Transcript Cyclosporin - Delia Colombo

Cyclosporin in
atopic dermatitis
Disclaimer
● This slide kit includes material on published preclinical and clinical studies in
psoriasis that, in some instances, reflect off-label use
● For each information mentioned in this slide kit, please ensure that you follow the
appropriate prescribing information
● The opinions expressed are those of the speaker and not of Novartis
2
Dermagora overview
● Experts from throughout Europe came together in July 2011 to:
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Outline the rationale for the use of cyclosporin in psoriasis and atopic dermatitis
Present an overview of its clinical efficacy, safety and effect on quality of life in psoriasis and atopic dermatitis
Outline existing guidelines for monitoring patients receiving cyclosporin therapy
Provide practical case examples
● This educational slide kit is the output from that meeting
● Dermagora faculty included:
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●
3
Prof. Hervé Bachelez, Saint-Louis University Hospital, Paris, France
Dr Delia Colombo, Marchesi Hospital, Milan, Italy
Prof. Serhat İnalöz, University of Gaziantep, Gaziantep, Turkey
Prof. Dimitrios Ioannidis, Aristotle University School of Medicine, Thessaloniki, Greece
Prof. Thomas Luger, University of Münster, Münster, Germany
Prof. Francisco Vanaclocha, Hospital 12 de Octubre, Madrid, Spain
Prof. Gino A. Vena, University of Bari, Bari, Italy
Contents
 Psoriasis – an overview




Pathophysiology and epidemiology
Burden of atopic dermatitis
Assessing disease severity
Treatment algorithm
 Cyclosporin in the treatment of atopic
dermatitis





4
Overview
Mechanism of action
Cyclosporin is a critical dose drug
Treatment overview
Efficacy data
 Cyclosporin safety management






Important adverse events
Monitoring
Tolerability profile
Cyclosporin and nephrotoxicity
Cyclosporin and hypertension/hyperlipidemia
Other safety considerations
 Identifying the cyclosporin patient
 Patient case studies
 Conclusions
 Summary
 The ‘ideal’ cyclosporin patient
Atopic dermatitis – an overview
5
Pathophysiology and epidemiology
Atopic dermatitis (AD) is one of the most common
chronic relapsing childhood dermatoses1
A variety of defects in the innate immune system collectively
affect the development and severity of AD2
Innate immune dysfunction in AD
Epithelial
barrier
Genetic (FLG)
Acquired (Th2 cytokines,
itch-scratch cycle)
FLG, LOR and INV,
lipid defects, TJ defects
Proteases
Genetic (SPINK5, KLK7)
Acquired (proteasesallergens and microbes)
Proteases
Protease inhibitors
Antimicrobial
proteins
Genetic (?)
Acquired (Th2 cytokines)
AMPs (HBD2, HBD3,
LL37)
IL-8/CXCL8 and
MIP3/CCL20
Innate
receptors
Genetic (?)
Acquired (?)
Altered expression or
function of PRRs (TLR2,
TLR9, NOD1-2, CD14,
MBL)
Innate
immune cells
Genetic (?)
Acquired (IL-8/CXCL8,
MIP3/CCL20, PMN
chemotaxis defect)
PMN
NK (circulation)
pDC
Microbes
Toxins
Allergens
TEWL
● Affects 10–30% of children3,4
● Vast majority develop disease
before age of 5 years3
● Persists into adulthood for 1–3%3,4
● Increase in cases in industrialised
nations over past few decades5,6
1. Lewis-Jones S. Int J Clin Pract. 2006 Aug;60(8):984-92.
2. De Benedetto et al. J Invest Dermatol. 2009 Jan;129(1):14-30.
3. Leung DY, et al. Ann Allergy Asthma Immunol. 2004 Sep;93(3Suppl 2):S1-21.
4. Larsen FS, Hanifin JM. Immunol Allergy Clinics NA 2002;22:1-25.
5. Matsumoto I, et al. Arerugi. 1999 Apr;48(4):435-42.
6. Schäfer T, et al. Br J Dermatol. 2000 Nov;143(5):992-8.
AD is often the first manifestation of the ‘atopic march’3
6
Burden of atopic dermatitis
Impairment of quality of life is greater than or equal to other
common childhood diseases such as asthma and diabetes1
Children’s Dermatology Life Quality Index (CLDQI) and Dermatology
Life Quality index (DLQI) scores stratified by patient-assessed severity2
CDLQI (child)
DLQI (adult)
25
Score
20
● Tiredness, mood changes and
impaired psychosocial functioning of
child and family
● Embarrassment, teasing and
bullying cause social isolation1
● Depression or school avoidance
● Lifestyle limited1
15
● Clothing, holidays, staying with friends,
owning pets, sports
10
● Parental exhaustion1
5
0
Mild
Moderate
Severe
Disease Severity
Patients with AD have inferior health-related
quality of life scores compared with
general population2
7
● Sleeplessness in over 60%1
● Restriction of normal family life
● Increased work in caring for child
● Costs involved in management
1. Lewis-Jones S. Int J Clin Pract. 2006 Aug;60(8):984-92.
2. Kiebert G, et al. Int J Dermatol. 2002 Mar;41(3):151-8.
Assessing disease severity
● HRQoL scores should be used in conjunction with objective measures of
severity, as part of the assessment process of a patient with atopic dermatitis1
● Clinical severity may be disproportionate to the clinical symptoms of the
condition2
● Definition of ‘severe’ atopic dermatitis includes:1–3
● Extensive skin involvement at risk for exfoliation
● Requirements for ongoing or frequent treatment with high-potency topical glucocorticoids or
systemic glucocorticoids
● Hospitalization for severe eczema or skin infections related to the atopic dermatitis
● Ocular or infectious complications
● Erythrodermic
● Significant disruption of quality of life (e.g. sleepless nights, school or work days lost, etc)
3.
8
1. Lewis-Jones S. Int J Clin Pract. 2006 Aug;60(8):984-92.
2. Griffiths CE, et al. Br J Dermatol. 2006 Jul;155 Suppl 2:1-16.
Leung DY, et al. Ann Allergy Asthma Immunol. 2004 Sep;93(3Suppl 2):S1-21.
Treatment algorithm for atopic
dermatitis: ICCAD II ⃰
Atopic dermatitis: Algorithm for treatment
Initial assessment of disease history, extent and severity
Include assessment of psychological distress, impact on family
Emollients, education
Disease remission
(No signs or symptoms)
Flare
●
●
●
●
Acute control of pruritus and inflammation
Topical corticosteroids or
Topical calcineurin inhibitors
Pimecrolimus BID or
Tacrolimus BID
Adjunctive therapy
● Avoidance of trigger
factors
● Bacterial infection:
●
Systemics, including
cyclosporin, are
recommended for the
treatment of severe
refractory disease
⃰International Consensus Conference on
Atopic Dermatitis II
9
●
●
Maintenance therapy
For disease persistence and/or frequent recurrences
At earliest signs of local recurrence use topical calcineurin
inhibitors to prevent disease progression
Long-term maintenance use of topical calcineurin inhibitors
Intermittent use of topical corticosteroids
●
●
●
●
●
●
●
Severe refractory disease
Phototherapy
Potent topical steroids
Cyclosporin
Methotrexate
Oral steroids
Azathioprine
Psychotherapeutic
●
●
●
oral and/or topical
antibiotics
Viral infections:
antiviral therapy
Psychological
interventions
Antihistamines
Ellis C et al. BJD 2003;148(Suppl. 63):3-10.
Cyclosporin in the treatment of
atopic dermatitis
10
Overview
Cyclosporin is a cyclic polypeptide immunosuppressant
consisting of 11 amino acids
Immunosuppressive
effects first discovered
in the 1970’s by
scientists at Sandoz
(Novartis)1
CH
HC
H
HO
CH2
CH
C
Calcineurin inhibitor
that acts selectively
on T-cells1
Indicated for the short term
treatment (8 weeks) of
patients with severe atopic
dermatitis in whom
conventional therapy is
ineffective or inappropriate2
H3C
MeVal
N
MeLeu
CH3
MeLeu
CH
D-Ala
C62H111N11O12
C
CH3
Abu
MeGly
O
MeLeu
Ala
MeLeu
Val
Highly effective
treatment due to its
rapid onset1
Mol. Wt. 1202.63
1. Amor KT et al. J Am Acad Dermatol. 2010;63(6):925-46.
2. Sandimmun Neoral Core Data Sheet.
11
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Mechanism of action
Cyclosporin induces immunosuppression by inhibiting
the first phase of T-cell activation1
‘Signal’
Ca2+
Inhibition of the enzyme
calcineurin (CaN) by
cyclosporin (CsA) reduces
the activation of the
transcription factor,
nuclear factor of activated
T-cells (NF-ATc) , causing
a reduction in the
transcription of a number
of cytokine genes,
particularly interleukin 21,2
CsA
T-cell receptor
Ion channel
Extracellular
Intracellular
Ca2+ +
CsA
CpN
CpN
CaN
NF-ATc
P
Dephosphorylation
P
NF-ATc
NF-ATn
+
T-cell
Nucleus
Interleukin 2 gene
1. Menter A et al. J Am Acad Dermatol. 2008 May;58(5):826-50.
2. Amor KT et al. J Am Acad Dermatol. 2010 Dec;63(6):925-46.
12
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Cyclosporin is a critical dose drug
Switching between formulations may lead to clinically
important changes in bioavailability and efficacy
● Cyclosporin is a critical dose drug with a narrow therapeutic index
● With the use of cyclosporin generics, an average of 20% lower bioavailability can
be expected, which means that efficacy may be unsatisfactory in isolated cases1
● The Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK
states that:2
● Cyclosporin must be prescribed and dispensed by brand name
● Patients should be stabilised on a single brand of cyclosporin because switching between
formulations without close monitoring may lead to clinically important changes in
bioavailability
● All products that contain cyclosporin are interchangeable only if careful therapeutic
monitoring takes place
● Prescribing and dispensing of cyclosporin should be by brand name to avoid inadvertent
switching
1. Pathirana D et al. JEADV 2009;23(Suppl.2):5-70.
2. MHRA Drug Safety Update. 2009; 3(5):1-2. Available here: http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON065444.
13
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Treatment overview
Cyclosporin offers patients rapid and effective relief
from the symptoms of atopic dermatitis1–5
Cyclosporin
Indication
The short-term treatment of severe atopic dermatitis that cannot be controlled
with topical therapy (Europe)
Although not FDA approved, cyclosporin is recommended for the treatment of
atopic dermatitis refractory to conventional treatment by:
● American Academy of Dermatology (AAD) Guidelines of Care committee
● European Academy of Dermatology and Venereology (EADV) European Task
Force on Atopic Dermatitis
● Japanese Dermatological Association committee for Guidelines for the
Management of Atopic Dermatitis
Recommended initial dosage
5 mg/kg daily, gradual tapering as dictated by the clinical response over the
next 3 months to a dose of 1.5 mg/kg/day
Recommended maintenance dosage
If maintenance therapy is needed, the lowest effective dose should be used
Response rate
Dose-dependent, patients treated with a higher initial dose (4–5 mg/kg/day) have
a 40% decrease in severity at 2 weeks
Patients treated with a lower initial dose (2.5–3 mg/kg/day) have a 22% decrease
in severity
3.
14
1. Amor KT, et al. J Am Acad Dermatol. 2010;63(6):925-46.
2. Hanifin JM, et al. J Am Acad Dermatol. 2004;50(3):391-404.
Darsow U et al. J Eur Acad Dermatol Venereol. 2010;24(3):317-28.
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
5.
4. Saeki H, et al. J Dermatol. 2009;36(10):563-77.
Schmitt J. J Eur Acad Dermatol Venereol. 2007;21(5):606-19.
Efficacy of cyclosporin
Numerous clinical trials confirm the efficacy of
cyclosporin in the treatment of atopic dermatitis
Meta-analysis: Mean relative change in severity of atopic dermatitis compared to
baseline after 6–8 weeks of continuous treatment with cyclosporin
Author, year
Mean change (95% CI)*
Harper 2000
Berth Jones 1996
Czech (300 mg) 2000
Czech (150 mg) 2000
Swoden 1991
Berth Jones 1997
Zurbriggen (S) 1999
Zurbriggen (N) 1999
Bunikowski 2001
Granlund 1995
van Joost 1994
Caproni 2000
–0.57 (–0.69,–0.45)
–0.57 (–0.68,–0.45)
–0.58 (–0.66,–0.50)
–0.48 (–0.56,–0.40)
–0.56 (–0.73,–0.39)
–0.35 (–0.43,–0.27)
–0.68 (–1.19,–0.17)
–0.69 (–0.99,–0.39)
–0.58 (–0.91,–0.24)
–0.62 (–0.88,–0.37)
–0.56 (–0.86,–0.26)
–0.54 (–0.62,–0.46)
Overall (95% CI)
–0.53 (–0.59,–0.47)
● Mean clinical
improvement in
disease severity was
55% (95%-CI 48–62%)
● Most of these patients
were not adequately
controllable with
standard topical
treatments
–1
–0.75
–0.5
–0.25
0
0.25
% change in mean severity of atopic dermatitis from baseline
(Negative change in severity indicates clinical improvement)
Schmitt J. J Eur Acad Dermatol Venereol. 2007;21(5):606-19.
15
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product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Rapid response to treatment
Cyclosporin is associated with a rapid response
to treatment in patients with atopic dermatitis
Author, year
Meta-analysis: Relative change in mean
disease severity after 2 weeks of treatment
with cyclosporin (mean and 95%-CI) stratified
by initial cyclosporin dosage
Berth-Jones 1996
Czech 2000
Sowden 1991
Zurbriggen (Sandimmun) 1999
Higher
cyclosporin
dosage
(4–5 mg/kg BW)
Zurbriggen (Neoral) 1999
Granlund 1995
van Joost 1994
POOLED
ESTIMATE
● Patients treated with an initial dose of 4–
5 mg/kg/day have a rapid response
● 40% decrease in severity at 2 weeks
● Patients treated with a lower initial dose
of 2.5–3 mg/kg/day have a 22%
decrease in severity at 2 weeks
40% (29%;51%)
Czech 2000
Berth Jones 1997
Lower
cyclosporin
dosage
(2.5–3 mg/kg BW)
Bunikowski 2001
Schmitt J. J Eur Acad Dermatol Venereol. 2007;21(5):606-19.
Pacor 2004
16
POOLED
ESTIMATE
22% (8%;36%)
0 10 20 30 40 50 60 70 80
Relative mean improvement in severity from baseline (%)
This tool may contain scientific/medical information on unapproved products or product uses. This information is for
educational purposes only. Please consult the applicable prescribing information for details on approved uses of products.
Improvement in quality of life
Short-course cyclosporin improves quality of life and
clinical outcome in patients with AD
Cyclosporin short-course therapy: Quality of life and clinical outcome
Improvement versus baseline (%)
Low dose cyclosporin
High dose cyclosporin
70
50
40
59.3
58.0
60
45.3
46.3
47.8
47.4
54.3
49.9
57.4
52.3
47.7 48.5
41.3
33.9
33.4
27.5
30
34.0
31.3
25.1
21.1
20
10
0
2 wk
8 wk
TBSA
score
2 wk
8 wk
Affected body
surface area
2 wk
8 wk
Itching
2 wk
8 wk
Sleep loss
2 wk
8 wk
DLQI
● 106 Adults randomized to
receive 150 mg (low) or 300
mg (high) of cyclosporin
microemulsion daily
● 45% improvement in TBSA
score by week 2; 58% by
week 8
● 59% improvement in sleep
loss by week 8
● 52% improvement in DLQI
scores by week 2
● Atopic dermatitis is often associated with severe itching
● A 47% improvement in itching was seen within 2 weeks in patients treated with the
high dose of cyclosporin
TBSA = total body surface area; DLQI = dermatology life quality index
17
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Czech W et al. J Am Acad Dermatol. 2000 Apr;42(4):653-9.
Cyclosporin safety management
18
Overview of adverse events
The adverse event profile and risk-benefit ratio of
cyclosporin is well understood
Very frequent
• None
Frequent
• Renal failure (dosedependent)
• Hypertension
• Gingival hyperplasia
• Reversible
hepatogastric
complaints
• Tremor
• Weariness
• Headache
• Burning sensation in
hands and feet
• Reversible elevated
blood lipids (esp. in
combination with
corticosteroids)
• Hypertrichosis
Occasional
• Seizures
• Gastrointestinal
ulcerations
• Weight gain
• Hyperglycemia
• Hyperuricemia
• Hyperkalemia
• Hypomagnesemia
• Acne
• Anemia
Rare
Very rare
• Ischemic heart
disease
• Pancreatitis
• Motor polyneuropathy
• Impaired vision
• Defective hearing
• Central ataxia
• Myopathy
• Erythema
• Itching
• Leucopoenia
• Thrombocytopenia
• Microangiopathic
hemolytic anemia
• Hemolytic uremic
syndrome
• Colitis (isolated
cases)
• Papillary
• oedema (isolated
cases)
• Idiopathic intracranial
hypertension (isolated
cases)
● Rate of adverse events generally demonstrates a clear dose-dependency
This list is not exhaustive; please refer to the local prescribing information.
19
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70.
Monitoring before and during therapy
with cyclosporin
● Complete physical examination
● Review of medical history
● Complete skin inspection
●
Initial
monitoring
All suspicious lesions should be biopsied and adequately treated before initiation of cyclosporin
● Blood pressure
●
Two measurements
● Baseline laboratories
●
Serum creatinine (two measurements), serum urea nitrogen, CBC, serum magnesium,
potassium, uric acid, lipids, liver enzymes, serum bilirubin
● Malignancy screening
● Tuberculin skin test (>5 mm induration considered positive)
● Serum creatinine and blood pressure
Monitoring
on therapy
●
Monitor monthly
● Other laboratory monitoring
●
CBC, uric acid, potassium, lipids, liver enzymes, serum bilirubin, and
magnesium should be monitored monthly
CBC; Complete blood count.
20
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
Tolerability profile of cyclosporin
Hypertension, hypercholesterolemia and increased
creatinine the most frequently reported adverse events
● The overall frequency of clinical events after treatment of 57% was distributed as
follows:
● Only 14% of patients were treated with:
● Antihypertensives
● Lipid lowering therapy
Diabetes
Neoplasm
Thrombocytopenia
Alteration of electrolytes
Uric acid disorders
Gingival hyperplasia
Anemia
Hypertrichosis
Gastrointerstinal symptoms
Increased creatinine
Hypercholesterolemia
Hypertension
0%
5%
10%
15%
20%
25%
Studio Retrospettivo, SIDEMAST 2006.
21
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Cyclosporin and nephrotoxicity
22
Incidence
At low cyclosporin doses, nephrotoxicity is infrequent
and reversible1,2
● The best predictive factor of nephrotoxicity is the percentage of serum
creatinine increase over baseline value2,3
●
●
●
●
2.5 mg/kg/day
cyclosporin
for 12 weeks
• 4% of patients have increase in creatinine of 50% above baseline
5 mg/kg/day
cyclosporin
for 12 weeks
• 13% of patients have increase in creatinine of 50% above baseline
• Reversible upon withdrawal of cyclosporin1
• Reversible upon withdrawal of cyclosporin1
Treatment duration longer than 3 years is a risk factor for interstitial renal fibrosis2–4
Older age, obesity and hypertension are also risk factors for kidney toxicity2,3
Scheme of administration does not appear to influence kidney toxicity2,3
Reversibility of nephrotoxicity after treatment withdrawal has been demonstrated1,2
1.
23
Feutren G, et al. Br J Dermatol 1990;122(suppl 36):57-69.
2.
Paul C et al. JEADV 2011;25(Suppl.2):2-11.
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
3.
Lowe NJ et al. J Am Acad Dermatol 1996;35:710-19.
4.
Young EW et al. Kidney Int 1994;46:1216-22.
Managing nephrotoxicity
Increases in serum creatinine can be reversed by dose
reduction or withdrawal of treatment
Serum creatinine  to ≥30–50% above baseline value
(even if within normal range)
Serum creatinine  to ≥50% above baseline value
(even if within normal range)
Reduce dose by at least 25%
Reduce dose by at least 50%
Repeat measurement within 30 days
Repeat measurement within 30 days
Creatinine  to <30% above baseline value
Creatinine remains ≥30% above baseline value
Continue cyclosporin treatment
Stop cyclosporin therapy
Pathirana D et al. JEADV. 2009;23:5-70.
24
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Drug interactions
There are a number of drugs that may
potentiate nephrotoxicity
Antibiotics
•
•
•
•
Antineoplastics
Gentamicin
Tobramycin
Vancomycin
Trimethoprimsulfamethoxazole
• Amphotericin B
• Ketoconazole
This list is not exhaustive; please refer to the local prescribing information.
25
•
•
•
•
• Melphalan
Antifungals
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product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Anti-inflammatory drugs
Diclofenac
Indomethacin
Naproxen
Sulindac
Immunosuppressives
• Tacrolimus
Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
Cyclosporin and
hypertension/hyperlipidemia
26
Incidence
Hypertension and hyperlipidemia often resolve after
discontinuation of cyclosporin1,2
Arterial
hypertension
Arterial hypertension in 2 to 15% of patients on cyclosporin1
Reversible upon withdrawal of cyclosporin2
Elevated triglycerides in 15% patients on cyclosporin2
Hyperlipidemia
Hypercholesterolemia in <3% of patients on cyclosporin2
Reversible upon withdrawal of cyclosporin2
1.
27
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70.
2. Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
Managing hypertension
Hypertension can be controlled with
antihypertensive agents
Sustained increased BP reading:
Diastolic ≥90 mmHg or systolic ≥140 mmHg
⃰Calcium channel blockers are a
preferred choice although
nifedipine should be avoided
because of increased risk of
gingival hyperplasia.
Reduce cyclosporin dose by 25–50%
Increased BP sustained after several dose reductions
Discontinue treatment
OR
Treat with antihypertensive agent⃰
Isradipine and amlodipine do
not alter cyclosporin levels and
are good choices. Beta-blockers
may also be used.
Angiotensin-converting enzyme
inhibitors and potassium-sparing
diuretics should be avoided as
may cause hyperkalemia.
Rosmarin DM et al. J Am Acad Dermatol. 2010;62:838-53.
Griffiths CEM, et al. Br J Dermatol 2004;150 (suppl 67): 11-23.
28
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Managing hyperlipidemia
Hyperlipidemia can be controlled with diet or the use of
statins*
Check lipids at the initiation of therapy and every
6 months for patients on prolonged continuous
therapy
Hypercholesterolemia (>300 mg/dL) and/or elevated
triglicerides (>750 mg/dL)
Low cholesterol, low-fat diet recommended
If no improvement, reduction in dose or discontinuation of
therapy with cyclosporin should be considered, depending
on the degree of hyperlipidemia
and the patient’s risk profile
*Close monitoring of patients in
whom cyclosporin and statins are
used together is recommended to
detect myopathy at an early stage.
Cyclosporin may reduce the
clearance of some HMG–CoA
reductase inhibitors.
Fluvastatin is the most studied drug
 Starting dose (20 mg daily for 12
weeks), increasing to 40 mg daily for
8 weeks
Pravastatin, atorvastatin and
lovastatin have cases of muscle
toxicity when combined with
cyclosporin
Pathirana D et al. JEADV. 2009;23:5-70.
Rosmarin DM et al. J Am Acad Dermatol. 2010;62:838-53.
29
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product uses. This information is for educational purposes only. Please consult
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Other safety considerations
30
Managing other adverse events
Gingival
hyperplasia
Better dental
hygiene/antiseptic
therapy
Dose reduction
Azithromycin
administered for
3 days
Increases in liver
function tests
Dose reduction of
25% and
reassessment
within 30 days
If values continue to
deviate,
cyclosporin should
be discontinued
Gastrointestinal
disorders
Taking of
cyclosporin on a
full stomach
Vasomotor
disturbancies/
paresthesia
If clinically relevant,
dose reduction
Absolute contraindications:
• Impaired renal function
• Insufficiently controlled arterial hypertension
• Severe infectious disease
• History of malignancy
• Current malignancy
• Simultaneous PUVA therapy
Necessary measures before and during treatment include
avoidance of sun exposure
Pathirana D et al. JEADV. 2009;23:5-70.
31
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Malignancy and cyclosporin
Incidence of nonskin malignancy was not higher in patients
treated with cyclosporin
● Prospective long-term cohort study investigating the incidence of malignancies
in severe psoriasis patients treated with cyclosporin
● Total of 1252 patients followed prospectively for up to 5 years
● Malignancies were recorded prospectively. Incidence rates for malignancies were compared
with the general population using standardized incidence ratios (SIR)
SIR
95% CI
Any malignancy
2.1
1.6–2.9
Any skin malignancy
6.1
3.8–9.1
Any nonskin malignancy
1.3
0.8–1.9
● The incidence of nonskin malignancy overall was not significantly higher in this
study than in the general population
● Duration of exposure to cyclosporin, exposure to psoralen and UVA, exposure
to methotrexate, and exposure to immunosuppressants showed a significant
effect on the incidence of nonmelanoma skin malignancies
Paul CF, et al. J Invest Dermatol. 2003;120:211–216.
32
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product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Immunosuppressant effects of
cyclosporin and risk of infection
● Cyclosporin may increase the general risk of bacterial, parasitic, viral, and
fungal infections, as well as the risk of infection with opportunistic pathogens1
● This increased risk of infection plays a minor role when treating psoriasis with cyclosporin1
● Vaccinations given concomitantly with cyclosporin may be less effective1,2
● Studies in patients with transplantation taking cyclosporin have shown inconsistent
effectiveness of the influenza vaccine2
● Live vaccines are contraindicated and should be avoided1,2
● Severe infectious disease is an absolute contraindication for cyclosporin use1
● Hepatitis profile including anti-HAV, HBsAg, anti-HBs, anti-HBc, anti-HCV and also anti-HIV
should be checked in patients treated with cyclosporin2,3
1.
33
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70.
2. Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
3. Inaloz SH et al. J Dermatol. 2008 May;35(5):276-82.
Pregnancy and cyclosporin
There is no indication of teratogenesis in the limited experience
of administering cyclosporin to pregnant women
Of the oral medications approved for psoriasis,
only cyclosporin should be considered in
pregnant women
Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53
● NTPR (National Transplant Pregnancy Registry) data suggest that parental
exposure to cyclosporin does not induce defects in children
● Although cyclosporin crosses the placenta, there is no evidence that it
causes harm to the foetus
Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
34
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Pregnancy and cyclosporin
Experience with cyclosporin in pregnant women is limited
● Pregnant women receiving immunosuppressive therapies after
transplantation, including cyclosporin and cyclosporin containing
regimens, are at risk of premature delivery (<37 weeks)
● A limited number of observations in children exposed to cyclosporin in
utero are available, up to an age of approximately 7 years. Renal function
and blood pressure in these children were normal
● However there are no adequate and well controlled studies in pregnant
women and, therefore, cyclosporin should not be used during pregnancy
unless the potential benefit to the mother justifies the potential risk to the
foetus
Sandimmun Neoral Core Data Sheet.
35
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product uses. This information is for educational purposes only. Please consult
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Drug interactions
There are a number of drugs that may affect serum
cyclosporin levels
Drugs that increase
cyclosporin
concentrations
• Antiarrhythmic agents: amiodarone
• Calcium channel blockers: diltiazem, nicardipine,
verapamil
• Diuretics: thiazides, furosemide, carbonic
anhydrase inhibitors
• Antifungals: ketoconazole, itraconazole,
fluconazole, voriconazole
• Antibiotics, macrolides: erythromycin,
clarithromycin, telithromycin, azithromycin
• Antibiotics, fluoroquinolones: ciprofloxacin,
norfloxacin
• Antibiotics, other: cephalosporins, doxycycline
Drugs that decrease
cyclosporin
concentrations
•
•
•
•
•
Antibiotics, beta lactams: nafcillin
Antibiotics, rifamycins: rifabutin, rifampin, rifapentine
Antifungals: griseofulvin
Anti-HIV drugs: efivarenz
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin,
valproic acid
• Retinoids: bexarotene
• Herbals: St John wort
• Other drugs: octreotide, ticlopidine, bosentan
This list is not exhaustive; please refer to the local prescribing information.
36
• Anti-HIV drugs, protease inhibitors: ritonavir,
indinavir, saquinavir, nelfinavir,
• Antimalarials: chloroquine, hydroxychloroquine,
primaquine
• Foods: grapefruit
• H2 antihistamines: cimetidine
• SSRIs: fluoxetine, sertraline
• Glucocorticoids: dexamethasone,
methylprednisolone
• Antineoplastics: doxorubicin, etoposide, imatinib
• Other drugs: allopurinol, bromocriptine, danazol,
metoclopramide, oral contraceptives, cholic acid,
ezetimibe
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult
the applicable prescribing information for details on approved uses of products.
Rosmarin DM, et al. J Am Acad Dermatol. 2010 May;62(5):838-53.
Identifying the cyclosporin patient
Case studies in atopic dermatitis
37
Case 1: Atopic dermatitis
38
Atopic dermatitis
Case study 1
Patient profile: 22 year old female, 52 kg, student, intermittent allergic rhinitis,
contact allergy to lanolin and fragrance mix
Disease status: Atopic dermatitis with onset in early childhood and long
remission (at least 10 years), reappearance during the last 4 years
● Relapsing eczematous lesions, especially on the
cutaneous folds and the hands
● Worsening of AD in the last 3 months with diffuse
lesions
● Marked involvement of the face, neck and hands
● Deterioration of the quality of life
o Severe generalized itch
o Interference with sleep and daily activities
o Psychosocial problems
39
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Previous therapy
Case study 1
● Topical corticosteroids (short intermittent courses) sufficient to control lesions
until the recent flare of AD
● Treatment with topical calcineurin inhibitors (TCIs)
● Intense burning at the site of application, especially on the face
● For this reason the patient refused to continue the use of TCIs
● Constant use of preventive measures against contact allergens
40
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Cyclosporin therapy and outcome
Case study 1
● Cyclosporin dose
● 250 mg/day (5 mg/kg/day)
● Disappearance of itch after
a few days
● Notable improvement of
skin lesions within a week
● Continuation of treatment
with 200 mg/day for another
2 weeks and then gradual
reduction of frequency by
removing a day per week
● Good tolerability
41
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Case 2: Atopic dermatitis
42
Atopic dermatitis
Case study 2
Patient profile: 16 year old female, 55 kg, secondary school student
Disease status: Atopic dermatitis for the last 2 years, with erythema, skin
dryness, excoriations and sleep loss, SCORAD >40
Previous therapy:
● Treated with topical therapy for 2 years
● Local agents including
● Tacrolimus, pimecrolimus, steroids, emollients
● Noncompliance and uncontrolled disease
43
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Cyclosporin therapy and outcome
Case study 2
● Treatment with cyclosporin 3 mg/kg/day for 2 weeks
● Insufficient efficacy
● SCORAD < 35% reduction
● Increased dose by 0.5 mg/kg/day per month
●
●
●
●
Significant improvement at maximum dose (5 mg/kg/day)
SCORAD reduction 70%
Maintenance at the efficient dose for 2 months & treatment cessation with dose tapering
Now 2 months off treatment at remission
● Total treatment duration: 7 months
● Side effects
● Hypertrichosis on the fifth month, reversed after treatment cessation.
● Herpes labialis treated with topical therapy
● This case illustrates that maximum dosing of cyclosporin in atopic dermatitis
should be pursued in case of partial initial response
44
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Case 3: Atopic dermatitis
45
Atopic dermatitis
Case study 3
Patient profile: 20 year old male, with personal history of asthma and allergic
rhinoconjunctivitis and familial history of both parents with allergic
rhinoconjunctivitis
Disease status: Atopic dermatitis for the last 6 years, with a clinical report of
almost continuous outbreaks of cutaneous lesions since 1 year old
Previous therapy:
● Treated with emollients and topical corticosteroids
● Frequent periods of oral prednisone with short and
partial improvements
46
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Cyclosporin therapy and outcome
Case study 3
● Treatment with oral cyclosporin 5 mg/kg/day over 3 months
● Tapered to 3.7 and 2.5 mg/kg/day during the following 2 months
● Almost total control was achieved
● Relapses occurred later
47
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Conclusions
48
Summary
● Cyclosporin offers patients rapid relief from the signs and symptoms of atopic
dermatitis
● Cyclosporin has a well established efficacy and safety profile
● Cyclosporin improves the quality of life of patients with atopic dermatitis
● Cyclosporin is a critical-dose drug and bioequivalence does not necessarily mean
therapeutic equivalence
Cyclosporin is an effective systemic therapy for severe atopic dermatitis
Cyclosporin provides patients with a rapid reduction in the signs and
symptoms of atopic dermatitis
49
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The ‘ideal’ cyclosporin patient
Male or female adult
patient, collaborative
and trustworthy
With moderate to
severe disease
resistant to
topical/conventional
therapies1,2
Without immune
deficiency, active
infection and/or
history of neoplastic
disorders1,2
With blood pressure
values within the
normal limit1,2
Without concomitant use of
nephrotoxic and/or
immunosuppressive drugs, as
well as drugs with potential
interactions with cyclosporin
metabolism1,2
With liver and kidney
function tests within
the normal range1,2
Without history of
excessive
photo(chemo)therapy,
and/or recent use of
radiotherapy1,2
1. Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70.
2. Sandimmun Neoral Core Data Sheet.
50
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product uses. This information is for educational purposes only. Please consult
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