Agitation
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Anorexia
Ataxia
Benign intracranial hypertension
BK virus associated with nephropathy
Blood pressure changes
Cholestasis
Coma
Confusion
Convulsions
Cortical blindness
Decrease in mental acuity
Diarrhoea
Disorientation
Dyspnoea
Encephalopathy
Fatigue
Flushing
Gingival hyperplasia
Gynaecomastia
Haemolytic uraemic syndrome
Headache
Hepatic failure
Hepatic impairment
Hepatitis
Hirsutism
Hyperglycaemia
Hyperkalaemia
Hyperlipidaemia
Hypertension
Hypertrichosis
Hyperuricaemia
Hypomagnesaemia
Increased susceptibility to infection
Insomnia
Jaundice
Leucopenia
Lymphoma
Lymphoproliferative disorders
Malignancies
Menstrual disturbances
Microangiopathic haemolytic anaemia syndrome
Migraine
Muscle weakness
Muscular cramps
Myalgia
Myopathy
Nausea
Oedema
Optic disc oedema
Pain in lower extremities
Pancreatitis
Papilloedema
Paraesthesia
Paresis
Peptic ulceration
Polyneuropathy
Polyomavirus associated nephropathy
Posterior reversible encephalopathy syndrome (PRES)
Progressive multifocal leukoencephalopathy (PML)
Pulmonary oedema
Pyrexia
Rash (allergic)
Reactivation of infection
Renal impairment
Renal structural changes
Serum creatinine increased
Skin neoplasm
Tachycardia
Thrombocytopenia
Thrombotic microangiopathy
Thrombotic thrombocytopenic purpura
Tremor
Visual disturbances
Vomiting
Weight gain
Wheezing

Presentation

Infusions of ciclosporin.

Drugs List

Therapeutic Indications

Uses

Prevention of rejection following bone marrow and stem cell transplantation
Prevention of rejection following solid organ transplant
Prophylaxis of graft-versus-host disease (GVHD)
Treatment of graft-versus-host disease (GVHD)
Treatment of transplant rejection after use of other immunosuppressants

Prevention of transplant rejection following solid organ transplants.
Treatment of organ transplant rejection in patients who previously received other immunosuppressive agents.
Prevention of transplant rejection following allogeneic bone marrow and stem cell transplantation.
Prophylaxis of graft-versus-host disease (GVHD) following allogeneic bone marrow transplant.
Treatment of established graft-versus-host disease (GVHD) following allogeneic bone marrow transplant.

Unlicensed Uses

Ulcerative colitis

Ulcerative colitis

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local protocols for the relevant indication should be consulted.

Adults

Elderly

Children

Administration

The concentrate for infusion is for intravenous administration over a period of 2 to 6 hours after dilution.

Contraindications

Neonates under 1 month
Breastfeeding

Precautions and Warnings

Allergic disposition
Children under 3 months
Alcoholism
Electrolyte imbalance
Epileptic disorder
Hepatic impairment
Hyperkalaemia
Hyperuricaemia
Pregnancy
Renal impairment

Administration of live vaccines is not recommended
Correct serum magnesium levels before commencing treatment
Premedication with antihistamine recommended
Treatment to be initiated and supervised by a specialist
Contains alcohol
Infusion concentrate contains polyoxyethylene hydrogenated castor oil
Resuscitation facilities must be immediately available
Monitor blood lipids before and during treatment
Consider immunosuppressant adjustment in the event of PML
Elderly: Monitor renal function and consider dose modification
Monitor and control serum magnesium levels in the peri-transplant period
Monitor blood pressure
Monitor for hypersensitivity reactions during infusion
Monitor hepatic function
Monitor renal function
Monitor serum potassium regularly
Advise patient to report headaches, seizures, confusion, visual disturbance
Consider immunosuppressant adjustment if BK virus nephropathy develops
Consider immunosuppressant adjustment if polyomavirus nephropathy develops
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Monitor for hypersensitivity reactions for at least 30 mins after admin
Oversuppression of immune system may increase susceptibility to infection
Discontinue if anaphylactoid reaction occurs
Discontinue if benign intracranial hypertension develops
Advise patient not to take echinacea products concurrently
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Avoid high dietary potassium intake
Advise patient to avoid exposure to sunlight and UV rays during treatment

During long-term therapy, some patients may develop structural changes in the kidney which in renal transplant recipients must be distinguished from chronic rejection.
In renal transplant patients, acute tubular necrosis is more likely if the machine perfusion time is more than 24 hours and the reanastomosis time more than 45 minutes.
In elderly patients, renal function should be regularly monitored. Hyperuricaemia may be aggravated by ciclosporin treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) also known as Reversible Posterior Leucoencephalopathy Syndrome (RPLS)
Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with this agent. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed, treatment should be discontinued and adequate blood pressure and seizure control administration is advisable. The safety of reinstating treatment in patients previously experiencing PRES is unknown.

Ciclosporin can cause gingival hyperplasia therefore routine dental check-ups (e.g. every three months) are recommended. In order to preclude or reduce gingival hyperplasia, teeth should be cleaned professionally and the patient should be instructed about measures necessary for personal dental hygiene.

Ciclosporin should be withdrawn immediately if benign intracranial hypertension is suspected due to risk of permanent visual loss.

Pregnancy and Lactation

Pregnancy

Use ciclosporin with caution in pregnancy.

Ciclosporin should only be used when the benefits outweigh the risks.

Data available from organ transplant recipients indicate that, compared with other immunosuppressive agents, ciclosporin treatment imposes no increased risk of adverse effects on the course or outcome of pregnancy, however there is an increased risk of premature birth.

Exposure to ciclosporin does not justify termination of pregnancy. A detailed foetal ultrasound examination should be offered to confirm normal morphologic development in the case of first-trimester exposure.

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

Ciclosporin is contraindicated in breastfeeding.

Ciclosporin is excreted into breast milk, although the concentrations are relatively low. A risk to neonates cannot be excluded.

Schaefer considers that this drug should pose no obstacle to breastfeeding, as long as breastfeeding did not take place for at least four hours after ciclosporin administration so as to avoid peak ciclosporin levels in milk.

LactMed states that limited information indicates that ciclosporin produces low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than two months.

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

Abdominal pain
Acne
Acute respiratory distress
Acute tubular necrosis
Agitation
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Anorexia
Ataxia
Benign intracranial hypertension
BK virus associated with nephropathy
Blood pressure changes
Cholestasis
Coma
Confusion
Convulsions
Cortical blindness
Decrease in mental acuity
Diarrhoea
Disorientation
Dyspnoea
Encephalopathy
Fatigue
Flushing
Gingival hyperplasia
Gynaecomastia
Haemolytic uraemic syndrome
Headache
Hepatic failure
Hepatic impairment
Hepatitis
Hirsutism
Hyperglycaemia
Hyperkalaemia
Hyperlipidaemia
Hypertension
Hypertrichosis
Hyperuricaemia
Hypomagnesaemia
Increased susceptibility to infection
Insomnia
Jaundice
Leucopenia
Lymphoma
Lymphoproliferative disorders
Malignancies
Menstrual disturbances
Microangiopathic haemolytic anaemia syndrome
Migraine
Muscle weakness
Muscular cramps
Myalgia
Myopathy
Nausea
Oedema
Optic disc oedema
Pain in lower extremities
Pancreatitis
Papilloedema
Paraesthesia
Paresis
Peptic ulceration
Polyneuropathy
Polyomavirus associated nephropathy
Posterior reversible encephalopathy syndrome (PRES)
Progressive multifocal leukoencephalopathy (PML)
Pulmonary oedema
Pyrexia
Rash (allergic)
Reactivation of infection
Renal impairment
Renal structural changes
Serum creatinine increased
Skin neoplasm
Tachycardia
Thrombocytopenia
Thrombotic microangiopathy
Thrombotic thrombocytopenic purpura
Tremor
Visual disturbances
Vomiting
Weight gain
Wheezing

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: June 2016

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.

Summary of Product Characteristics: Sandimmun concentrate for infusion 50mg/ml. Novartis Pharmaceuticals UK Ltd. Revised July 2015.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 22 August 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
Cyclosporine Last revised: 26 April 2016
Last accessed: 20 May 2016