CsA

1. CYCLOSPORINE-A

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. 
Cyclic Non-Ribosomal Peptide - 11 Amino Acids

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. 
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. 
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

8. US FDA approved :
1.Psoriasis
2.Severe psoriasis
3.Recalcitrant, treatment resistant psoriasis
IN EU / AUSTRALIA :
1. Atopic dermatitis
2. Psoriasis

9. 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)

10. 
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

11. 
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)

12. 1.Renal
Dysfunction
2.Uncontrolled
HTN
3.Hypersensitivity
4.Cutaneous
5.Cured
to CsA or its ingredients
T cell Lymphoma
/ Persistent Malignancies

13. 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

14. 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)

15. DOSE INDEPENDENT :
Neurological
effects :
CsA < 02 months
Tremors
Paresthesia
headache
Hyperaesthesia

16. •
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
•
•

17. 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)

20. •
Oral solution contains 100 mg/ml and should be
diluted with apple juice or orange juice
before it is administered to make it palatable.

21. 
OPHTHALMIC EMULSION 0.05%

22. 
INJECTABLE preparation
50 mg / mL (Sandimmune)

23. 
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

24. Potentiate / Inc Risk of ADRs :
K+ Sparing Diuretics (Hyperkalemia)
HMGCoA Reductase Inhibitor (Rhabdomyolysis)
Colchicine (Myopathy)
Potentiate Renal Dysfunction
Aminoglycosides, TMP-SMX, Amphotericin-B,
NSAIDs

25. •
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.

26. •
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.

27. •
•
•
•
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)

28. 
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)

29. 
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

30. 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

31. WARD
1.BP
record twice daily
2.Urea,
Creatinine, K, Mg, Uric Acid
Twice in the first week
Weekly thereafter till discharge

32. 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

33. 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)

34. •
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

35. 
Serum Creatinine rises by at least 50% above the
baseline value, CsA should be discontinued until
serum Creatinine returns to baseline.

36. THANK YOU