Ciclosporin oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of ciclosporin.
Drugs List
Therapeutic Indications
Uses
Active progressive rheumatoid arthritis in combination with methotrexate
Nephrotic syndrome
Prevention of rejection following bone marrow and stem cell transplantation
Prevention of rejection following solid organ transplant
Prophylaxis of graft-versus-host disease (GVHD)
Severe active rheumatoid arthritis-other regimens unsuitable/ineffective
Severe atopic dermatitis when other regimens unsuitable/ineffective
Severe psoriasis when other regimens unsuitable/ineffective
Treatment of graft-versus-host disease (GVHD)
Treatment of transplant rejection after use of other immunosuppressants
Uveitis
Prevention of transplant rejection following solid organ transplantation.
Treatment of organ transplant rejection in patients who previously received other immunosuppressive agents.
Prevention of rejection after 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.
Severe atopic dermatitis when other regimens unsuitable/ineffective.
Severe, active rheumatoid arthritis when other regimens unsuitable/ ineffective.
Active progressive rheumatoid arthritis in combination with methotrexate.
Severe psoriasis when other regimens unsuitable/ineffective.
Nephrotic syndrome due to primary glomerular diseases.
Sight threatening intermediate or posterior non-infectious uveitis when conventional therapy has failed or caused unacceptable toxicity.
Behcet uveitis with repeated inflammatory attacks involving the retina in patients without neurological manifestations.
Unlicensed Uses
Ulcerative colitis
Ulcerative colitis in children
Dosage
Oral ciclosporin products are not bioequivalent and alterations in the brand prescribed may lead to changes in the patient's serum ciclosporin concentration. Therefore, it is recommended that ciclosporin is always prescribed as a brand. Patients should not be transferred to any other formulations of oral ciclosporin without the appropriate monitoring of ciclosporin serum concentrations, renal function and blood pressure.
Adults
Solid organ transplantation
Initial: 10 to 15 mg/kg/day given in 2 divided doses 4 to 12 hours before transplantation, continue for 1 to 2 weeks post operatively.
Maintenance: Gradually reduce to a dose of 2 to 6 mg/kg/day given in 2 divided doses. The dose should be adjusted by monitoring ciclosporin trough levels and renal function.
When ciclosporin is given concomitantly with other immunosuppressant therapy a lower initial dose may be used in the range of 3 to 6 mg/kg/day (orally in 2 divided doses).
Bone marrow transplantation, prevention and treatment of graft-versus- host disease
Intravenous administration is usually preferred for initiation of therapy, but oral treatment may be used.
Initial: 12.5 to 15 mg/kg/day, given in 2 divided doses, from the day before transplantation.
Maintenance: 12.5 mg/kg/day in 2 divided doses should be continued for at least 3 months (preferably 6 months post-transplant), before decreasing to zero (may take up to a year after transplantation).
Higher doses or use of the intravenous product may be required in cases of gastrointestinal disturbances reducing absorption.
If graft versus host disease develops after ciclosporin has been discontinued, treatment should be restarted at a dosage of 10 to 12.5 mg/kg
Nephrotic syndrome
Initial:5mg/kg/day orally in 2 divided doses.
Maintenance: Reduce dose to the lowest therapeutically effective level.
Discontinue treatment in absence of efficacy after 3 months treatment for minimal change glomerulonephritis and focal segmental glomerulosclerosis or 6 months treatment for membranous glomerulonephritis.
Rheumatoid arthritis
Initial: 2.5mg to 3mg/kg/day for 6 weeks, given in 2 divided doses.
Maintenance: If necessary dose may be increased gradually after 6 weeks to a maximum of 5mg/kg daily. 12 weeks of treatment may be required for an adequate response.
Maintenance dosage should be adjusted individually to the lowest effective dose and treatment re-evaluated after 6 months.
Rheumatoid arthritis in combination with weekly methotrexate in patients with inadequate response to methotrexate monotherapy
Initial: 1.25mg/kg twice daily.
Maintenance: If necessary dose may be increased gradually after 6 weeks to a maximum of 5mg/kg daily.
Atopic dermatitis (16 years of age or over)
2.5mg/kg/day in 2 divided doses. If good initial response is not achieved within 2 weeks, increase rapidly to maximum 5mg/kg/day.
An initial dose of 5mg/kg/day in 2 divided doses if dermatitis very severe.
Severe psoriasis (16 years of age or over)
Initial: 2.5mg/kg/day in 2 divided doses, increased gradually to a maximum of 5mg/kg/day if no improvement within 1 month (discontinue if response still insufficient within 6 weeks).
An initial dose of 5mg/kg/day is justified if condition requires rapid improvement.
Maintenance: Titrate the dose to the lowest effective level not exceeding 5mg/kg/day in 2 divided doses.
Once satisfactory response is achieved, ciclosporin may be discontinued and subsequent relapse managed with re-introduction at the previously effective dose.
Endogenous uveitis
Initial: 5 mg/kg/day in 2 divided doses until remission of active uveal inflammation and improvement in visual acuity.
In refractory cases dose may be increased to 7 mg/kg/day for a limited period.
Initial remission or to counteract inflammatory ocular attacks, systemic corticosteroid treatment may be added if ciclosporin does not control the situation sufficiently. After 3 months the corticosteroids may be tapered to the lowest effective dose.
Maintenance: Dose should be slowly reduced to the lowest effective level, this should not exceed 5 mg/kg/day during remission phases.
Children
There is limited data in young children. The manufacturer suggests only use in transplantation and nephrotic syndrome and only describes doses for nephrotic syndrome.
Consult local protocols for dosage recommendations.
Organ and Bone marrow transplant
The manufacturers state that transplant recipients from 1 year of age have received the drug at the recommended doses with no particular problem. Paediatric patients often required and tolerated higher doses of ciclosporin than adults.
Nephrotic syndrome
Initial: 6mg/kg/day given in 2 divided doses.
Maintenance: Reduce dose to the lowest effective dose.
Refractory ulcerative colitis (unlicensed)
Children 2 to 18 years: 2mg/kg twice daily, dose adjusted according to levels and response. Maximum dose 5mg/kg twice daily.
Severe atopic dermatitis (unlicensed)
Children 1 month to 18 years: 1.25mg/kg twice daily, if good initial response not achieved within 2 weeks, increase rapidly to a maximum of 2.5mg/kg twice daily. Initial dose of 2.5mg/kg twice daily for 8 weeks, may be considered if condition is very severe.
Severe psoriasis (unlicensed)
Children 1 month to 18 years: 1.25mg/kg twice daily, increased gradually to a maximum of 2.5mg/kg twice daily if no improvement within 1 month (discontinue if response still insufficient after 3 months). Initial dose of 2.5 mg/kg twice daily may be considered if condition requires rapid control. The maximum duration of treatment is 1 year unless other treatments cannot be used.
Patients with Renal Impairment
Pre-existing
Manufacturers contraindicate ciclosporin use for the treatment of psoriasis, atopic dermatitis rheumatoid arthritis and uveitis in patients with pre-existing impaired renal function.
Nephrotic syndrome
Manufacturers state that in the treatment of nephrotic syndrome in patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
Drug induced
Non-transplantation indications
Manufacturers suggest a dose reduction of between 25 to 50% if estimated GFR decreases by 25% below baseline and further dose reductions if estimated GFR decreases below 35%.
Alternatively some manufacturers suggest a dose reduction of between 25 to 50% if serum creatinine increases and remains more than 30% above baseline during treatment and a 50% reduction if serum creatinine levels increase by more than 50%.
If dose reduction is not successful at improving levels within one month, treatment should be discontinued.
Additional Dosage Information
Oral ciclosporin formulations are not bioequivalent and should be prescribed by brand.
If it is necessary to convert patients from one proprietary brand to another, an initial mg for mg conversion is recommended with subsequent dose titration, if required. It is important that practitioners, pharmacists and patients are aware that substitution between formulation should only be carried out with appropriate monitoring of ciclosporin blood concentrations, serum creatinine levels and blood pressure. Monitoring should occur prior to conversion, after 4 to 7 days and additional follow up may be required in the first 8 to 12 weeks. Dose should be adjusted depending on these results.
Therapeutic Drug Monitoring
Refer to local therapeutic drug monitoring service for specific local ciclosporin guidelines.
The routine determination of the minimum ciclosporin concentration in whole blood is an important safety measure within the scope of therapy monitoring in transplant patients. Blood ciclosporin levels should serve as a reference for treatment and should be supplemented by additional clinical and laboratory parameters.
Contraindications
Concurrent ultraviolet light therapy
Neonates under 1 month
Any malignancy - if treating atopic dermatitis
Any malignancy - if treating nephrotic syndrome
Any malignancy - if treating psoriasis
Any malignancy - if treating rheumatoid arthritis
Any malignancy - if treating uveitis
Breastfeeding
Renal impairment at baseline - if treating atopic dermatitis
Renal impairment at baseline - if treating psoriasis
Renal impairment at baseline - if treating rheumatoid arthritis
Renal impairment at baseline - if treating uveitis
Uncontrolled hypertension - if treating atopic dermatitis
Uncontrolled hypertension - if treating nephrotic syndrome
Uncontrolled hypertension - if treating psoriasis
Uncontrolled hypertension - if treating rheumatoid arthritis
Uncontrolled hypertension - if treating uveitis
Uncontrolled systemic infection - if treating atopic dermatitis
Uncontrolled systemic infection - if treating nephrotic syndrome
Uncontrolled systemic infection - if treating psoriasis
Uncontrolled systemic infection - if treating rheumatoid arthritis
Uncontrolled systemic infection - if treating uveitis
Precautions and Warnings
Acute infection
Children under 18 years
Epileptic disorder
Hepatic impairment
Hereditary fructose intolerance
Hyperkalaemia
Hyperuricaemia
Hypomagnesaemia
Neurological Behcet's syndrome
Pregnancy
Renal impairment
Administration of live vaccines is not recommended
Atopic dermatitis:Allow herpes simplex infection to clear before initiating
Atopic dermatitis:control staphylococcus skin infection with antibacterials
May be increased risk of skin cancer
Not all available brands are licensed for all indications
Psoriasis:exclude pre-malignant disease before treatment
Treatment to be initiated and supervised by a specialist
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain castor oil polyoxyl which may cause diarrhoea
Some formulations may contain alcohol
Prescribing by brand recommended to ensure consistent bioavailability
Atopic dermatitis:monitor renal function twice before initiating treatment
Monitor blood lipids before and during treatment
Monitor hepatic function before treatment and regularly during treatment
Nephrotic syndrome: Monitor serum Cr twice before initiation of treatment
Psoriasis:measure renal function twice before initiation of treatment
Rheumatoid arthritis:monitor serum Cr twice before initiating treatment
Uveitis: Monitor renal function twice before initiating
Atopic dermatitis: Biopsy if lymphadenopathy persists
Atopic dermatitis: monitor serum creatinine monthly after 1st 3 months
Atopic dermatitis: Reduce dose if eGFR falls 25% or more below baseline
Atopic dermatitis:monitor serum creatinine every 2 weeks for 1st 3 months
Behcet's syndrome: Monitor neurological status
Consider immunosuppressant adjustment in the event of PML
Consider monitoring plasma drug levels
Elderly: Monitor renal function and consider dose modification
Monitor and control serum magnesium levels in the peri-transplant period
Monitor blood pressure
Monitor renal function regularly
Monitor serum potassium regularly
Nephrotic syndrome: consider renal biopsies if treatment duration >1 year
Nephrotic syndrome: Reduce dose if eGFR falls 25% or more below baseline
Psoriasis: Reduce dose if eGFR falls 25% or more below baseline
Psoriasis:monitor serum creatinine every 2 weeks for first 3 months
Psoriasis:monitor serum creatinine monthly after 1st 3 months of treatment
Rheumatoid arthritis: Reduce dose if eGFR falls 25% or more below baseline
Rheumatoid arthritis:monitor serum creatinine every 2 weeks in 1st 3 months
Rheumatoid arthritis:monitor serum creatinine monthly after 1st 3 months
Uveitis: Reduce dose if eGFR falls 25% or more below baseline
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
Oversuppression of immune system may increase susceptibility to infection
Atopic dermatitis: stop if Cr not reduced within a month of dose reduction
Atopic dermatitis:discontinue if hypertension cannot be controlled
Discontinue if benign intracranial hypertension develops
Nephrotic syndrome: Stop if Cr not reduced within a month of dose reduction
Psoriasis: discontinue if Cr not reduced within a month of dose reduction
Psoriasis:discontinue if hypertension cannot be controlled
Rheumatoid arthritis: stop if Cr not reduced within month of dose reduction
Rheumatoid arthritis:discontinue if hypertension cannot be controlled
Uveitis: Discontinue if Cr not reduced within a month of dose reduction
Not licensed for all indications in all age groups
Advise patient not to take echinacea products concurrently
Advise patient not to take St John's wort concurrently
Avoid high dietary potassium intake
Do not eat grapefruit products with or one hour before dose
Advise patient on need for adequate dental hygiene & regular dental checks
Advise patient to avoid exposure to sunlight and UV rays during treatment
Hyperuricaemia, may be aggravated by ciclosporin 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.
Consider immunosuppressant adjustment if BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy (PML) or polyomavirus associated nephropathy (PVAN) develops. These conditions are often related to immunosuppressive burden. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed, treatment should be adjusted or permanently discontinued.
Monitor blood lipids before and one month after initiating treatment. Should blood lipids become elevated, the intake of dietary fats should be restricted and/or ciclosporin dose should be reduced.
Nephrotic syndrome
It may be difficult to distinguish ciclosporin induced renal dysfunction from that caused by the disease. If ciclosporin treatment has been maintained for more than 1 year, perform annual renal biopsies to assess disease progression and the extent of any ciclosporin induced changes in renal morphology.
Pregnancy and Lactation
Pregnancy
Ciclosporin should be used 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
Counselling
Advise patients to keep the medicine measure for the oral solution away from all other liquids (including water).
Advise patients not to consume a diet high in potassium.
Advise patients not to use grapefruit juice to dilute the oral solution, nor to ingest grapefruit products with, or one hour prior to the dose of ciclosporin.
Advise patient not to take echinacea products concurrently
Advise patients to avoid taking St John's Wort concurrently.
Advise patients to avoid excessive UV light.
Advise patients of need for high oral hygiene standards.
Side Effects
Abdominal pain
Agitation
Anaemia
Anorexia
Ataxia
Basal cell carcinoma
Benign breast neoplasm
Benign intracranial hypertension
BK virus associated with nephropathy
Cholestasis
Coma
Confusion
Convulsions
Cortical blindness
Decrease in mental acuity
Diarrhoea
Disorientation
Encephalopathy
Fatigue
Fluid retention
Gastro-intestinal disturbances
Gingival hyperplasia
Gynaecomastia
Haemolytic uraemic syndrome
Headache
Hepatic failure
Hepatic impairment
Hepatitis
Hypercholesterolaemia
Hyperglycaemia
Hyperkalaemia
Hyperlipidaemia
Hypertension
Hypertrichosis
Hyperuricaemia
Hypomagnesaemia
Infections
Insomnia
Jaundice
Lymphoma
Lymphoproliferative disorders
Malignancies
Menstrual disturbances
Microangiopathic haemolytic anaemia syndrome
Migraine
Muscle weakness
Muscular cramps
Myalgia
Myopathy
Nausea
Oedema
Optic disc oedema
Pancreatitis
Papilloedema
Paraesthesia
Paresis
Polyneuropathy
Polyomavirus associated nephropathy
Posterior reversible encephalopathy syndrome (PRES)
Progressive multifocal leukoencephalopathy (PML)
Rash (allergic)
Renal impairment
Renal structural changes
Serum creatinine increased
Serum urea increased
Skin papilloma
Squamous cell carcinoma
Thrombocytopenia
Tremor
Visual disturbances
Vomiting
Weight gain
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 2015
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, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Summary of Product Characteristics: Capimune 25mg capsules. Generics UK Ltd. Revised May 2014.
Summary of Product Characteristics: Capimune 50mg capsules. Generics UK Ltd. Revised May 2014.
Summary of Product Characteristics: Capimune 100mg capsules. Generics UK Ltd. Revised May 2014.
Summary of Product Characteristics: Capsorin 25mg capsules. Morningside Healthcare Ltd. Revised March 2015.
Summary of Product Characteristics: Capsorin 50mg capsules. Morningside Healthcare Ltd. Revised March 2015.
Summary of Product Characteristics: Capsorin 100mg capsules. Morningside Healthcare Ltd. Revised March 2015.
Summary of Product Characteristics: Capsorin 100mg per ml oral solution. Morningside Healthcare Ltd. Revised May 2015
Summary of Product Characteristics: Deximune capsules. Dexcel Pharma. Revised January 2014.
Summary of Product Characteristics: Neoral Soft Gelatin Capsules. Novartis Pharmaceuticals UK Ltd. Revised January 2015.
Summary of Product Characteristics: Neoral Oral Solution. Novartis Pharmaceuticals UK Ltd. Revised January 2015.
Summary of Product Characteristics: Sandimmun 25mg capsules. Novartis Pharmaceuticals UK Ltd. Revised February 2014.
Summary of Product Characteristics: Sandimmun 50mg capsules. Novartis Pharmaceuticals UK Ltd. Revised February 2014.
Summary of Product Characteristics: Sandimmun 100mg capsules. Novartis Pharmaceuticals UK Ltd. Revised February 2014.
Summary of Product Characteristics: Sandimmun Oral solution. Novartis Pharmaceuticals UK Ltd. Revised February 2014.
Summary of Product Characteristics: Vanquoral 10mg capsules. Teva UK Ltd. Revised April 2014.
Summary of Product Characteristics: Vanquoral 25mg capsules. Teva UK Ltd. Revised April 2014.
Summary of Product Characteristics: Vanquoral 50mg capsules. Teva UK Ltd. Revised April 2014.
Summary of Product Characteristics: Vanquoral 100mg capsules. Teva UK Ltd. Revised April 2014.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 29 October 2018.
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
Ciclosporin Last revised: 30 January 2015
Last accessed: 24 September 2015.
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