Cyclosporine by Aseem

1,168 views

Published on

CsA

0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,168
On SlideShare
0
From Embeds
0
Number of Embeds
5
Actions
Shares
0
Downloads
126
Comments
0
Likes
3
Embeds 0
No embeds

No notes for slide

Cyclosporine by Aseem

  1. 1. CYCLOSPORINE-A
  2. 2.  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-TransplantRejection (1983)  NEORAL for Psoriasis / RA (FDA approved in 1997) 
  3. 3.  Cyclic Non-Ribosomal Peptide - 11 Amino Acids
  4. 4.  Neoral has 10-54%  Bioavailability Sandimmune (‘Pre-digested, Modified’ form by ME) than  Metab by CY P450 3A4 enzyme system in liver  Excreted by the way of bile through faeces (90%), with only 6 % excreted in urine
  5. 5.  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
  6. 6.  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
  7. 7. US FDA approved : 1.Psoriasis 2.Severe psoriasis 3.Recalcitrant, treatment resistant psoriasis IN EU / AUSTRALIA : 1. Atopic dermatitis 2. Psoriasis
  8. 8. 1. 2. 3. 4. 5. 6. Papulosquamous dermatoses : Lichen Planus Bullous dermatoses : Pemphigus, Pemphigoid, Epidermolysis Bullosa Acquisita, Linear IgA Bullous dermatoses Autoimmune connective tissue disorders : Dermatomyositis, SLE, Scleroderma Neutrohilic dermatoses : Behcet’s Syndrome, PG Atopic dermatitis Alopecia (AA / LPP)
  9. 9.  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
  10. 10.  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)
  11. 11. 1.Renal Dysfunction 2.Uncontrolled HTN 3.Hypersensitivity 4.Cutaneous 5.Cured to CsA or its ingredients T cell Lymphoma / Persistent Malignancies
  12. 12. 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
  13. 13. 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)
  14. 14. DOSE INDEPENDENT : Neurological effects : CsA < 02 months Tremors Paresthesia headache Hyperaesthesia
  15. 15. • Malignancy : Non-Melanoma Skin Cancers • Dyselectrolytemia: Hyperkalemia Hyperuricemia Hypomagnesemia Hyperlipidemia (esp TRIGs) • Mucocutaneous : hypertrichosis (60%), gingival hyperplasia (30%), Acne (16%), Folliculitis (12%) Gastrointestinal : nausea, abdominal discomfort, diarrhea Musculoskeletal : myalgia, lethargy, arthralgia • •
  16. 16. 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)
  17. 17. • Oral solution contains 100 mg/ml and should be diluted with apple juice or orange juice before it is administered to make it palatable.
  18. 18.  OPHTHALMIC EMULSION 0.05%
  19. 19.  INJECTABLE preparation 50 mg / mL (Sandimmune)
  20. 20.  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 ) Rifampicin Terbinafine
  21. 21. Potentiate / Inc Risk of ADRs : K+ Sparing Diuretics (Hyperkalemia) HMGCoA Reductase Inhibitor (Rhabdomyolysis) Colchicine (Myopathy) Potentiate Renal Dysfunction Aminoglycosides, TMP-SMX, Amphotericin-B, NSAIDs
  22. 22. • 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.
  23. 23. • For patient with Chronic Plaque type Psoriasis :Start with 2.5 to 3 mg/kg/day If 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.
  24. 24. • • • • 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)
  25. 25.  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)
  26. 26.  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
  27. 27. BASELINE : Clinical : 1.Complete history and physical examination (to rule out active infection, tumours) 2.Baseline BP Lab inv : 1.Baseline Serum Urea / Creatinine levels 2.Other baseline renal evaluation : Urine RE/ME 3.CBC / LFT with Enzymes 4.Serum Lipid Prolfile 5.Mg2+, K+, Serum Uric Acid
  28. 28. WARD 1.BP record twice daily 2.Urea, Creatinine, K, Mg, Uric Acid Twice in the first week Weekly thereafter till discharge
  29. 29. 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 profile 2.Lab surveillance every 2 weeks X 02 months then Monthly till on CsA
  30. 30. 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)
  31. 31. • Reduce CsA dose by at least 1 mg/kg/day (for at least 1 month) • Creatinine decreases to <30% of baseline Creat. remains >30% • CsA can be continued at new dosage stop CsA treatment Creat returns to within 10% of baseline CsA treatment can be resumed at lower dosage
  32. 32.  Serum Creatinine rises by at least 50% above the baseline value, CsA should be discontinued until serum Creatinine returns to baseline.
  33. 33. THANK YOU

×