Uses and Administration of Ciclosporin in Kenya
Ciclosporin or Cyclosporin in Kenya is a powerful immunosuppressant which appears to act specifically on lymphocytes, mainly helper T-cells. It inhibits the activation of calcineurin, an important step in the production of lymphokines including interleukin-2, resulting in a depression of cell-mediated immune response. Unlike cytotoxic immunosuppressants such as cyclophosphamide it has little effect on bone marrow.
Ciclosporin is used in Kenya, usually with corticosteroids (and often with other immunosuppressants), in organ and tissue transplantation for the prophylaxis of graft rejection, or in the management of graft rejection in patients previously treated with other immunosuppressants. It is also used in severe forms of atopic dermatitis, psoriasis, or rheumatoid arthritis, usually when conventional therapy is ineffective or inappropriate, and is used in nephrotic syndrome.
Ciclosporin has been tried in various other diseases in Kenya considered to have an auto-immune component as indicated by the cross-references given below; they include aplastic anaemia, asthma, Beh√ßet’s syndrome, chronic active hepatitis, multiple sclerosis, myasthenia gravis, sarcoidosis, scleritis or uveitis, scleroderma, and various skin disorders.
Cyclosporin is given by mouth as liquid-filled capsules or as an oily solution, which may be diluted with milk or fruit juice (not grapefruit) immediately before administration to improve palatability. Microemulsion formulations with improved bioavailability are available in a number of countries including Kenya. When changing between preparations, the initial dose of the new formulation should be the same (mg for mg), and should subsequently be adjusted as necessary based on blood-cyclosporin concentrations, serum creatinine, and blood pressure monitoring. The daily dose of ciclosporin is taken in 2 divided doses, although the conventional formulation is sometimes given as a single daily dose.
In organ transplantation the usual initial dose of ciclosporin is 10 to 15 mg/kg daily, given by mouth, beginning 4 to 12 hours before transplantation, and continued for 1 to 2 weeks; lower initial doses may be given with other immunosuppressants (e.g. with corticosteroids or as part of ‘triple’ or ‘quadruple’ therapy). Dosage may subsequently be reduced gradually to a daily maintenance dose of 2 to 6 mg/kg.
Kidney function and blood pressure should be monitored regularly, as well as blood concentrations of ciclosporin, and dosage should be adjusted as necessary. Hepatic function should also be monitored keenly overtime.
Ciclosporin may also be given intravenously, at one-third of the oral dose, in patients in whom oral dosage is not feasible. It is given by slow intravenous infusion over 2 to 6 hours, the 5% concentrate being diluted 1:20 to 1:100 in sodium chloride 0.9% or glucose 5%, to give a 0.05 to 0.25% solution of ciclosporin. Because of the risk of anaphylactoid reactions, which have been attributed to the polyethoxylated castor oil vehicle, patients should be transferred to oral therapy as soon as possible.
For the prevention of graft rejection in bone marrow transplantation, and prevention and treatment of graft-versus-host disease, an initial dose of 3 to 5 mg/kg daily by the intravenous route is recommended, starting the day before transplantation and continuing for up to 2 weeks until maintenance by mouth, in doses of 12.5 mg/kg daily can be instituted. If oral treatment is used to initiate therapy the recommended dose is 12.5 to 15 mg/kg daily followed by 12.5 mg/kg daily for maintenance. The maintenance dose is continued for at least 3 to 6 months, then gradually reduced until ciclosporin is withdrawn altogether; this may take up to a year after transplantation.
In the treatment of psoriasis, ciclosporin may be given in usual initial doses of 2.5 mg/kg daily (a maximum of 5 mg/kg daily is recommended in the UK and Kenya and 4 mg/kg daily in the USA), in 2 divided doses by mouth, reduced once remission is achieved to the lowest effective maintenance dose. Treatment should be stopped if there is insufficient response to the maximum dose within 6 weeks. A similar dosage range may be given for a maximum of 8 weeks in the treatment of severe atopic dermatitis.
In treatment of rheumatoid arthritis in Kenya; ciclosporin may be given by mouth in initial daily doses of 2.5 mg/kg, divided into two doses, for a period of 6 or 8 weeks. If the clinical effect is insufficient dosage may then be gradually increased to a maximum of 4 mg/kg daily; if there is no response after 3 to 4 months, treatment should be stopped.
For nephrotic syndrome secondary to glomerular kidney disease (minimal change nephropathy, focal glomerulosclerosis, or membranous nephropathy) dosage of ciclosporin depends on age and renal function. To induce remission in patients with normal renal function 5 mg/kg daily may be given to adults and 6 mg/kg daily to children, in 2 divided doses by mouth. In patients with renal impairment the initial dose should not exceed 2.5 mg/kg daily. Treatment may be stopped if there is no response after 3 months (or 6 months in patients with membranous nephropathy). In patients who do respond, maintenance doses should be gradually reduced to the minimum effective value.
Eye drops containing ciclosporin 0.05% are used in the management of dry eye associated with ocular inflammation.
Ciclosporin can inhibit the P-glycoprotein cellular pump responsible for multidrug resistance, and has been given with antineoplastics to raise their intracellular concentrations. Nonimmunosuppressive ciclosporin analogues such as valspodar are also being investigated for their ability to reverse multidrug resistance.
Common Adverse Effects and Side Effects of Cyclosporin
Nephrotoxicity, manifesting as raised serum creatinine and urea, is the major adverse effect of ciclosporin and occurs in approximately one-third of all Kenyan patients. It is related to drug-plasma concentrations and is usually reversible on reduction of the dose. In renal graft recipients episodes of nephrotoxicity may be difficult to distinguish from graft rejection. Interstitial fibrosis may develop during long-term therapy.
Other frequent adverse effects include hypertension, gastrointestinal disturbances, hepatotoxicity, hypertrichosis, gum hyperplasia, tremor, headaches, hyperlipidaemias, electrolyte disturbances (hyperkalaemia, hypomagnesaemia), paraesthesia, hyperuricaemia, and muscle cramps and myalgia. Less commonly, anaemia, rashes, weight increase, oedema, pancreatitis, myopathy, neuropathy, and convulsions have been reported. Optic disc oedema, including papilloedema secondary to benign intracranial hypertension, has occurred rarely.
Anaphylactoid reactions have occurred following intravenous administration; it has been suggested that these represent a reaction to the polyethoxylated castor oil vehicle of the intravenous preparation.
There is an increased incidence of certain malignancies and a predisposition to infection in patients receiving ciclosporin therapy.
Incompatibility of Cyclosporin
- 1. Pearson SD, Trissel LA. Leaching of diethylhexyl phthalate from polyvinyl chloride containers by selected drugs and formulation components. Am J Hosp Pharm 1993; 50: 1405¬ñ9. PubMed
Stability of Ciclosporin
- 1. McLeod HL, et al. Stability of cyclosporin in dextrose 5%, NaCl 0.9%, dextrose/amino acid solution, and lipid emulsion. Ann Pharmacother 1992; 26: 172¬ñ5. PubMed
- 2. Ghnassia LT, et al. Stability of cyclosporine in an extemporaneously compounded paste. Am J Health-Syst Pharm 1995; 52: 2204¬ñ7. PubMed
Can a Breastfeeding Mother Take Cyclosporin?
The American Academy of Pediatrics considers that ciclosporin may possibly suppress the immune system in a nursing infant. However, a study in the breast-fed infants of 7 women receiving ciclosporin found that the amounts ingested produced undetectable blood concentrations in the infants. In another case it was estimated that a breast-fed infant received less than 100 micrograms/kg of ciclosporin daily.
Pregnancy and the use of Cyclosporin in Kenya.
Ciclosporin has been used successfully in pregnant women. However, in common with other immunosuppressants, fetal growth retardation may be a significant problem. Patients with hypertension or graft dysfunction are more likely to have adverse outcomes, so patients should have stable graft function and be on maintenance therapy before considering pregnancy. Serum ciclosporin concentrations may fall during pregnancy
- 2. Armenti VT, et al. National Transplantation Pregnancy Registry (NTPR): cyclosporine dosing and pregnancy outcome in female renal transplant recipients. Transplant Proc 1996; 28: 2111¬ñ12. PubMed
but although frequent monitoring is necessary, the suppressed auto-immune state of pregnancy may protect against rejection episodes. Ciclosporin should be used at the lowest possible dose to maintain efficacy, and one review has recommended that the daily dose should be kept below 5 mg/kg.
One case of osseous malformation, resulting in hypoplasia of the right leg has been reported in an infant born to a ciclosporin-treated mother.
Interactions of Cyclosporin with other drugs
Ciclosporin is extensively metabolised in the liver and plasma-ciclosporin concentrations may be affected by inducers or competitive inhibitors of hepatic enzymes, particularly cytochrome P450 isoenzyme CYP3A4. For example, use of carbamazepine, phenytoin, phenobarbital, rifampicin, and other inducers of hepatic enzymes may lead to lower plasma concentrations of ciclosporin, and increased plasma concentrations have been reported with some antifungals, macrolide antibiotics, some calcium-channel blockers, sex hormones, corticosteroids and grapefruit juice. In transplant patients frequent measurement of plasma ciclosporin and, if necessary, ciclosporin dosage adjustment is required, particularly during the introduction or withdrawal of other drugs.
Concurrent use of statins may increase the risk of myopathy and rhabdomyolysis. Potassium-sparing diuretics should be avoided because of the risk of hyperkalaemia, and patients taking ciclosporin should avoid a high dietary intake of potassium. The risk of gingival hyperplasia may be increased by amlodipine or nifedipine.
During treatment with ciclosporin, vaccination may be less effective, and the use of live vaccines should generally be avoided.
Care should be taken when ciclosporin is given concomitantly with other nephrotoxic drugs in Kenya.
Single-ingredient Preparations of Cyclosporin
The symbol ¬§ denotes a preparation which is discontinued or no longer actively marketed.
KENYA: ARPIMUNE Arg.: Cermox; Gengraf; Sandimmun; Austral.: Cysporin; Neoral; Sandimmun; Austria: Cicloralhexal; Sandimmun; Belg.: Neoral-Sandimmun; Sandimmun; Braz.: Gengraf; Sandimmun; Sigmasporin¬§; Canad.: Neoral; Sandimmune; Chile: Sandimmun; Denm.: Sandimmun; Fin.: Sandimmun; Fr.: Neoral; Sandimmun; Ger.: Cicloral; Sandimmun; Gr.: Sandimmun Neoral; Sandimmun; Hong Kong: Gengraf; Sandimmun; Hung.: Sandimmun; India: Imusporin; Panimun Bioral; Sandimmun Neoral; Irl.: Neoral; Sandimmun; Israel: Deximune; Sandimmun; Sangcya; Ital.: Sandimmun; Malaysia: Sandimmun; Mex.: Colosina¬§; Immulem; Sandimmun; Neth.: Neoral; Sandimmune; Norw.: Sandimmun; NZ: Neoral; Sandimmun; Port.: Sandimmun; S.Afr.: Ciclohexal; Sandimmun; Singapore: Sandimmun Neoral¬§; Spain: Sandimmun; Swed.: Sandimmun; Switz.: Neoral; Sandimmun; Thai.: Consupren; Sandimmun; UAE: Sigmasporin; UK: Neoral; Sandimmun; Sangcya¬§; USA: Gengraf; Neoral; Restasis; Sandimmune;