Intravenous Prophylaxis of graft rejection in bone marrow transplantation
Adult: Initially, 3-5 mg/kg daily via infusion over 2-6 hours given on the day before transplantation and continued for up to 2 weeks postoperatively until oral maintenance doses can be initiated.
Intravenous Immunosuppression in organ transplantation
Adult: In patients whom oral dosage is not feasible: Approx 1/3 of the oral dose via slow infusion over 2-6 hours. Alternatively, initial dose of 5-6 mg/kg daily via slow infusion over 2-6 hours given 4-12 hours before transplantation and continued postoperatively. Transfer to oral therapy as soon as possible. Dosing information may vary between countries and individual products, refer to detailed product or local treatment guideline.
Intravenous Graft versus host disease
Adult: As prophylaxis and treatment: Initially, 3-5 mg/kg daily via infusion over 2-6 hours given on the day before transplantation and continued for up to 2 weeks postoperatively until oral maintenance doses can be initiated.
Ophthalmic Keratoconjunctivitis sicca
Adult: As 0.09% eye drop solution or 0.05% eye drop emulsion: Instil 1 drop onto each eye bid (approx 12 hours apart). As 0.1% eye drop emulsion: Instil 1 drop once daily onto the affected eye(s) at bedtime. Child: ≥16 years As 0.05% eye drop emulsion: Same as adult dose.
Ophthalmic Severe keratitis in dry eye disease
Adult: In patients who are unresponsive to treatment with tear substitutes: As 0.1% eye drop emulsion: Instil 1 drop once daily onto the affected eye(s) at bedtime.
Oral Nephrotic syndrome
Adult: Induction of remission: 5 mg/kg daily in 2 divided doses. Reduce maintenance dose to the lowest effective value. Discontinue treatment if response is not achieved after 3-6 months (depending on the type of glomerulopathy). Child: ≥16 years 6 mg/kg daily in 2 divided doses.
Oral Severe active rheumatoid arthritis
Adult: In patients with refractory cases: Recommended dose: 3 mg/kg daily in 2 divided doses for 6 weeks. Dose may be increased gradually according to patient tolerability and response. Max: 5 mg/kg daily. Alternatively, as monotherapy or in combination with low-dose methotrexate (in patients with insufficient response to methotrexate monotherapy): Initially, 2.5 mg/kg daily in 2 divided doses. Titrate maintenance dose individually to the lowest effective value according to patient tolerability. Dosing information may vary between countries and individual products, refer to detailed product or local treatment guideline.
Oral Severe psoriasis
Adult: In patients with refractory cases or whom standard therapy is inappropriate: Initially, 2.5 mg/kg daily in 2 divided doses. Dose may be increased gradually if there is no improvement after 1 month. Discontinue treatment if response is insufficient to the max dose within 6 weeks or once satisfactory response is achieved. Subsequent relapse may be managed with re-introduction of the previous effective dose. Max: 5 mg/kg daily or 4 mg/kg daily. Titrate maintenance dose individually to the lowest effective value.
Oral Immunosuppression in organ transplantation
Adult: Initially, 10-15 mg/kg daily given in 2 divided doses starting 4-12 hours before transplantation and continued for 1-2 weeks postoperatively, being gradually reduced based on blood levels according to local immunosuppressive protocols. Usual maintenance: 2-6 mg/kg daily in 2 divided doses. Lower initial doses may be given in combination with other immunosuppressants (e.g. corticosteroids).
Oral Severe atopic dermatitis
Adult: In patients with refractory cases or whom standard therapy is inappropriate: Initially, 2.5 mg/kg daily in 2 divided doses, may be increased rapidly to 5 mg/kg daily within 2 weeks if response is inadequate. Reduce dose gradually and discontinue treatment once satisfactory response is achieved. Max duration of treatment: 8 weeks. Max: 5 mg/kg daily.
Oral Prophylaxis of graft rejection in bone marrow transplantation
Adult: As an alternative initial therapy: 12.5-15 mg/kg daily in 2 divided doses starting on the day before transplantation. Maintenance: 12.5 mg/kg daily in 2 divided doses for 3-6 months. Dose may be reduced gradually until withdrawn, may take up to 1 year after transplantation.
Oral Graft versus host disease
Adult: As an alternative initial treatment or prophylaxis: Initially, 12.5-15 mg/kg daily in 2 divided doses starting on the day before transplantation. Maintenance: 12.5 mg/kg daily in 2 divided doses for 3-6 months. Dose may be reduced gradually until withdrawn.
Renal Impairment
Nephrotic syndrome:
Initially, 2.5 mg/kg daily.
Hepatic Impairment
PO; IV:
Severe: Dose reduction may be necessary.
Administration
May be taken with or without food. Take consistently w/ regard to time of day & relation to meals. Avoid grapefruit juice.
Reconstitution
Oral solution: Mix the required dose with the appropriate diluent (e.g. orange juice). Avoid mixing with grapefruit juice. IV inj: Further dilute 1 mL (50 mg) with 20-100 mL of 0.9% NaCl or 5% dextrose in water. Reconstitution may vary among preparations, refer to specific product guidelines.
Contraindications
Non-transplant indications: Abnormal renal function (except in nephrotic syndrome), uncontrolled hypertension, malignant neoplasms, uncontrolled infections. Psoriasis; atopic dermatitis: Patient receiving psoralen and ultraviolet A (PUVA) photochemotherapy, ultraviolet B (UVB) irradiation, or other radiation therapy. Concomitant use with coal tar, methotrexate or other immunosuppressive agents (in psoriatic patient). Lactation. Ophthalmic: Active or suspected ocular or peri-ocular infection, malignancies or premalignant conditions.
Special Precautions
Patients with hyperuricaemia; on K-rich diet; history of ocular herpes, glaucoma (ophthalmic). Hepatic impairment. Children. Pregnancy. Patient taking substrates of P-glycoprotein (P-gp) or organic anion transporter proteins (OATP) and products containing St. John’s wort. Avoid immunisation with live vaccines.
Adverse Reactions
Significant: Infections (bacterial, fungal, parasitic, viral), gingival hyperplasia, nephrotoxicity (e.g. renal dysfunction, increased serum creatinine and urea), seizures, encephalopathy (including posterior reversible encephalopathy syndrome), hypertension, microangiopathic haemolytic anaemia, thrombocytopenia, hyperkalaemia, hyperuricaemia; anaphylactoid reactions (IV). Blood and lymphatic system disorders: Anaemia, leucopenia. Cardiac disorders: MI. Eye disorders: Eye pain, burning or foreign body sensation in the eye, visual disturbance, conjunctival hyperemia, blepharitis, epiphora, eye discharge, eye irritation. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain/discomfort, dyspepsia, flatulence, tongue and tooth disorders, constipation, dysphagia, eructation, esophagitis, peptic ulcer, gastritis, gastroenteritis, glossitis, salivary gland enlargement, pancreatitis. General disorders and administration site conditions: Pyrexia, fatigue, increased sweating, asthenia. Immune system disorders: Angioedema. Metabolism and nutrition disorders: Decreased or increased weight, anorexia, hyperglycaemia, hyperlipidaemia, hypomagnesaemia. Musculoskeletal and connective tissue disorders: Muscle cramps, arthralgia, myalgia. Nervous system disorders: Tremor, headache, paraesthesia, neuropathy. Psychiatric disorders: Anxiety, confusion. Renal and urinary disorders: Haematuria, UTI, micturition urgency. Reproductive system and breast disorders: Gynaecomastia, menstrual disorder. Respiratory, thoracic and mediastinal disorders: Bronchospasm, upper respiratory tract infections, dyspnoea, rhinitis, cough. Skin and subcutaneous tissue disorders: Hirsutism/hypertrichosis, rash, abnormal pigmentation, dermatitis, dry skin, eczema, pruritus, urticaria, acne, nail disorder. Vascular disorders: Flushing. Potentially Fatal: Polyoma virus infections (e.g. JC virus-associated progressive multifocal leucoencephalopathy, polyoma virus-associated nephropathy due to BK virus), lymphomas and other malignancies (particularly of the skin), hepatotoxicity (usually manifested as increased hepatic enzymes and bilirubin) and liver injury (e.g. cholestasis, jaundice, hepatitis, liver failure).
Do not switch between brands or dosage forms unless instructed by your doctor. Avoid excessive exposure to sunlight or artificial UV light, use protective measures (e.g. sunscreen, protective clothing). Ophthalmic: Ciclosporin eye drops may cause blurred vision or other visual disturbances, if affected, do not drive or operate machinery. Remove contact lenses before administration and allow a 15-minute interval before reinserting lenses.
Monitoring Parameters
Perform physical and dermatological examination prior to treatment in patients with psoriasis or atopic dermatitis. Monitor plasma ciclosporin concentrations (particularly in transplant patients receiving conventional formulation), renal (serum BUN and creatinine) and liver function, serum glucose, serum lipids (prior to and after 1st month of therapy), blood pressure, uric acid, serum electrolytes (e.g. K, Mg) periodically or as clinically indicated. Assess for hypersensitivity reactions for 30 minutes after IV administration; hepatotoxicity, nephrotoxicity, secondary malignancy, infection, diabetes mellitus, progressive cognitive or motor deficits. Ophthalmic: Perform regular eye examination or reassess treatment every 6 months.
Overdosage
Symptoms: Headache, drowsiness, vomiting, tachycardia; transient hepatotoxicity and nephrotoxicity. Management: Symptomatic and supportive treatment. Stomach may be emptied by inducing emesis and performing gastric lavage.
Drug Interactions
Decreased plasma concentrations with inducers of CYP3A4 and/or P-gp (e.g. carbamazepine, nevirapine, phenytoin, phenobarbital, rifampicin, bosentan, orlistat). Increased plasma concentrations with CYP3A4 inhibitors (e.g. ketoconazole, azithromycin, ritonavir, delavirdine). Concomitant use with HMG-CoA reductase inhibitors (statins) may potentiate the risk of myopathy and rhabdomyolysis. May increase risk of gingival hyperplasia with nifedipine or amlodipine. May increase risk of hyperkalaemia with K-sparing diuretics, angiotensin II receptor antagonists, ACE inhibitors, K-containing products. May diminish efficacy of live vaccines. May increase plasma concentrations of substrates of CYP3A4, P-gp (e.g. aliskiren, dabigatran) and OATP. May increase risk of nephrotoxicity with aminoglycosides (e.g. gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim and sulfamethoxazole, fibric acid derivatives (e.g. fenofibrate, bezafibrate), NSAIDs (e.g. naproxen), melphalan, H2-receptor blockers (e.g. cimetidine), methotrexate, tacrolimus, everolimus. Potentially Fatal: Increased risk of developing malignancies of the skin with coal tar and other immunosuppressive agents (e.g. methotrexate) in psoriatic patients.
Food Interaction
Increased bioavailability of ciclosporin with grapefruit or grapefruit juice resulting in increased plasma concentrations. Decreased serum plasma concentrations with St. John’s wort.
Lab Interference
Cross reactivity may occur during radioimmunoassay and fluorescence polarisation immunoassay.
Action
Description: Mechanism of Action: Ciclosporin is a potent immunosuppressant that primarily acts on the helper T-cells. It inhibits the activation of calcineurin and blocks the release and production of interleukin-II, thereby decreasing cell-mediated immune response.
Synonyms: cyclosporin A, cyclosporine. Pharmacokinetics: Absorption: Incomplete and variable absorption from the gastrointestinal tract (conventional). Time to peak plasma concentration: Within 1.5-2 hours (microemulsion/modified); 2-6 hours (conventional). Distribution: Widely distributed throughout the body, particularly in tissues and body fluids including the liver, pancreas, and lungs. Crosses the placenta, enters breast milk. Volume of distribution: 3.5 L/kg. Plasma protein binding: 90-98%, mainly to lipoproteins. Metabolism: Extensively metabolised in the liver by the CYP3A4 isoenzyme via monohydroxylation, dihydroxylation and N-demethylation; undergoes extensive first pass effect after oral administration. Excretion: Mainly via faeces; urine (6%, 0.1% as unchanged drug). Elimination half-life: 10-27 hours (conventional); 5-18 hours (microemulsion/modified).
Chemical Structure
Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5284373, Cyclosporin A. https://pubchem.ncbi.nlm.nih.gov/compound/Ciclosporin. Accessed Oct. 27, 2020.
Storage
Microemulsion/modified cap/oral solution: Store between 20-25°C. Conventional cap/oral solution: Store below 30°C. Solution for inj: Store below 30°C. Protect from light. Ophthalmic drops: Store between 20-25°C. Do not freeze. Storage conditions may vary among individual products (refer to detailed product guideline).
L04AD01 - ciclosporin ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants. S01XA18 - ciclosporin ; Belongs to the class of other ophthalmologicals .
References
Anon. Cyclosporine (EENT). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 16/06/2020.Anon. Cyclosporine (Ophthalmic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/06/2020.Anon. Cyclosporine (Systemic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/06/2020.Anon. Cyclosporine. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 16/06/2020.Buckingham R (ed). Ciclosporin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/06/2020.Capsorin 100 mg/mL Oral Solution (Morningside Healthcare Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 16/06/2020.Cequa Solution/Drops (Sun Pharmaceuticals Industries, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/06/2020.Joint Formulary Committee. Ciclosporin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/06/2020.Neoral Capsule, Liquid Filled Neoral Solution (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/06/2020.Neoral Soft Gelatin Capsules 25 mg (Novartis Pharmaceuticals UK Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 18/09/2020.Restasis Multidose Emulsion (Allergan, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/06/2020.Sandimmun Concentrate for Solution for Infusion 50 mg/mL (Novartis Pharmaceuticals UK Limited). MHRA. https://products.mhra.gov.uk/. Accessed 16/06/2020.Sandimmun Neoral Oral Solution (Delpharm Huningue S.A.S.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 16/06/2020.Sandimmun Neoral Soft Gelatin Capsule (Catalent Germany Ederbach GmbH). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 16/06/2020.Sandimmune Capsule, Liquid Filled, Sandimmune Injection, Sandimmune Solution (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/06/2020.Syncloral 25 mg Capsules, Soft (Teva UK Limited). MHRA. https://products.mhra.gov.uk/. Accessed 16/06/2020.
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