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Home , Apremilast, Dimethyl fumarate

738FM.8 BIOLOGICS FOR THE TREATMENT OF (ADULTS)

Based upon: NICE CG 153 Psoriasis: The assessment and management of psoriasis (October 2012)

NICE Technology Appraisals (TAs): 103 July 2006 134 January 2008 146 June 2008 180 September 2009 updated March 2017 350 June 2015 419 November 2016 442 April 2017 475 September 2017 511 March 2018 521 June 2018 574 April 2019 575 April 2019 596 August 2019

Thames Valley Priorities Committee Policy TVPC44: Sequential use of a third or subsequent biologic therapy for psoriasis (issued September 2019)

The drugs included in this guideline are for use in secondary care only (RED listed on the Bucks formulary). They may only be initiated by a Dermatology specialist with expertise in the use of biologic therapies in treating psoriasis.

NICE Compliance/High Cost Drug Forms • A high cost drug form must be completed before initiating and continuing treatment with any of the biologics or drugs included in this guideline. • The forms are completed and submitted on the Blueteq website. • If the Blueteq website is not accessible, forms are also available via the Buckinghamshire Formulary www.bucksformulary.nhs.uk (they can only be downloaded if the user is linked to the Buckinghamshire Healthcare NHS Trust (BHT) server). They can be obtained by emailing [email protected].

Guideline 738FM.8 1 of 6 Uncontrolled if printed Use standard systemic therapies for psoriasis including , and phototherapy No – consider Is the patient’s condition failing to respond, or is the patient intolerant of, or has a alternative contraindication to, the standard systemic therapies? standard treatment options Yes

If the patient has both psoriasis and , take into account both conditions before initiating or making changes to treatment with biologic drugs (see also commissioning algorithm for psoriatic arthritis, TA 199 and TA 220)

What are the patient’s PASI and DLQI scores?

Key to terms: PASI <10 PASI ≥10 PASI ≥20 Patient is not eligible for PASI: Psoriasis area and and and and severity index treatment with biologic drugs DLQI of ≤10 DLQI of >10 DLQI >18 DLQI: Dermatology life quality index CG: NICE clinical guideline

Listed in order of cost (drug and administration cost), with the lowest cost first- note 1 pg.3 st (ONLY for PASI ≥20 and DLQI >18) (TA 146, CG 153) TNF-alpha inhibitor (consider as 1 choice if joint involvement) (TA 134, CG 153) TNF alpha (TA 103, CG 153) TNF-alpha inhibitor (TA 419) PDE-4 inhibitor inhibitor (TA 475) immunomodulator st Tildrakizumab (TA 575) IL-23 inhibitor NOTE: Infliximab may be considered 1 choice treatment for: Patients with life threatening Risankizumab (TA 596) IL-23 inhibitor Brodalumab (TA 511) IL-17 inhibitor conditions requiring rapid disease control or (TA 350) IL-17A inhibitor obese patients with joint involvement (arthritis) Guselkumab (TA 521) IL-23 inhibitor who cannot be given adalimumab or Ixekizumab (TA 443) IL-17A inhibitor Ustekinumab (TA 180, CG 153) IL-12 and IL-23 inhibitor Certolizumab (TA 574) TNF-alpha inhibitor

Is there an adequate response to treatment defined as either:

A 75% reduction in PASI score (PASI 75) from start of treatment or A 50% reduction in PASI score (PASI 50) and five-point reduction in DLQI from start of treatment? Maintain same Yes – maintain Response to be first measured at: treatment and same treatment and • 12 weeks for brodalumab, etanercept, ixekizumab and secukinumab monitor patient monitor patient • 14 weeks for infliximab Yes • 16 weeks for adalimumab, apremilast, certolizumab, dimethyl fumarate, guselkumab, risankizumab • 28 weeks for tildrakizumab, ustekinumab

Patient on apremilast or dimethyl fumarate or first or Patient on third-line biologic AND failed second-line biologic response to apremilast or dimethyl fumarate (When a change from a 1st line drug is required only due to a

documented local injection site reaction, this will not be considered to be a second biologic)

Yes Is the patient continuing to show an adequate response to treatment as defined above? • Is the patient continuing to show an adequate response to treatment (as defined above) and No • Is the patient continuing to tolerate the Change to a 4th or subsequent agent is treatment and funded if the 4th agent has a mode of • Is the patient still without contraindication action which has not been used before to the treatment?

Change to a 4th biologic with a mode No of action that has been used before is

NOT normally funded. An Individual Consider changing to an alternative Funding Request needs to be made biologic or apremilast or dimethyl fumarate. via CCG. NOTE: a 4th agent is only funded if its mode of action has not been used before

Guideline 738FM.8 2 of 6 Uncontrolled if printed

Notes 1. Choice of biologic drug • In line with NICE guidance, if more than one agent is suitable at particular points in the treatment algorithm, the drug with the lowest acquisition cost (drug and administration cost) is recommended. Where appropriate, a biosimilar product should be used in preference to the originator brand. To facilitate these decisions, the Bucks algorithm lists drugs in order of cost with the least expensive first. • However, drug costs should not override the need for the chosen drug to be the most ‘suitable’ and ‘clinically appropriate’ for the patient. The choice of treatment should be made after discussion between the clinician and the patient about the advantages and disadvantages of the treatments available. This may include considering associated conditions 2. Maximum number of biologic drugs funded • The sequential use of up THREE biologics is normally funded. • A third biologic is only funded if recommended by a consultant Dermatologist with expertise in biological drugs when the second biologic is unsuitable due to inadequate response, intolerance or contraindication. • If a patient is required to switch from a biosimilar to an originator drug due to an adverse drug reaction, or if there is an injection site reaction to any biologic, this will not be classed as a switch to an alternative biologic drug. The exceptions to the rule of a ‘maximum of THREE biologic drugs’ is: • Switching to a biologic drug with a mode of action that the patient has not previously tried. In these cases only, the maximum number of sequential biologic treatments funded will be FOUR3.

PRESCRIBING INFORMATION Adalimumab (TNF-alpha inhibitor) ALL prescribing and dispensing must be by brand name. For information about the biosimilar brands, see the formulary entry for adalimumab www.bucksformulary.nhs.uk. Use of different brands may alter the position of adalimumab in the algorithm. • Dose: Initially 80 mg by subcutaneous (s/c) injection, followed by 40 mg every other week, starting 1 week after the initial dose. • Response to treatment is measured at 16 weeks. • Beyond 16 weeks, patients with inadequate response to 40 mg every other week may benefit from an increase in dosage to 40 mg every week or 80 mg every other week. The benefits and risks of continued 40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in a patient with an inadequate response after the increase in dosage. If adequate response is achieved with 40 mg every week or 80 mg every other week, the dosage may subsequently be reduced to 40 mg every other week.

Apremilast (PDE-4 inhibitor) • Note: This is not a biologic. • Dose: 30 mg twice daily PO, approximately 12 hours apart with no food restrictions. • An initial titration schedule is shown in Table 1. No re-titration is required after initial titration. Table 1: Apremilast dose titration schedule Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 and thereafter AM AM PM AM PM AM PM AM PM AM PM 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg

Brodalumab (IL-17 inhibitor) • Dose: 210 mg by s/c injection at weeks 0, 1 and 2, followed by 210 mg every 2 weeks.

Certolizumab (TNF-alpha inhibitor) • Dose: 400 mg (given as 2 s/c injections of 200 mg each) at weeks 0, 2 and 4, followed by 200 mg every 2 weeks. (If response is insufficient a dose 400 mg every 2 weeks can be considered.)

Guideline 738FM.8 3 of 6 Uncontrolled if printed Dimethyl fumarate Note this is not a biologic. All prescribing must include the brand name (Skilarence®). For further details see formulary entry for dimethyl fumarate - www.bucksformulary.nhs.uk. • Dose: Treatment is started at a low initial dose with subsequent gradual increases. • Week 1: 30 mg PO once daily (1 in the evening). • Week 2: 30 mg PO twice daily (1 tablet in the morning and 1 in the evening). • Week 3: 30 mg PO three times daily (1 tablet in the morning, midday, and evening). • Week 4: 120 mg PO once daily (1 tablet in the evening). • Subsequent 5 weeks: the dose is increased by 120 mg per week (see table below). • Maximum daily dose: 720 mg (3 x 2 x 120 mg tablets). Table 2: Dimethyl fumarate dose titration schedule Week Number of tablets Total daily dose (mg) of Morning Midday Evening dimethyl fumarate Skilarence® 30 mg 1 0 0 1 30 2 1 0 1 60 3 1 1 1 90 Skilarence® 120 mg 4 0 0 1 120 5 1 0 1 240 6 1 1 1 360 7 1 1 2 480 8 2 1 2 600 9+ 2 2 2 720

Stop treatment if there is inadequate response at week 16.

Etanercept (TNF-alpha inhibitor) Note: ALL prescribing and dispensing must be by brand name. For information about the biosimilar brands, see the formulary entry for etanercept in www.bucksformulary.nhs.uk. Use of different brands may alter the position of etanercept in the costing table. • Dose: 50 mg by s/c injection once weekly. Alternatively, 50 mg twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 50 mg weekly. • Treatment should be discontinued in patients who show no response after 12 weeks.

Guselkumab (IL-23 inhibitor) • Dose: 100 mg by s/c injection at weeks 0 and 4, followed by 100 mg s/c injection maintenance dose every 8 weeks. • Response reviewed at 16 weeks.

Infliximab (TNF-alpha inhibitor) Note: ALL prescribing and dispensing of infliximab must be by brand name. For information about the biosimilar brands, see the formulary entry for etanercept in www.bucksformulary.nhs.uk. Use of different brands may alter the position of etanercept in the costing table. • Dose: 5 mg/kg by intravenous (IV) infusion followed by 5 mg/kg IV infusions at weeks 2 and 6 after the first infusion, then every 8 weeks thereafter. • The manufacturer recommends to calculate the dose based upon actual body weight (ABW). • If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.

Ixekizumab (IL-17A inhibitor) • Dose: 160 mg by s/c injection (two 80 mg injections) at week 0, followed by 80 mg (one s/c injection) at weeks 2, 4, 6, 8, 10 and 12, then maintenance dosing of 80 mg s/c (one injection) every 4 weeks. • Stop treatment if there is inadequate response at week 12. Guideline 738FM.8 4 of 6 Uncontrolled if printed Risankizumab (IL-23 inhibitor) • Dose: 150 mg by s/c injection (two 75 mg injections) at week 0, week 4, and every 12 weeks thereafter. • If there is no response at 16 weeks, discontinue treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Secukinumab (IL-17A inhibitor) • Dose: 300 mg by s/c injection at weeks 0, 1, 2, 3 and 4 followed by monthly maintenance dosing. Each 300 mg dose is given as one s/c injection of 300 mg or as two s/c injections of 150 mg.

Tildrakizumab (IL-23 inhibitor) • Dose: 100 mg by s/c injection at weeks 0, 4 and every 12 weeks thereafter. • 200 mg by s/c injection may provide greater efficacy in patients with certain characteristics (e.g. high disease burden, body weight ≥90 kg) • Discontinue treatment if no response after 28 weeks of treatment. • Some patients with initial partial response may subsequently improve with continued treatment beyond 28 weeks.

Ustekinumab (IL-12 and IL-23 inhibitor) • Dose: − Body weight <100 kg: 45 mg by s/c injection at weeks 0 and week 4, followed by 45 mg every 12 weeks thereafter. − Body weight >100 kg: 90 mg by s/c injection at weeks 0 and week 4, followed by 90 mg every 12 weeks thereafter. • Treatment is discontinued in patients who have shown no response up to 28 weeks of treatment.

References 1. Smith CH, Anstey AV et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009; 161 987 – 1019. 2. MHRA: Ustekinumab (Stelara®): Risk of exfoliative . Drug Safety Update, Volume 8, Issue 6, January 2015. 3. Thames Valley Priorities Committee Commissioning Policy TVPC 44: Sequential use of a third or subsequent biologic therapy for psoriasis. June 2019. http://www.fundingrequests.cscsu.nhs.uk/wp-content/uploads/2019/07/TVPC44-Sequential-use- of-a-third-or-subsequent-biologic-therapy-for-psoriasis-Jan-19-v1.1-BU.pdf 4. MHRA Apremilast (Otezla® ▼): Risk of suicidal thoughts and behaviour. Drug Safety Update volume 10 issue 6, January 2017: 3. 5. NICE TA 419: Apremilast for treating moderate to severe plaque psoriasis. November 2016. 6. NICE TA 350: Secukinumab for treating moderate to severe plaque psoriasis. July 2015. 7. NICE TA 146: Adalimumab for the treatment of adults with psoriasis. June 2008. 8. NICE TA 103: Etanercept and for the treatment of adults with psoriasis. July 2006. 9. NICE TA 180: Ustekinumab for the treatment of adults with moderate to severe psoriasis. September 2009. Updated March 2017. 10. NICE TA 442: Ixekizumab for treating moderate to severe plaque psoriasis. April 2017. 11. NICE TA 475: Dimethyl fumarate for treating moderate to severe plaque psoriasis. September 2017. 12. NICE TA 574: for treating moderate to severe plaque psoriasis. April 2019. 13. NICE TA 575: Tildrakizumab for treating moderate to severe plaque psoriasis. April 2019. 14. NICE TA 596: Risankizumab for treating moderate to severe plaque psoriasis. 21 August 2019. 15. Summary of Product Characteristics Adalimumab Humira® 40 mg solution for injection in pre-filled syringe last updated on emc: 04 Dec 2020 https://www.medicines.org.uk/emc/product/7986/smpc 16. Summary of product characteristics Apremilast Otezla 30 mg film-coated tablets last updated on the emc 15th April 2020 https://www.medicines.org.uk/emc/product/3648/smpc 17. Summary of product characteristics Certolizumab pegol Cimzia® 200 mg solution for injection in pre-filled pen last updated on the emc 30th Oct 2020. https://www.medicines.org.uk/emc/product/7387/smpc

Guideline 738FM.8 5 of 6 Uncontrolled if printed 18. Summary of Product Characteristics Dimethyl Fumarate Skilarence® 30 mg gastro-resistant tablets last updated on the emc 26th Oct 2020 https://www.medicines.org.uk/emc/product/752/smpc 19. Summary of Product Characteristics Etanercept Benepali® 50mg solution for injection pr-filled pen last updated on the emc 25th Jan 2021 https://www.medicines.org.uk/emc/product/1987/smpc 20. Summary of Product Characteristics Guselkumab Tremfya® 100 mg solution for injection in pre- filled pen last updated on the emc 1st Dec 2020. https://www.medicines.org.uk/emc/product/9587 21. Summary of Product Characteristics Infliximab Inflectra® 100 mg powder for concentrate for solution for infusion last updated on the emc 7th Oct 2020 https://www.medicines.org.uk/emc/product/3710 22. Summary of Product Characteristics Ixekizumab Taltz® 80 mg solution for injection in pre-filled pen last updated on the emc 7th Jan 2021 https://www.medicines.org.uk/emc/product/8199/smpc 23. Summary of Product Characteristics for Risankizumab Skyrizi® 75mg solution for injection pre-filled syringe last updated on the emc 27th Feb 2021 https://www.medicines.org.uk/emc/product/10199/smpc 24. Summary of product characteristics Secukinumab Cosentyx® 150 mg solution for injection in pre- filled pen last updated on the emc 8th Dec 2020. https://www.medicines.org.uk/emc/product/3669/smpc 25. Summary of Product Characteristics for Tildrakizumab Ilumetri® 100 mg solution for injection in pre-filled syringe. Last updated on the emc 22nd Jan 2019 https://www.medicines.org.uk/emc/product/9819 26. Summary of Product Characteristics Ustekinumab Stelara® 45 mg solution for injection in pre-filled syringe last updated on the emc 19th Jan 2021. https://www.medicines.org.uk/emc/product/7638/smpc

See also: Guideline 222 Adult and Paediatrics Injectables Guide (BHT users only)

Title of Guideline Biologics for the Treatment of Psoriasis (Adults) Guideline Number 738FM Version 8 Effective Date April 2021 Review Date April 2024 Original Version Published March 2010 Approvals: Dermatology SDU 23rd July 2020 Medicines Value Group 23rd July 2020 Medicines Check (Pharmacy) 12th March 2021 Clinical Guidelines Group 16th March 2021 Author/s Dr Amal Eissa, Consultant Dermatologist Kirsty Habibi-Parker, MRC Pharmacist Maire Stapleton, Formulary Manager SDU(s)/Department(s) responsible Dermatology for updating the guideline Pharmacy Uploaded to Intranet 9th April 2021 Buckinghamshire Healthcare NHS Trust/Buckinghamshire Clinical Commissioning Group

Guideline 738FM.8 6 of 6 Uncontrolled if printed