Page 1

Now approved for intermittent and continuous dosing 1

Make hiding from plaque psoriasis part of the PAST

ENB221 Date of preparation: Dec 2009


A clearer FUTURE for your patients can begin with ENBREL


When you choose ENBREL, you choose experience... • 17 years of collective clinical experience2A • 1.9 million patient-years of postmarketing experience across indications3A

• Celebrating 5 years as an approved treatment for moderate to severe plaque psoriasis1,2B

...and flexibility for your plaque psoriasis patients • Now approved for both intermittent and continuous dosing

1

• The first and only biologic indicated for chronic severe paediatric plaque psoriasis1,4-8


64% of patients achieved a clear † or almost clear response by Week 24 Treatment success using PGA* in a 24-week clinical trial of adult patients with moderate to severe plaque psoriasis 18 Double-blind period

Patients (%) achieving clear or almost clear status on PGA (LOCF)

70 60 50

Open-label period

ENBREL 50 mg QW Placebo

(n=90)

64%

(n=96)

(n=46) (n=36)

39%**

40

42%

30 20 10

4%

**

P < 0.001 Enbrel® v Placebo

0 2

4

8

12

16

20

24

Weeks

• Significant improvement in patient’s quality of life from as early as 2 weeks 18 • Many more patients achieved clear or almost clear skin when treatment with ENBREL continued from 12 to 24 weeks 18 * PGA (Physician’s Global Assessment) is a six-point scale with 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = marked, 5 = severe † Clear or almost clear response = PGA score of 0-1

18


18

Patient (%) acheiving PASI 75 response (LOCF)

PASI 75 at 24 weeks with Enbrel 50 mg once weekly 18

100

80

Double-blind period

Open-label period

ENBREL 50 mg QW Placebo

(n=96) (n=90)

(n=46)

71%

60

(n=36)

38% *

40

44%

20

2%

*

P < 0.0001 Enbrel® v Placebo

0 2

4

8

12

16

20

24

Weeks

• Patients who were switched from Placebo to Enbrel at week 12 demonstrated similar PASI 75 responses 18 • 69% of ENBREL patients achieved a PASI 50 response at 12 weeks 18

Early Clearance

71% of patients achieved PASI 75 at 24 weeks


Now approved for intermittent and continuous dosing

ENBREL allows you to adapt treatment to meet patientsâ&#x20AC;&#x2122; needs ENBREL is the only biologic offering 2 dosing schedules for adult patients with moderate to severe plaque psoriasis...1,4,5,8 NOW APPROVED

Intermittent therapy

Continuous therapy

for patients requiring an interruption to treatment

for patients who require treatment beyond 24 weeks

...and 2 starting doses 50 mg

50 mg

BIW Weeks 1-12, then 50 mg QW

QW from the start


>80% of re-treated adult patients achieved skin clearing*equivalent to their initial treatment cycle 19

PGA † response at 12 weeks in initial and re-treatment phases

Flexible Dosing

Initial responders* (n=226)‡

83% Re-treatment responders* (n=187)

Percentage of patients achieving PGA ≤2

ENBREL 25 mg twice weekly

With both continuous and intermittent treatment, a majority of patients were satisfied with their therapy.19 * Skin clearing (treatment response) defined as a PGA ≤2 † PGA (Physician’s Global Assessment) is a six-point scale with 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = marked, 5 = severe ‡ 226 of original baseline population of 359 achieved a treatment response of PGA ≤2


ENBREL works differently

1,4-8

A unique mechanism of action • ENBREL is the only soluble receptor for tumor necrosis factor (TNF) and is fully human1

No neutralizing antibodies • ENBREL is not associated with the production of neutralizing antibodies1 • Neutralizing antibodies have been associated with lower response rates1,4,5,20,21

Short half-life • ENBREL has a short half-life (<3 days), which can result in rapid elimination from the body1,22 • The relatively shorter half-life of ENBREL may add an extra measure of flexibility if treatment has to be interrupted for any reason, such as pregnancy or planned surgery1,22

Etanercept1

Structure

Soluble receptor for TNF and fully human

Adalimumab4

Infliximab5

Ustekinumab8

Human monoclonal Chimeric monoclonal Human monoclonal antibody antibody. antibody

Presence of neutralizing antibodies

No

Yes

Yes

Yes

Half-life

< 3 days

14 days

8-9.5 days

21 days

This table is not intended to imply any comparison of efficacy or safety.


New administration option

make the self-injection process simple, secure and sure

1

1 1Simple 1 1Delivering ENBREL at the click of a button

2

Secure 2

safety mechanism 2 Built-in 2 3prevents accidental activation 3 3 Needle safety shield keeps 3 the needle covered before, during, and after an injection

4

Sure 4

clicks signal the 4 Audible 4 5 beginning and end of the injection 5 5 Inspection window turns 5 completely purple to confirm delivery of a full dose

3

4 4 4 4

Available for new patients in convenient pre-filled pen 50 mg once-weekly dosing

5 5 5 5

Mode of Action

1 11 1

2 2 2 2

3 3 3


Documented long-term safety data for moderate to severe plaque psoriasis 9

In a 96-week psoriasis clinical trial, ENBREL demonstrated a consistent long-term safety profile 9 • Total exposure to ENBREL was more than 1,000 patient-years9 Reported cases through 96 weeks9

Tuberculosis

0

Opportunistic Infections

0

No significant difference in malignancy risk between ENBREL and controls in clinical trials in Rheumatoid Arthritis patients 1,3B,10 • Overall rates of malignancies in patients receiving Enbrel were similar to those reported for the general population.1

Studied in over 3,000 adult plaque psoriasis patients 3C • Safety profile was consistent across adult and paediatric populations12-14 • No new safety findings were reported in paediatric patients12


Safety profile established over 17 years of collective clinical experience 2A

Rates of serious infections (SIs),* serious adverse events (SAEs), and malignancy with ENBREL were consistently low for up to 10 years in RA clinical studies 3B,15

RA

s

SIs in long-standing RA 14† 0.08

SI rate (per patient-year)

0.07

0.02

0.02

0.06 0.05

0.05

0.04

0.04

0.04

ENBREL in controlled trials

ENBREL overall through 10 years

0.03 0.02 0.01 0

ENBREL in controlled trials

ENBREL overall through 10 years

Placebo or MTX in controlled trials

• Overall rate of SAEs with ENBREL in long-standing RA through 10 years (0.19 per patient-year) was similar to placebo and ENBREL in controlled trials (0.20 for placebo, 0.15 for ENBREL)3B,15 • Overall malignancy rates did not increase with long-term use3B,15

The first and only biologic indicated for chronic severe paediatric plaque psoriasis1,4-8

*Serious infections were defined as infections requiring hospitalizations or intravenous antibiotics. †

Long-standing RA = patients with disease duration >3 years.

Safety


ABBREVIATED PRESCRIBING INFORMATION Before prescribing Enbrel please refer to full Summary of Product Characteristics. Presentation: Enbrel powder and solvent: Enbrel 25 mg powder and solvent for solution for injection. Each vial contains 25 mg etanercept and each pre-filled syringe contains 1 ml water for injections. Enbrel pre-filled syringe: Enbrel 25 mg and 50 mg solution for injection in pre-filled syringe. Each pre-filled syringe contains either 25 mg or 50 mg etanercept. Enbrel Pre-filled Pen (MYCLIC®): Enbrel 50 mg solution for injection in pre-filled pen. Each pre-filled pen contains 50 mg etanercept. Enbrel paediatric: Enbrel 25 mg powder and solvent for solution for injection for paediatric use. Each vial contains 25 mg etanercept and each pre-filled syringe contains 1 ml bacteriostatic water for injections Uses: Adults: Moderate to severe active rheumatoid arthritis (RA), in combination with methotrexate, when response to Disease Modifying Anti Rheumatic Drugs (DMARDS), including methotrexate (unless contraindicated), has been inadequate. Enbrel can be given as monotherapy in the case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Severe, active and progressive RA without prior methotrexate treatment. Enbrel alone or with methotrexate has been shown to reduce the rate of progression of joint damage measured by X-ray and to improve physical function. Patients with moderate to severe plaque psoriasis (PP) who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporine, methotrexate or PUVA. Active and progressive psoriatic arthritis (PsA) when response to DMARDS has been inadequate. Enbrel has been shown to improve physical function in PsA patients, and to reduce the progression rate of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of PsA. Severe active ankylosing spondylitis (AS) when response to conventional therapy has been inadequate. Children aged 4-17 years (25 mg only): Active polyarticular juvenile idiopathic arthritis (JIA) when inadequate response to, or intolerant of methotrexate. Children aged 8-17 years: Chronic severe psoriasis when inadequately controlled by, or intolerant to, other systemic therapies or phototherapies. Dosage: By subcutaneous injection. Adults: RA – 25 mg twice weekly or 50 mg once weekly PP - 25 mg twice weekly or 50 mg once weekly for up to 24 weeks. Alternatively 50 mg twice weekly for up to 12 weeks followed by 25 mg twice weekly or 50 mg once weekly for a further 12 weeks if needed. Continuous therapy may be appropriate for some adult patients. Discontinue if no response after 12 weeks. For re-treatment: 25 mg twice weekly or 50 mg once weekly for up to 24 weeks. AS and PsA – 25 mg twice weekly or 50 mg once weekly. Children aged 4-17 years: JIA in children aged 4-17 years – 0.4 mg/kg (maximum dose 25 mg) twice weekly with an interval of 3 – 4 days. Children aged 8-17 years: Plaque psoriasis in children aged 8-17 years – 0.8 mg/kg (maximum per dose 50 mg) once weekly for up to 24 weeks. Discontinue if no response after 12 weeks. For re-treatment: 0.8 mg/kg (maximum per dose 50 mg) once weekly for up to 24 weeks. Contra-indications: All presentations: Hypersensitivity to any of the ingredients, sepsis or risk of sepsis, active infections. Enbrel paediatric: Must not be given to premature babies or neonates as the bacteriostatic water for injections contains benzyl alcohol. Warnings and Precautions: Enbrel should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA, JIA, PsA, AS, PP or Paediatric PP. Patients treated with Enbrel should be given the Patient Alert Card. Use carefully in patients predisposed to, or with history of, infection due to underlying diseases other than RA (e.g. advanced or poorly controlled diabetes) or with history of blood dyscrasias, pre-existing or predisposition to CNS demyelinating disease or congestive heart failure. Cases of active tuberculosis have been reported, therefore all patients should be evaluated for both active and inactive TB prior to being treated with Enbrel. If active TB is diagnosed, Enbrel should not be initiated. Caution should be used when administering Enbrel to patients identified as carriers of hepatitis B virus and there have been reports of worsening hepatitis C in patients receiving Enbrel. Use with caution in patients with a history of hepatitis C. Whether treatment with Enbrel might influence the development and course of active and/or chronic infections is unknown. Concurrent administration of Enbrel and anakinra has been associated with increased risk of serious infections and neutropenia, and is therefore not recommended. In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events, and is therefore not recommended. Use caution when considering combination therapy with sulfasalazine. Reports of various malignancies have been received in the post-marketing period, therefore with current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk elimination. Caution should be exercised when considering TNF-antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy. Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including Enbrel, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded. Non-melanoma skin cancer (NMSC) has been reported in patients treated with TNF-antagonists, including Enbrel. Periodic skin examination is recommended for all patients who are at increased risk of NMSC, including patients with psoriasis or a history of PUVA therapy. Enbrel has not been studied in combination with other systemic therapies or phototherapy for the treatment of psoriasis. Monitor closely if patient develops new infection during treatment. Discontinue treatment if serious infection or allergic reaction develops or if blood dyscrasias are confirmed. Caution should be used in patients who have moderate to severe alcoholic hepatitis and Enbrel should not be used in patients for the treatment of alcoholic hepatitis. Discontinue temporarily if significantly exposed to varicella virus. Live vaccines should not be given concurrently with Enbrel. Treatment with Enbrel may result in the formation of autoantibodies. Enbrel is not recommended for the treatment of Wegener’s granulomatosis. There have been reports of hypoglycaemia following initiation of Enbrel in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some patients. Paediatric patients should have received all vaccines recommended in current immunization guidelines prior to starting Enbrel. Enbrel paediatric: Contains benzyl alcohol as an excipient which may cause toxic and/or anaphylactic reactions in infants and children up to 3 years old. Pregnancy & Lactation: Enbrel is not recommended in pregnant or breast-feeding women. ®

ENB/2010/051

Undesirable Effects: Adults: Very common side effects reported with clinical trial and post marketing experience include infections and injection site reactions. Common adverse events were allergic reactions, pruritus, autoantibody formation and fever. Uncommon side effects have included serious infections, thrombocytopenia, uveitis, interstitial lung disease (including pneumonitis and pulmonary fibrosis), non-melanoma skin cancers, angioedema, urticaria rash, psoriasiform rash and psoriasis. Rare reports include lupus-like syndrome, CNS demyelinating disorders, seizures, serious allergic/ anaphylactic reactions, elevated liver enzymes, cutaneous vasculitis, Stevens-Johnson syndrome, erythema multiforme, anaemia, leukopenia, neutropenia, pancytopenia, lymphoma, worsening of congestive heart failure, tuberculosis and opportunistic infections (including invasive fungal, protozoal, bacterial and atypical mycobacterial infections). Aplastic anaemia and toxic epidermal necrolysis have been reported very rarely. The frequency of leukaemia, macrophage activation syndrome and anti-neutrophilic cytoplasmic antibody positive vasculitis has not been accurately estimated through clinical studies. In clinical trials serious adverse events occurred with a frequency similar to placebo and methotrexate. These included: serious infections, malignancies, asthma, heart failure, MI and ischaemia, chest pain, syncope, cerebral ischaemia, hyper- and hypotension, cholecystitis, pancreatitis, GI haemorrhage, bursitis, confusion, depression, dyspnoea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism (PE), membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leucopenia, paresis, paresthesia, vertigo, allergic alveolitis, angioedema, scleritis, bone fracture, lymphadenopathy, ulcerative colitis, intestinal obstruction, eosinophilia, haematuria and sarcoidosis. Rate of new malignancies were similar to that expected for the population studied. Postmarketing studies have also reported the following: blood dyscrasias, congestive heart failure and various malignancies. Fatal outcomes associated with serious infections, pancytopenia, aplastic anaemia and interstitial lung disease have also been reported. In some postmarketing reports, particular fungal or other opportunistic infections were not recognized, resulting in delay of appropriate treatment, and sometimes death. Paediatrics (25 mg only): Generally as for adults, except the following were more common: headaches, nausea, vomiting and abdominal pain. In addition the following were reported as severe events: varicella, appendicitis, gastroenteritis, depression/ personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus and soft tissue /post operative wound infection. Legal Category: POM. Package Quantities: Enbrel powder and solvent: Each carton contains 4 vials of Enbrel 25 mg powder, 4 pre-filled syringes of water for injections, 4 needles, 4 vial adaptors and 8 alcohol swabs. Enbrel pre-filled syringe: Each carton contains either 4 pre-filled syringes of Enbrel 25 mg or 4 pre-filled syringes of Enbrel 50 mg and 8 alcohol swabs. Enbrel Pre-filled Pen (MYCLIC): Each carton contains 4 pre-filled pens containing 50 mg of Enbrel and 8 alcohol swabs. Enbrel paediatric: Each carton contains 4 vials of Enbrel 25 mg powder, 4 pre-filled syringes of bacteriostatic water for injections, 8 empty plastic syringes, 20 needles and 24 alcohol swabs. European Marketing Authorisation Number: Enbrel powder and solvent 25 mg: EU/1/99/126/003 Enbrel pre-filled syringe 25 mg: EU/1/99/126/013 Enbrel pre-filled syringe 50 mg: EU/1/99/126/017 Enbrel Pre-filled Pen (MYCLIC) 50 mg: EU/1/99/126/020 Enbrel paediatric: EU/1/99/126/012. European Marketing Authorisation Holder: Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Berkshire, SL6 0PH, UK. Further information is available from the Local Representative of the Marketing Authorisation Holder: Ireland - Wyeth Pharmaceuticals Ltd, Plaza 254, Blanchardstown Corporate Park 2, Ballycoolin, Blanchardstown, Dublin 15 Tel: 01 4493 500. API Reference Number: API_VENB_040_01July10 References: 1. Enbrel Summary of Product Characteristics, Wyeth Pharmaceuticals. 2. Wyeth Pharmaceuticals Data on File a) HHS letter; b) EMEA Approval. 3. Amgen Data on File a) Global Safety Memorandum July 2009; b) CSR 016.0018; c) CSR 103795. 4. Humira Summary of Product Characteristics, Abbott Laboratories. 5. Remicade Summary of Product Characteristics, Centocor Inc. 6. Orencia Summary of Product Characteristics, Bristol-Myers Squibb. 7. MabThera Summary of Product Characteristics, F. Hoffman-La Roche Ltd. 8. Stelara Summary of Product Characteristics, Janssen-Cilag Ltd. 9. Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50 mg etanercept twice weekly in patients with psoriasis. Arch Dermatol. 2007;143:719-726. 10. Okada SK, Siegel JN. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis [letter]. JAMA. 2006;296:2201-2202. 11. Gordon KB, Gottlieb AB, Giannini EH, et al. Clinical trial safety data of events of interest in patients receiving etanercept (ENBREL®) across approved indications. Presented at the American Academy of Dermatology Annual Meeting 2007. Poster 2610. 12. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358:241-251. 13. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2014-2022. 14. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152:1304-1312. 15. Weinblatt ME, Genovese MC, Bathon JM, et al. Safety and efficacy of etanercept (Enbrel®) treatment in North American patients with early and long-standing rheumatoid arthritis: 10 years of clinical experience. Poster presented at the American College of Rheumatology (ACR), October 24-29, 2008; San Francisco, CA. 16. Davis JC Jr, van der Heijde, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rhuem. 2003;48:3230-3236. 17. Lovell DJ, Reiff A, Jones OY, et al, for the Paediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of etanercept in children with polyarticularcourse juvenile rheumatoid arthritis. Arthritis Rheum. 2006;54:1987-1994. 18. van de Kerkhof PCM, Segaert S, Lahfa M, et al. Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. Br J Dermatol. 2008;159:1177-1185. 19. Ortonne J-P, Taïeb A, Ormerod AD, et al. Patients with moderate-to-severe psoriasis recapture clinical response during re-treatment with etanercept. Br J Dermatol. 2009;1-6. Published online June 2009. DOI 10.1111/j.1365-2133.2009.09238.x. 20. Radstake TRDJ, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann RheumDis. 2008;1-18. Published online November 2008. DOI 10.1136/ard.2008.092833. 21. Bartelds GM,Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:921-926. 22. Buxton ILO. Pharmacokinetics and pharmacodynamics: the dynamics of drug absorption, distribution, action, and elimination. In: Brunton LL, Lazo JS, Parker KL, et al, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY:McGraw Hill; 2006.

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