Cyclosporin

ADMINISTRATION ROUTES:

PO, IV

ALTERNATIVE NAMES:

Neoral, Sandimmun

ICU INDICATIONS:

It is unusual for this medication to be commenced in the ICU. Patients admitted to ICU may be on cyclosporin at the time of admission for the following indications:

1. Solid organ transplant rejection prophylaxis
2. Bone marrow transplant rejection prophylaxis
3. Inflammatory disorders such as rheumatoid arthritis, uveitis and psoriasis

Note: Decisions about indications and dosage of cyclosporin in ICU patients should be made in consultation with the relevant specialty team (Renal, Haematology, Rheumatology etc.)

PRESENTATION AND ADMINISTRATION:

IV:

Cyclosporin injection is a concentrate that must be diluted prior to IV infusion. It is an oily, faintly yellow coloured solution that contains polyoxyethylated castor oil 65% w/v, ethanol 33% v/v and with air in vials replaced by nitrogen

Dilute the concentrate 1:20 to 1:100 by volume (e.g. 50 mg in 20-100 mL) with compatible IV fluid. Ensure concentrate is well mixed in diluent fluid to reduce risk of an initial bolus of heavier non-solubilised polyoxyethylated castor oil, which carries an increased risk of anaphylactoid reactions. Diluted solution for infusion is clear and oily. Visually inspect infusion concentrated and infusion solution for particulate matter and/or discolouration. Administer diluted infusion solution over 2-6 hours

Compatible with: Normal saline, 5% dextrose

Use glass containers or 5% dextrose in EXCEL containers (non PVC).

Do not mix with other fluids or medications.

Discard any remaining concentrate after preparation of required dose.

Discard any diluted fluid not used within 24 hours of preparation.

Store at room temperature. Protect from light

PO:

Neoral 25mg, 50 mg and 100 mg capsules Neoral oral solution (100 mg/mL)

DOSAGE:

Dosing should be titrated based on clinical assessments of rejection and tolerability and is generally directed by the primary medical team responsible for the transplant (Renal, Haematology etc.)

IV:

Variable. General range 1-5 mg/kg/day

PO:

Variable. General range 3-15 mg/kg/day

Note: Recommended IV dosage is approximately one third of oral dosage

See Laboratory Tests for information about mandatory therapeutic drug monitoring

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Dose reduction is generally required and is based on therapeutic drug monitoring (see Laboratory Tests for information about therapeutic drug monitoring)

DOSAGE IN PAEDIATRICS:

Seek specialist paediatric advice

CLINICAL PHARMACOLOGY:

Cyclosporin is a potent immunosuppressive agent that prolongs survival of allogeneic transplants involving kidney, liver, heart, pancreas, bone marrow, small intestine, and lung.

CONTRAINDICATIONS:

1. Hypersensitivity to cyclosporin
2. Uncontrolled hypertension
3. Malignancy

WARNINGS:

Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the degree of immunosuppression in patients treated with cyclosporin.

Cyclosporin can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporin therapy.

Cyclosporin can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses.

PRECAUTIONS:

General:

During treatment with cyclosporin, vaccination may be less effective; and the use of live attenuated vaccines should be avoided

Laboratory Tests:

Cyclosporin has a narrow therapeutic index with variable pharmacokinetics; therapeutic monitoring is required in critically ill patients. It is usually appropriate to measure levels twice weekly.

Two strategies are used for monitoring:

• Measure concentration of drug 1 hour before the next dose ('trough sampling', termed C0)
• Measure concentration of drug 2 hours after a dose is given (termed C2)

C0 sampling has been widely used although this may be a weak indicator of drug absorption. Moreover, the results are assay-dependent as samples of this type contain a large proportion of metabolite that may interfere.

C2 sampling is an acceptable surrogate for absorption (measured as the area under the concentration-time curve). Moreover, most of the measured drug found at this time is parent drug, making the measurement relatively free of interference from metabolites. One disadvantage is the need for samples to be taken close to the 2 hour time-point (+ or -15 minutes).

Factors affecting the target ranges for treatment include time of sampling (C0 or C2), organ transplanted, time since transplantation, and other medications.

Specific recommended target concentrations for transplant patients may vary in individual cases on the basis of age, gender, renal function, number of episodes of rejection, and concomitant immunosuppressive medication. Guidance to therapeutic ranges is shown below.

Target C0 (trough) ranges are as follows:

Organ	Phase	Target Range C0 (ng/mL)
Liver	Induction	225-300
Liver	Maintenance	100-150
Heart	Induction	250-325
Heart	Maintenance	125-175
Kidney	Induction	150-225
Kidney	Maintenance	100-180
Bone Marrow	Induction	95-205
Bone Marrow	Maintenance	95-205
Autoimmune	Induction	150-200
Autoimmune	Maintenance	100-150

Target C2 ranges are as follows:

Organ	Time Post Transplant	Target Range C2 (ng/mL)
Liver	0-3 months	800-1200
Liver	3-6 months	640-960
Liver	>6 months	480-720
Kidney	1 month	1360-2040
Kidney	2 months	1200-1800
Kidney	3 months	1040-1560
Kidney	4-6 months	880-1320
Kidney	6-12 months	720-1080
Kidney	>12 months	640-960
Lung	0-2 days	>800
Lung	1-7 days	1200
Lung	1-4 weeks	1200-1700
Lung	2 months	1000-1500
Lung	3 months	800-1200
Lung	4-6 months	700-1000
Lung	7-12 months	600-900
Lung	>12 months	600-800

Note: samples for therapeutic monitoring should be collected in an EDTA (Purple tube). Clearly write on the sample request when the sample was taken with respect to the dose:

• Samples for C0 monitoring must be taken one hour before the next dose is due
• Samples for C2 monitoring must be taken 2 hours +/-15 minutes after the most recent dose

Drug/Laboratory Test Interactions:

Nil of note

IMPORTANT DRUG INTERACTIONS IN ICU:

All of the individual drugs listed below are known to interact with cyclosporin

Drugs That May Potentiate Renal Dysfunction:

• Antibiotics: Gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole

• Antineoplastics: Melphalan

• Antifungals: Amphotericin B, ketoconazole

• Anti-Inflammatory Drugs: Azapropazon, diclofenac, naproxen, sulindac, colchicine

• Gastrointestinal Agents: Cimetidine, ranitidine

• Immunosuppressives: Tacrolimus

Drugs That Alter Cyclosporin Concentrations:

Cyclosporin is extensively metabolised by cytochrome P-450 3A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporin concentrations. Substances that are inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporin concentrations. Monitoring of circulating cyclosporin concentrations and appropriate dosage adjustment are essential when these drugs are used concomitantly.

Drugs That Increase Cyclosporin Concentrations

• Calcium Channel Blockers: Diltiazem, nicardipine, verapamil

• Antifungals: Fluconazole, itraconazole, ketoconazole

• Antibiotics: Clarithromycin, erythromycin, quinupristin/daldopristin

• Glucocorticoids: Methylprednisolone

• Other Drugs: Allopurinol, bromocriptine, danazol, metoclopramide, colchicine, amiodarone

The HIV protease inhibitors (e.g. indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporin, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly

Drugs/Dietary Supplements That Decrease Cyclosporin Concentrations

• Antibiotics: Nafcillin, rifampin
• Anticonvulsants: Carbamazepine, phenobarbital, phenytoin
• Other Drugs: Octreotide, ticlopidine, orlistat, St. John's Wort

Other Drug Interactions:

Cyclosporin may reduce the clearance of digoxin, colchicine, prednisolone and HMG- CoA reductase inhibitors (statins). Severe digitalis toxicity has been seen within days of starting cyclosporin in several patients taking digoxin. There are also reports on the potential of cyclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction.

Cyclosporin should not be used with potassium-sparing diuretics because hyperkalaemia can occur.

ADVERSE REACTIONS:

Central nervous system:

Tremor, convulsions, headache, paraesthesia

Cardiovascular system:

Hypertension, arrhythmia

Gastrointestinal system:

Stomatitis, gum hyperplasia, diarrhoea, nausea/vomiting, hepatotoxicity, abdominal discomfort

Haematological system:

Leukopaenia, Lymphoma

Urogenital system:

Renal failure

Endocrine system:

Hirsutism, Gynaecomastia

Musculoskeletal system:

Cramps

Metabolic system:

Hypomagnesaemia