CYCLOSPORINE-A

1970 – Borel (Sandoz lab) at Basel, Switzerland, from common soil fungus Tolypocladium inflatum gams (erst. Beauveria nivea) ; Antifungal / Immunosuppressant

02 formulations : SANDIMMUNE for Px of Organ-Transplant-

Rejection (1983) NEORAL for Psoriasis / RA (FDA approved in

1997)

Cyclic Non-Ribosomal Peptide - 11 Amino Acids

Neoral has 10-54% Bioavailability than Sandimmune (‘Pre-digested, Modified’ form by ME)

Metab by CY P450 3A4 enzyme system in liver

Excreted by the way of bile through faeces (90%), with only 6 % excreted in urine

Hepatic dysfunction / CYP3A4 Inhibitors may prolong the half life and requires dose adjustment

Renal Disease does not alter Clearance

Peak Levels in 02 – 04 hrs

t1/2 = 05-18 hrs

Clearance Rate : 05-07 mL/min/kg

Inhibits production of Pro-inflammatory IL-2 by inhibiting calcineurin thus decreases T cell proliferation

Calcineurin inhibition leads to reduced activity of the transcription factor NFAT-1 (Nuclear Factor Activated T cells)

Inhibits INF-gamma production by T lymphocytes and thus reduces keratinocyte proliferation by downregulating ICAMs-1

US FDA approved :1.Psoriasis2.Severe psoriasis3.Recalcitrant, treatment resistant psoriasis

IN EU / AUSTRALIA :1. Atopic dermatitis2. Psoriasis

1. Papulosquamous dermatoses : Lichen Planus

2. Bullous dermatoses : Pemphigus, Pemphigoid, Epidermolysis Bullosa Acquisita, Linear IgA Bullous dermatoses

3. Autoimmune connective tissue disorders : Dermatomyositis, SLE, Scleroderma

4. Neutrohilic dermatoses : Behcet’s Syndrome, PG

5. Atopic dermatitis6. Alopecia (AA / LPP)

Granulomatous dermatoses : Granuloma Annularae, Sarcoidosis

Keratinization Disorders (PRP)

Chronic Actinic Dermatoses

Urticaria (CIU / Cold / Solar)

Others : Morphea, Prurigo Nodularis, Reactive Arthritis, Dyshidrotic Eczema, Eosinophilic Folliculitis

RA (Unresponsive to MTX)

ORGAN-DONOR-TRANSPLANT-REJECTION Prophylaxis in Renal / Liver / Heart

Prevention of GVHD in Bone Marrow Transplant

KERATOCONJUNCTIVITIS SICCA (Topical prep)

Brain Trauma (Orphan Indication)

1.Renal Dysfunction

2.Uncontrolled HTN

3.Hypersensitivity to CsA or its ingredients

4.Cutaneous T cell Lymphoma

5.Cured / Persistent Malignancies

1. Age < 18 or > 64 (CsA has been used in AD in Children > 01 year @ 5mg/kg/day with high efficacy, less side effects (Dec BA, better Clearance) but RCTs not performed)

2. Controlled HT

1. On medications that interfere with CsA metabolism

2. On medications that potentiate renal dysfunction

3. Pregnancy, lactation – Cat C

DOSE RELATED :

•Renal Dysfunction – dose related toxicity. To avoid it, the dose of CsA < 5 mg/kd/day

•HTN – mean diastolic BP > 90 mmHg – direct vasoconstrictor effect of CsA on vascular smooth muscles in kidneys but it could also be secondary to renal dysfunction. (Reversible)

DOSE INDEPENDENT :

Neurological effects :

CsA < 02 months

Tremors ParesthesiaheadacheHyperaesthesia

• Malignancy : Non-Melanoma Skin Cancers

• Dyselectrolytemia: HyperkalemiaHyperuricemia Hypomagnesemia Hyperlipidemia (esp TRIGs)

• Mucocutaneous : hypertrichosis (60%), gingival hyperplasia (30%), Acne (16%), Folliculitis (12%)

• Gastrointestinal : nausea, abdominal discomfort, diarrhea

• Musculoskeletal : myalgia, lethargy, arthralgia

Capsule form

•25 / 100 mg Strength (Neoral) 50 mg (Gengraf)•Inactive Ingredients - SLS / Talc / Purified Water•In 10 % v/w Absolute Alcohol as Vehicle•In a Soft, Gelatin Capsule as a Micro-Emulsion

•MRP - Rs 380 for 05 Capsules Marketed as NEORAL (NOVARTIS) / ARPIMUNE ME-100 (RPG LS) / CYCLOPHIL ME-25 (STRIDES)

• Oral solution contains 100 mg/ml and should be diluted with apple juice or orange juice

before it is administered to make it palatable.

OPHTHALMIC EMULSION 0.05%

INJECTABLE preparation

50 mg / mL (Sandimmune)

CYP3A4-inhibitors (Inc B/A) Macrolides (Erythromycin > Clarithromycin > Azith)◦Antifungals (Keto >Itraconazole > Flucanozole)◦Protease Inhibitors (Saquinavir / Nelfinavir / Darun.)◦H2 blockers (Cimetdine > Ranitidine)◦Grapefruit Juice (by >50%)◦Antiarrythmic Agents (Verapamil / Diltiazem)

Drugs that Decrease B/A of CsA AEDs (Phenobarbitol / Phenytoin )RifampicinTerbinafine

Potentiate / Inc Risk of ADRs :K+ Sparing Diuretics (Hyperkalemia)HMGCoA Reductase Inhibitor (Rhabdomyolysis)Colchicine (Myopathy)

Potentiate Renal DysfunctionAminoglycosides, TMP-SMX, Amphotericin-B, NSAIDs

• For patients with Severe, inflammatory flares of Psoriasis or Recalcitrant psoriasis :-Start with max dermatological dose of 5mg/kg/day administered over 2 doses (Rapid Onset of Action)

• As soon as the patient is no longer in distress, the dose of CsA can be decreased in decrements of 1mg/kg daily every 02 weeks until the minimum effective dosage for maintenance therapy.

• For patient with Chronic Plaque type Psoriasis :-Start with 2.5 to 3 mg/kg/dayIf improvement has not occurred by 1 month increase the CsA dose by 0.5 to 1 mg/kg daily every 2 weeks as necessary but not to exceed maximum dose of 5 mg/kg

• If there is insufficient response to 5mg/kg for 3 continuous months, CsA should be discontinued.

• While stopping CsA, it should be gradually tapered as Rebound is possible after sudden discontinuation.

• US FDA : CsA can be used continuously for 01 year

• Worldwide Consensus Guidelines : upto 02 years can be used.

• Recommended is short term use of CsA for 3 to 6 months ideally, especially for Psoriasis (Intermittent, Short Term, RESCUE therapy)

Open-label trials in PsA with 6mg/kg/day X 08 weeks with significant efficacy noted; Relapse in 02 weeks.

Rotational therapy (06 months CsA followed by MTX upto 15mg/wk) caused significant (>50%) reduction in Joint tenderness and Swelling)

Non-Bioequivalence between Sandimmune / Gengraf-Neoral

Before Meals / After Meals due to fatty food interaction

Dose-calculation based on IBW > ABW due to lean body fat

BASELINE :

Clinical :1.Complete history and physical examination (to rule out active infection, tumours)2.Baseline BP

Lab inv :1.Baseline Serum Urea / Creatinine levels2.Other baseline renal evaluation : Urine RE/ME3.CBC / LFT with Enzymes4.Serum Lipid Prolfile5.Mg2+, K+, Serum Uric Acid

WARD

1.BP record twice daily

2.Urea, Creatinine, K, Mg, Uric Acid Twice in the first week Weekly thereafter till discharge

FOLLOW UP :•Examination :1.Re-evaluate every 2 weeks X 02 months then monthly 1.BP on each visit

•Lab inv.1.Urea, Creatinine, Urinanalysis, Se Electrolytes, Uric acid, Lipid profile2.Lab surveillance every 2 weeks X 02 months then Monthly till on CsA

Serum creatinine rises >30% above patient’s baseline

Repeat measurement within 2 weeks

Creatinine is sustained at >30% above patients baseline

Reduce CsA dose by at least 1 mg/kg/day (for at least 1 month)

• Reduce CsA dose by at least 1 mg/kg/day (for at least 1 month)

• Creatinine decreases Creat. remains >30% to <30% of baseline

• CsA can be continued stop CsA treatment at new dosage Creat returns to within 10% of baseline

CsA treatment can be resumed at lower dosage

Serum Creatinine rises by at least 50% above the baseline value, CsA should be discontinued until serum Creatinine returns to baseline.

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