Cyclosporine in Dermatology.pdf

CYCLOSPORINE IN
DERMATOLOGY
Presenter
Dr. Nur-A-Tasmin Tahnin
Resident, MD Phase B
Department of Dermatology and Venereology
BSMMU
Supervisor
Dr. M. Abu Hena chowdhury
Associate Professor
Department of Dermatology and Venereology
BSMMU

INTRODUCTION
• Cyclosporine (CsA) is a calcineurin inhibitor that acts selectively on T cells
• In 1970, Borel discovered and isolated cyclosporine from the soil fungus
Tolypocladium inflatum gam
• CsA, was approved for prophylaxis of organ rejection in the United States in 1995
• Since 1997, it has been used for its indication of psoriasis and off-label for various
other inflammatory skin conditions
• CsA is important, because there is minimal use of CsA in clinical dermatology
because of fear of serious adverse effects (SAE) such as nephrotoxicity and
malignancy
• However, with proper usage and monitoring, CsA can be used with its maximum
potential in the field of dermatology

FORMULATION & DOSAGE
Generic Name Trade Name Manufacturer Tablet/ Capsule Special
Tablet/ Capsule Sizes Formulations
Sizes
Sandimmune Sandimmune Novartis 25, 50, 100 mg IV 50 mg/mL,
Oral solution 100
mg/mL
Cyclosporine Neoral, Gengraf Novartis 25, 50, 100 mg Oral solution 100
mg/ML
(Wolverton and Wu 2020)

PHARMACOKINETICS
Drug name Peak
level
Bioavailable
(%)
Protein
binding
Half life Metabolism Excretion
Cyclosporine
(Sandimmune)
2-4 H 30 90 5-18 h Primarily
hepatic
Primarily
hepatobiliary
(renal 6%)
Cyclosporine
(Neoral,
Gengraf)
2-4 H Increased;
~10-54%
more than
Sandimmune
90 5-18 h Primarily
hepatic
Primarily
hepatobiliary
(renal 6%)

MECHANISM OF ACTION OF CYCLOSPORINE
Inhibit a (IFN-γ)
• ;
Inhibit ICAM-1
T cell activation
Inhibit trafficking of
inflammatory cells
(Flores et al. 2019)

▪
INDICATION
Other Dermatologic Uses (Off-Label)
US FDA–approved Indications: ▪ Atopic dermatitis
Psoriasis
▪ Severe psoriasis
▪ Recalcitrant, treatment-resistant
psoriasis
▪ Disabling psoriasis (including
localized versions such as hand
and foot psoriasis)
Bullous dermatoses
▪ Pemphigus
▪ Pemphigoid
▪ Epidermolysis bullosa acquisita
▪ Linear IgA bullous dermatosis
Autoimmune connective tissue diseases
• Dermatomyositis
• Lupus erythematosus, Scleroderma
▪ Lichen planus

INDICATION
Neutrophilic dermatoses Other dermatoses
Behçet disease
Pyoderma gangrenosum
Granulomatous dermatoses
Granuloma annulare
Sarcoidosis
Disorders of keratinization
Pityriasis rubra pilaris
Photosensitivity dermatoses
Chronic actinic dermatitis
Other:
Alopecia areata
Lichen planopilaris
▪ Prurigo nodularis
▪ Chronic urticaria
▪ Stevens-Johnson syndrome/toxic
epidermal necrolysis
▪ Eosinophilic cellulitis
▪ Morphea
▪ Scleromyxedema
▪ Purpura pigmentosa chronica
▪ Papular erythroderma of Ofuji
▪ Kimura’s disease
▪ Reactive arthritis

CONTRAINDICATION OF CSA THERAPY
• Hypersensitivity to cyclosporine or components of formulation
• Malignancies
• Radiation therapy
• Abnormal renal function
• Uncontrolled hypertension
• Concomitant PUVA/UVB therapy
(Kang et al. 2019)

COMMON ADVERSE EFFECTS OF
CYCLOSPORINE
Renal
▪ Renal dysfunction
Musculoskeletal
Cardiovascular ▪ Myalgia, lethargy, arthralgia
▪ Hypertension
Gastrointestinal
Common
side effects
Laboratory Abnormalities
▪ Hyperkalemia
▪Nausea, abdominal discomfort, Diarrhea
Neurologic
▪ Tremor
▪ Headache
▪ Hyperuricemia (occasionally precipitates
gout)
▪ Hypomagnesemia
Mucocutaneous
▪ Hypertrichosis
▪ Gingival hyperplasia
Hyperlipidemia
Other: Paresthesia, hyperesthesia
Rarely: hyperbilirubinemia
Malignancy

(Kang et al. 2019), (Rajagopalan et al 2022)

DOSAGE AND TREATMENT REGIMENS
The initial dosage of CsA for the treatment of psoriasis should depend on the
clinical state of the patient being treated
Conditions defined as:
1. Severe psoriasis:
➢Severe, inflammatory flares of psoriasis
➢Truly recalcitrant cases (psoriasis that has failed to respond to many other treatment
modalities
➢Where rapid improvement is critical
▪ Recommend starting CsA dosage: 5 mg/kg daily administered in two divided doses
When effective control is achieved:
▪ Maintaining that effective dose for at least 2 to 3 months

DOSAGE
▪ Dosage of CsA can be reduced in decrements of 1 mg/kg daily every other week
until the minimum effective dosage for maintenance therapy is defined
2. Moderate to severe:
▪ Generalized but relatively stable plaque-type psoriasis
▪ Cases where the severity lies between moderate and severe
Starting dose: start with a relatively low dose: 2.5 to 3 mg/kg per day
▪ If improvement in psoriasis has not occurred by 1 month, increase the CsA dosage
in increments of 0.5 to 1 mg/kg day every 2 weeks as necessary, but not to exceed
the maximum dose of 5 mg/kg daily

CONTINUATION OF THERAPY
▪ According to FDA guideline CsA can be used continuously for upto 1 year
▪ Worldwide consensus guideline recommended, continuous courses may be
continued upto 2 years
▪ After 2 years of continuous, uninterrupted CsA use, one has to discontinue CsA to
give the kidneys a ‘CsA holiday’
▪ In this situation, there is no guideline on how long a patient needs to be off CsA
before another course of CsA treatment can be restarted
▪ However, most widely used indication is use of CsA for 3-4 months at a time
▪ Break off at least 12 weeks (3 months) between another course

DISCONTINUATION OF THERAPY
▪ CsA should be discontinued if insufficient response after 3 months on the
maximum dose of 5 mg/kg per day
▪ CsA should be gradually tapered while an alternative therapy is instituted
▪ Sudden withdrawal may result in, rebound in disease activity, including
pustular flares

MONITORING GUIDELINE
Baseline:
1. Examination
▪ Complete history and physical examination (to rule out active infections,
malignancy)
▪ Two baseline blood pressures at least a day apart
2. Laboratory
▪ Baseline serum creatinine levels (two baseline creatinine values at least a day
apart)
▪ Blood urea nitrogen (BUN)
▪ Complete blood count (CBC)
▪ Liver function tests (especially SGOT/AST and SGPT/ALT)
▪ Fasting lipid profile—triglycerides, cholesterol, high-density lipoprotein (HDL)

MONITORING GUIDELINE
Other Laboratory tests:
▪ Magnesium (may not be relevant if CsA usage is limited in duration)
▪ Potassium
▪ Uric acid (mainly relevant for patients at risk for gout)

DRUGS THAT INTERACT WITH
CYCLOSPORINE
CYP3A4 inhibitors: which ↑ CsA drug levels and resultant toxicity—
renal, HBP, lipids, etc.
▪ Macrolide antibacterial
▪ Azole, triazole antifungals
▪ Calcium channel blockers
▪ Fluoroquinolones
▪ HIV-1 protease inhibitors
▪ Nutritional products
▪ Miscellaneous
▪ Erythromycin >> clarithromycin >
azithromycin
▪ Ketoconazole >> itraconazole >
fluconazole (only >200 mg daily)
daily)
▪ Diltiazem, verapamil
▪ Ciprofloxacin
▪ Ritonavir, indinavir >> saquinavir,
nelfinavir
▪ Grapefruit, grapefruit juice
▪ Danazol

DRUGS THAT INTERACT WITH
CYCLOSPORINE
CYP3A4 inducer: with resultant ↓ CsA drug levels and loss efficacy;
▪ Rifamycin antibacterials:
▪ Aromatic anticonvulsants:
▪ Rifampin, rifabutin
▪ Phenytoin, carbamazepine, phenobarbital
Potential nephrotoxic:
▪ Aminoglycosides, others
▪ Antifungals:
▪ Anti-inflammatory:
▪ Immunosuppressants, Wide variety—
relatively uncommon to have these SAE
in dermatology:
▪ Gentamicin, tobramycin, TMP/SMX,vancomycin
▪ Amphotericin B
▪ NSAID: indomethacin, naproxen, etc
▪ Biologics, JAK inhibitors, traditional
(azathioprine, mycophenolates, etc.),
chemotherapy
▪ Vaccines Live, attenuated (e.g.,
Zostavax)
▪ Immunize at least 2 weeks before CsA; risk of
(1) low/no immune response, (2) disseminated

VZV (or other severe
infections depending on
vaccine)
(Wol
verto
n
and
Wu
2020
)

FOLLOW UP
Examination
▪ Bood pressure checked at each visit
▪ Re-evaluate the patient every 2 weeks for 1–2 months
▪ Then every monthly/ 4-6 weeks while on cyclosporine
Laboratory
▪ Laboratory surveillance every 2 weeks for the first 1–2 months
▪ then monthly while on cyclosporine

FOLLOW UP
Test to do:
▪ Renal function—serum creatinine, BUN, urinalysis
▪ CBC, Liver function tests (especially SGOT and SGPT) (seldom affected)
▪ Lipids—triglycerides, cholesterol
▪ Serum electrolyte: Potassium
▪ Magnesium (may not be relevant if CsA usage is limited in duration, done at 4 months)
▪ Uric acid Indicated Infrequently
Selected Patients
▪ Creatinine clearance (consider if 1–2 years therapy)
▪ Serum cyclosporine A (CsA) level
▪ Kidney biopsy (very rarely) (Wolverton and Wu 2020)

COMPLICATIONS MANAGEMENT
(HYPERTENSION)
▪ Hypertension develops in approximately 27% of psoriasis patients on CsA
▪ Usually mild and is generally reversible after dose reduction
▪ Elevated blood pressure can be adequately treated with antihypertensive medications &
does not necessitate withdrawal of CsA
▪ Cyclosporine should be discontinued if blood pressure does not normalize, (140/90 mm
Hg) after multiple-dose reductions
Drug of choice:
▪ Ca channel blocker: amlodipine, nifedipine, Isradipine (more preferred)
▪ Angiotensin-converting-enzyme (ACE) inhibitors, ARB
▪ B blocker

STEPS TO FOLLOW WITH RISING
CREATININE
Serum creatinine rises >30% above patient’s
baseline
Repeat measurement within 2 weeks
Creatinine is sustained at >30% above patient’s baseline
Reduce CsA dose by at least 1 mg/kg per day (for at least 1 month)/2-4 weeks

STEPS TO FOLLOW WITH RISING CREATININE
Reduce CsA dose by at least 1 mg/kg per day (for at least 1 month)
Creatinine remains > 30% above patient’s baseline
Creatinine decreases to <30%
above patients baseline
Stop CsA treatment
CsA treatment can be continued at
new dosage
Discontinue drug if >50%
Creatinine returns to within 10% of patient’s baseline
CsA treatment can be resumed at lower dosage

MANAGEMENT OF HYPERLIPIDEMIA
• Hyperlipidemia is a relatively common AE of CsA
• Initial intervention should begin with dietary changes and an increase in physical activity
If these measures are unsuccessful:
• The dose of CsA may be reduced
• A lipid-lowering agent should be added (avoid Statin: Atorvastatin, simvastatin due to
drug interaction, Fluvastatin is safe)

MANAGEMENT OF CUTANEOUS
ADVERSE EFFECTS
❑Hypertrichosis occurs in virtually all patients on long-term CsA
❑Gingival hypertrophy is reported in up to 70% of CsA
❑Gingival hyperplasia may improve with careful dental hygiene
❑Gingival hyperplasia and hypertrichosis are dose-dependent and the these
side effects are reversible

MANAGEMENT OF COMPLICATION
▪ Paresthesia, tremors, headaches, nausea, and malaise are
usually self-limiting after several weeks of treatment
▪ Hyperkalemia may respond to reduced potassium in the diet
▪ Hyperuricemia is rarely occurred
(Kang et al. 2019)

MANAGEMENT OF COMPLICATION
• Increased risk of non-melanoma skin cancer (NMSC)
• Increased risk of lymphoma (B-cell lymphoma, cutaneous T cell lymphoma)
(Mostly reported in organ transplant patients)
No skin cancer reported in dermatology:
▪ With 6 months of continuous CsA
▪ Intermittent dose upto 2 years
(With increased duration>2 years continuous dose and high dose >5kg,
some malignancy reported sporadically)

SPECIFIC INDICATION OF
CYCLOSPORINE IN PSORIASIS AND
VARIOUS OTHER DISEASES

CYCLOSPORINE IN PSORIASIS
• Cyclosporine in doses of 2.5 and 5 mg/kg/d produced PASI 75 rates between 28% to 85% and
50% to 97% respectively
• After drug withdrawal in PASI 75 responders, the average length of time before restarting
systemic therapy was found to be 182 days
• Methotrexate and CsA can be given concomitantly with appropriate clinical and laboratory
monitoring and was proven to effective with reversible side effects (Mohanan et al. 2014)
• Concomitant therapy: Methotrexate is preferred first choice and apremilast as second choice.
Acitretin and emollients along with weekend potent topical steroids for recalcitrant lesions for a
few week also considered
(Rajagopalan et al. 2022)

CYCLOSPORINE IN AD
• Recommended dose of 2.5–5 mg/kg/d of CsA for AD. Duration of treatment depends on
the age and severity of AD
• CsA is effective in controlling severe AD in children over a one-year period and is well
tolerated
• Longer duration was preferred (>3-4) as no better alternative second-line treatment is
available for AD
• The preferred age is two years and above because of the vaccination schedule
• CsA is very safe in children, almost 10 times safer as compared to adults
• In extensive AD but intractable pruritus, oral CsA can be used as a weekend therapy 5
mg/kg/d dose of CsA on saturday and sunday

CYCLOSPORIN IN URTICARIA
• CsA can be used in urticaria but only when antihistamines fail and
prolonged steroid treatment is required
• One effective regimen is stated as, 3 mg/kg/d for 6 weeks, followed
by 2 mg/kg/d for 3 weeks and 1 mg/kg/d for 1 week and subsequent
discontinuation
• CsA prescribing dose is 2.5–5 mg/kg/d for 8-12 weeks

CYCLOSPORINE IN PRURIGO NODULARIS
• Cyclosporine as a preferred systemic therapy for severe, recalcitrant
disease
• Average dose is 3.1mg/kg/day with a notice in improvement within 3
weeks
• Plan to transition to topical, systemic therapy or phototherapy over the
course of 3-6 months
(Wiznia et al. 2018)

CYCLOSPORINE IN PYODERMA
GANGRENOSUM
▪ Alternative first line treatment for patients who can not tolerate
systemic glucocorticoid in severe/refractory PG
▪ Also used as adjunctive to glucocorticoid
▪ 4mg/kg/day is equivalent to corticosteroid 0.75mg/kg
▪ Duration is based on treatment response with recommended duration
of less than 1 year (6-7 months duration mostly)
(Kang et al. 2019)

CYCLOSPORINE IN LICHEN PLANUS
▪ 2.5–5.0 mg/kg/d as the optimum dose in LP, while other treatment
fails
▪ 8–16 weeks as the optimum duration
▪ CsA oral solution is not preferred in oral LP. As it is not practical,
because of its cost and availability issues

CYCLOSPORINE IN SJS/TEN
• CsA (5 mg/kg/day) is recommend as the first line-specific immunomodulatory agent
in SJS/TEN on account of its (i) efficacy, (ii) safety, (iii) rapid reepithelization, (iv)
decrease hospital stay, and (v) reduced morbidity and mortality (Balai et al. 2021)
• Optimal dose is 3-5mg/kg, in two divided doses with an average treatment duration
of 10-14 days
• Symptom improvement starts within 24 hours following initiation of CsA therapy
• Average response time after CsA administration was 2.2 day

ROLE OF CSA IN ALOPECIA AREATA
• In monotherapy, the optimal target dose of CsA is 5 mg/kg/d, whereas an
association with corticosteroids, it is 3 mg/kg/d
• The target dose should be maintained for not less than 6 months and
preferentially for 12 months
• CsA in combination with prednisolone for the treatment of alopecia areata
is preferred
• Relapse is high with CsA in alopecia areata

ROLE OF CYCLOSPORINE IN THE
PEDIATRIC POPULATION
CsA can be prescribed in the pediatric population for indications such as:
❑Childhood psoriasis
❑Pediatric dermatoses
❑Auto-immune hemolytic anemia (AIHA)
❑Relapsing nephrotic syndrome
Dose: 2.5–5.0 mg/kg/d in the pediatric population, although 5-7mg/kg can be given
Duration: 14–16 weeks as the optimum mean duration (even more is relatively safer)
❑nausea, abdominal pain, and hypertrichosis are the most common adverse effects

CYCLOSPORINE IN PREGNANCY
▪ CsA can be prescribed in second and third trimesters of pregnancy
▪ CsA crosses the placental blood barrier and is a category C drug in pregnancy, therefore,
it should be withheld in the first trimester
▪ The pregnancies in women treated with cyclosporine are considered high risk
▪ No increase in the risk of teratogenicity, although there were trends towards low birth
weight and prematurity
Lactation:
▪ Avoid use of CsA
▪ Possible risk of infant immunosuppression

CYCLOSPORINE AVAILABILITY & COST IN
BANGLADESH
▪ Available formulation: Capsule, oral, No IV formulation available
▪ Manufacturer: Novartis (Bangladesh) Ltd.
▪ Cap Neoral (25 mg)
MRP- BDT -59 TK
▪ Cap Neoral (50mg)
MRP-BDT 118 TK
▪ Cap Neoral (100)
MRP-BDT 235 TK
❑ With lowest 2.5mg/kg/day or 150 mg/day on average 60kg person,
cost for 3 months therapy: (BDT 353/day, BDT 10,855/3 months)
❑ With highest 5mg/kg/day or 300 mg/day on average 60kg person,
cost for 3 months therapy: (BDT 705/day, BDT 21,620/ 3months)

CYCLOSPORINE AVAILABILITY & COST IN
BANGLADESH
❑Oral Cyclosporine Solution (suitable for children unable to take
capsule)
Manufacturer: Incepta pharmaceuticals
Trade name: Sporium (50 ml Solution)
• Formulation: 100mg/ml
• Price: 2300 tk
(Currently supply not available in Bangladesh)

TAKE HOME MESSAGE
• CsA can be effectively used for severe disease, with consideration to add other
systemic therapy for long time maintenance
• CsA at a dose of 2.5-5mg/kg/day is preferred for whatever the disease in
Dermatology
• Optimum duration is 3-4 months use continuously at a time (selectively up to 1 year)
• A 3 months Cyclosporine free duration to be maintained between second cycle
• Adverse effects of CsA is low and manageable within the recommended dose and
duration in Dermatology
• Most adverse effects are reversible on dose reduction & discontinuation of therapy
• It is preferred not to use >5mg/kg/d and 6 months duration on continuous therapy
• Cost issues need to be considered

REFERENCES
• Balai, M., Meena, M., Mittal, A., Gupta, L.K., Khare, A.K. and Mehta, S., 2021. Cyclosporine in Stevens-Johnson
syndrome and toxic epidermal necrolysis: Experience from a tertiary care centre of South Rajasthan. Indian
Dermatology Online Journal, 12(1), p.116.
• Flores, C., Fouquet, G., Moura, I.C., Maciel, T.T. and Hermine, O., 2019. Lessons to learn from low-dose
cyclosporin-A: a new approach for unexpected clinical applications. Frontiers in immunology, 10, p.588
• Kang, S., Sewon Kang, Masayuki Amagai, Anna L. Bruckner, Alexander H. Enk, David J. Margolis, Amy J.
McMichael, Jeffrey S. Orringer., 2019. Fitzpatrick's Dermatology, 2-Volume Set (EBOOK). McGraw Hill
Professional.
• Mohanan, S., Ramassamy, S., Chandrashekar, L.
combination methotrexate–cyclosporine therapy in
treatment, 25(1), pp.50-53.
and Thappa, D.M., 2014. A retrospective analysis of
moderate–severe psoriasis. Journal of dermatological
• Rajagopalan, M., Saraswat, A., Chandrashekar, B.S., Dhar, S., Dogra, S., Tahiliani, S. and Raj, P., 2022. Role of
Cyclosporine (CsA) in Immuno-dermatological Conditions. Indian Dermatology Online Journal, 13(5), pp.585-
599.
• Wiznia, L.E., Callahan, S.W., Cohen, D.E. and Orlow, S.J., 2018. Rapid improvement of prurigo nodularis with
cyclosporine treatment. Journal of the American Academy of Dermatology, 78(6), pp.1209-1211
• Wolverton, S.E. and Wu, J.J., 2019. Comprehensive dermatologic drug therapy. Elsevier Health Sciences.

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