Cyclosporine

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Neoral
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Indications

Main indications

  • Psoriasis : (FDA-approved for ttt of psoriasis in adults(At 2.5 and 5 mg/kg/d for 12 to 16 weeks).
  • Severe psoriasis – Recalcitrant psoriasis: 5 mg/kg daily in two divided doses to be be reduced by 1 mg/kg daily every other week.
  • Stable moderate and severe ps : 2.5–3 mg/kg dailyto be increased by 0.5 to 1 mg/kg/day every other week until clinical improvement is seen or a maximum dose of 4–5 mg/kg/day.
  • Hand and foot psoriasis.
  • Psoriasis in Patients with major life events (such as a wedding).

Off-label indications

  • Severe atopic dermatitis : 2.5–5 mg/kg daily for 6 wks in children from 2 to 16 years of age.
  • Pyoderma gangrenosum.
  • Chronic idiopathic urticaria : 4 mg/kg daily.
  • Lichen planus.
  • Bullous dermatoses : Pemphigus – Pemphigoid- Epidermolysis bullosa acquisita-Linear IgA bullous dermatosis.
  • Autoimmune connective tissue diseases: Dermatomyositis-Lupus erythematosus-Scleroderma.
  • Neutrophilic dermatoses : Behçet’s disease – Pyoderma gangrenosum.
  • Alopecia : Alopecia areata – Lichen planopilaris.
  • Granulomatous dermatoses : Granuloma annulare-Sarcoidosis.
  • Disorders of keratinization : Pityriasis rubra pilaris.
  • Photosensitivity dermatoses : Chronic actinic dermatitis.
  • Others : (Eosinophilic cellulitis-Kimura’s disease-Morphea-Prurigo nodularis-Papular erythroderma of Ofuji-
  • Persistent papular acantholytic dermatosis-Purpura pigmentosa chronica-Reiter’s syndrome-Scleromyxedema).

Dosage

  • 3–5 mg/kg/d divided into 2 BID.

Baseline Monitoring

Examination

  • Complete history and physical examination.
  • Two baseline blood pressures at least a day apart.

Lab

  • Serum creatinine levels (two baseline creatinine values at least a day apart)
  • Baseline renal evaluation – BUN, urinalysis with microscopic examination (optional).
  • CBC, ALT, AST, γ‐glutamyl transferase (γ‐GT), bilirubin.
  • Fasting lipid profile – triglycerides, cholesterol, HDL, cholesterol.
  • Consider PPD.
  • Pregnancy test if indicated.

Patients with a low muscle mass may have signifcant nephrotoxicity even though their serum creatinine remains within the normal range, so baseline values should always be considered.

Follow Up Monitoring

Examination

  • Re-evaluate the patient every 2 weeks for 1–2 months, then every 4–6 weeks while on cyclosporine.
  • Blood pressure checked at each visit.

Lab

Every 2 weeks for the first 1–2 months, then monthly while on cyclosporine.

  • Renal functions – serum creatinine, BUN, urinalysis.
  • Liver function tests.
  • Lipids – triglycerides, cholesterol.
  • Serum CsA level in selected pts.

Side effects

  • Renal dysfunction.
  • Hypertension.
  • Neurologic (Tremor- Headache – Paresthesia – hyperesthesia).
  • Hypertrichosis.
  • Gingival hyperplasia.
  • Nausea, abdominal discomfort, Diarrhea.
  • Myalgia, lethargy, Arthralgia.
  • Hyperkalemia -Hyperuricemia -Hypomagnesemia-Hyperlipidemia.

Contraindications

  • Absolute
    • Signifcantly decreased renal function.
    • Uncontrolled hypertension.
    • Hypersensitivity to CsA.
    • Clinically cured or persistent malignancy (except nonmelanoma skin cancers).
    • Cutaneous T-cell lymphoma.
  • Relative
    • Age <18 years or >64 years.
    • Controlled hypertension.
    • Planning to receive a live attenuated vaccination.
    • Medications that interfere with CsA metabolism or potentiate renal dysfunction.
    • Active infection or evidence of immunodefciency.
    • Concomitantly receiving phototherapy, methotrexate, or other immunosuppressive agents.
    • Unreliable patients.

Pregnancy and lactation

  • Pregnancy Category C.
  • The manufacturer recommends avoiding cyclosporin in pregnancy unless the benefits to the mother outweighs the risks.
  • potential risks to the fetus.
  • Excreted in breast milk, do not use with breast feeding.

Drug interactions

  • Drugs that increase cyclosporine drug levels – CYP 3A4 inhibition
    • Antifungals: ketoconazole, itraconazole, fluconazole, vorinconazole.
    • Diuretics: furosemide, thiazides, carbonic anhydrase inhibitors.
    • Calcium channel antagonists: diltiazem, nicardipine, verapamil.
    • Corticosteroids: high-dose methylprednisolone.
    • Antiemetics: metoclopramide.
    • Antibiotics: macrolides, fluoroquinolones.
    • Antiarrhythmics: amiodarone.
    • Antimalarials: hydroxychloquine, chloroquine.
    • Anti-HIV drugs: ritonavir, indinavir, saquinavir, nelfinavir.
    • SSRIs: fluoxetine, sertraline.
    • Others: Allopurinol, bromocriptine, danazol, amphotericin B, oral contraceptives.
  • Drugs that reduce cyclosporine drug levels – CYP 3A4 induction
    • AntiTB : Rifampin, rifabutin.
    • Antibacterial : Nafcillin.
    • Anticonvulsants: Carbamazepine, phenobarbital, phenytoin, valproic acid.
    • Others : Octreotide, ticlopidine.
  • Drugs + cyclosporine >> potentiate renal toxicity
    • Antibiotics : Aminoglycosides Tobramycin, gentamicin, Trimethoprim/sulfamethoxazole, vancomycin.
    • Antivirals: acyclovir.
    • Antifungals: Amphotericin B, ketoconazole.
    • NSAID : Indomethacin, naproxen, diclofenac.
    • H2 antihistamines : Cimetidine, ranitidine.
    • Immunosuppressants: Tacrolimus, melphalan.
  • Medications whose levels increase when taken concomitantly with cyclosporine
    • Calcium channel blockers: diltiazem, nicardipine, verapimil \n
    • Erectile dysfunction drugs: sildenafil, tadalafil, vardenafil \n
    • Statins: atorvastatin, lovastatin, simvastatin \n
    • Benzodiazepines: midazolam, triazolam \n
    • Others: prednisolone, digoxin, colchicine, digoxin, diclofenac, bosentan.
  • Methotrexate + cyclosporine = each drug can reduce the elimination of the other.
  • Grapefruit juice is also a CYP450 inhibitor and should be avoided while taking cyclosporin.

Drug info

  • CsA induced HTN is usually mild and is generally reversible after dose reduction or discontinuation of CsA.
  • The initial dosage of CsA for the treatment of psoriasis should depend on the clinical state of the patient being treated.
  • If there is insufficient response after 3 months on the maximum dose of 5 mg/kg daily, CsA should be discontinued.
  • For obese patients, the ideal body weight should be used to calculate the starting dosage of CsA.
  • Cyclosporine is best used on a short-term basis (<6–12 months) to control flares of psoriasis relatively quickly and to provide an alternative to the patient’s current regimen.
  • Calcium channel blockers of the dihydropyridine class are the recommended first-line antihypertensive agents.
  • Use during pregnancy should be considered only in exceptional patients for whom the potential benefits dramatically outweigh the risks

Precautions

  • Grapefruit juice affects the metabolism of CsA and should be avoided.
  • Serum creatinine is kept within 25% of the patient’s baseline creatinine level.
  • Blood pressure and serum creatinine should be measured before conversion from sandimmune to neoral, in addition to 2, 4, and 8 weeks thereafter.


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