Ciclosporin a

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Ciclosporin; Cyclosporine; Cyclosporins

Definition
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Immunosuppressive, highly lipophilic, membrane permeable, cyclic polypeptide ( calcineurin inhibitors). Binds in the cytoplasm to the immunophilin cyclophilin (CyP; responsible for the intracellular metabolism of newly synthesized proteins).

Pharmacodynamics (Effect)
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The binding of the CyA/CyP complex to the Ca/Calmodulin dependent phosphatase calcineurin is responsible for the therapeutic effect.

Calcineurin is responsible for the dephosphorylation of the nuclear factor of activated T cells (NFAT).

NFAT is translocated into the cell nucleus where it induces the transcription of numerous genes.

The phosphatase activity of the enzyme calcineurin is inhibited by binding to the CyA/CyP complex, thus inhibiting the translocation of NFAT. The result: inhibition of the transcription of numerous cytokine genes such as IL-1, IL-2, IL-4, IL-8 (see below interleukins), TNF-alpha, INF-gamma.

Indication
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Drug of the 2nd to 3rd choice for autoimmune diseases and diseases associated with impaired keratinization, especially systemic lupus erythematosus, systemic scleroderma, M. Behçet, dermatomyositis, sarcoidosis, T-cell lymphomas, pemphigus vulgaris, bullous pemphigoid, psoriasis vulgaris, atopic eczema (most severe forms), lichen planus mucosae (topical application also possible), rheumatoid arthritis.

Limited indication
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For example, cutaneous precanceroses or carcinomas, hyperlipidemia, hyperuricemia, pregnancy (intrauterine growth retardation).

Dosage and method of use
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  • Systemic: Initial 2.5-7.5 mg/kg bw/day p.o., after one month gradual reduction to a maintenance dose of 1-2.5 mg/kg bw/day. By determining the blood plasma level, an optimal effective level of 100-200 ng/ml can be set (blood sample in the morning, before taking the preparation!).

Notice! Before the therapy: BB and check of the kidney function!

Undesirable effects
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Cutaneous ADRs: hyperhidrosis, allergic reactions, urticaria, pruritus, periorbital edema, benign ( sebaceous gland hyperplasia) and malignant skin tumors (especially in combination with phototherapy), acne, hirsutism, hypertrichosis, gingival hyperplasia.

Extracutaneous ADRs: BB alterations, hyperglycaemia, gynaecomastia, amenorrhoea, spermatogenesis inhibition, sinusitis, gastrointestinal disorders, liver damage, hypertension, edema, headache, seizures, paresthesias, kidney damage, hearing loss, visual disturbances, myalgias, arthralgias, rhabdomyolysis.

Interactions
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The interaction of Ciclosporin with CYP enzymes (CYP3A4) can lead to an increased or decreased clerance of drugs (see also enzyme induction). S. Tab.

Contraindication
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Hypertension, children and adolescents < 18 years of age (in case of psoriasis vulgaris indication), severe liver damage (in case of psoriasis vulgaris indication), lactation, hypersensitivity to the active substance or excipient Cremophor EL, pustular psoriasis, psoriatic erythroderma.

Notice! After a Ciclosporin therapy, PUVA therapy must not be used because of an increased risk of spinocellular carcinoma!

Recipe(s)
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Ciclosporin A adhesive paste 2,5%.

Ciclosporin A solution 1-2% (according to Altmeyer - R047)

Preparations
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Sandimmun, Sandimmun Optoral; Immunosporin

Note(s)
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  • Conclusion for the indication psoriasis: Ciclosporin is an effective antipsoriatic agent (rapid reduction of PASI and skin findings as well as increase of the patient's quality of life); side effects (malignomrisko, nephrotoxicity, hypertension) are to be minimized by an advantage of short-term therapy over long-term therapy.
  • Ciclosporin A (e.g. immunosporin) is approved for systemic therapy of atopic eczema. Encouraging studies have been published regarding the effectiveness of Ciclosporin for the systemic treatment of severe forms of atopic eczema. 73 volunteers were treated with Ciclosporin (2.5-5 mg/kg bw/day) on average over 1.13 years. Within the first weeks of therapy, a rapid clinical improvement was observed, with 77% of the subjects receiving successful treatment. The main adverse drug reactions were creatinine increase and arterial hypertension. A rebound phenomenon (recurrence of clinical symptoms, more severe than before therapy) occurred in 8% of the subjects after the end of treatment.

Notice! Practical advice to reduce potential nephrotoxicity: Limit the dose of Ciclosporin to max. 5 mg/kg bw/day. Check creatinine 2 times before starting therapy. Serum creatinine follow-up every 2 weeks for the first 3 months, then monthly. Regular control of the blood pressure. The duration of therapy should be kept as short as possible.

Literature
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  1. Bornhovd EC et al (2000) Immunosuppressive macrolides and their use in dermatology. Dermatologist 51: 646-654
  2. Boschnakow A et al (2003) Ciclosporin A-induced sebaceous gland hyperplasia. Br J Dermatol 149: 198-200
  3. Heydendael VM et al (2003) Methotrexate versus cyclosporine in moderate to severe chronic plaque psoriasis. N Engl J Med 349: 658-665
  4. Hijnen DJ et al (2007) Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol 21: 85-89
  5. Ho VC (2004) The use of ciclosporin in psoriasis: a clinical review Br J Dermatol 150 (Suppl. 67): 1-10
  6. Ortiz-Urda S et al (2003) New immunosuppressive agents for treating psoriasis. dermatologist 54: 230-236
  7. Sano S et al (2003) Treatment of primary erythromelalgia with cyclosporine. N Engl J Med 349: 816-817
  8. Zouboulis C et al (2003) Ciclosporin A - induced sebaceous glands hyperplasia. Br J Dermatol 149: 198-200

Tables
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Significant interactions of Ciclosporin A

Allopurinol

Allopurinol levels ↑

Acetazolamide

Renal damage, Ciclosporin toxicity ↑

Barbiturates

Ciclosporin levels ↓

Calcium antagonists

Ciclosporin level ↑, if necessary reduce Ciclosporin dosage

Carbamazepine

Ciclosporin levels ↓

Colchicine

Myopathy risk ↑, kidney damage, rhabdomyolysis

Coumarins

Coumarin effect ↓, thrombosis risk ↑

Diflunisal

Mutual toxicity ↑, careful monitoring of kidney function

Digoxin

Digoxin toxicity ↑

diuretics, potassium-sparing

Hyperkalemia, avoid combination

Furosemide

hyperuricemia, attack of gout

Grapefruit juice

Ciclosporin levels up to 1/3 ↑, kidney damage

HMG-CoA reductase inhibitor

Myopathy risk ↑, avoid combination

Potassium preparations

Hyperkalemia, avoid combination

Contraceptives, hormonal

Ciclosporin levels ↑, liver damage

Live virus vaccines

Vaccine effect ↓, avoid combination

Metamizole

Ciclosporin levels ↓

Metoclopramide

Ciclosporin levels ↑, liver and kidney damage

NSAID

Kidney damage, check kidney function under therapy

Phenytoin

Ciclosporin levels ↓

Prednisolone

Prednisolone mirror ↑

Thiazide diuretics

kidney damage, gout, avoid combination

Inactivated vaccines

Vaccine effect ↓

Ursodesoxycholic acid

Ciclosporin levels ↑

Authors

Last updated on: 29.10.2020