OTEZLA 30mg tablets medication leaflet

Otezla 10 mg film-coated tablets

Otezla 20 mg film-coated tablets

Otezla 30 mg film-coated tablets

Otezla 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of apremilast.

Each film-coated tablet contains 57 mg of lactose (as lactose monohydrate).

Otezla 20 mg film-coated tablets

Each film-coated tablet contains 20 mg of apremilast.

Each film-coated tablet contains 114 mg of lactose (as lactose monohydrate).

Otezla 30 mg film-coated tablets

Each film-coated tablet contains 30 mg of apremilast.

Each film-coated tablet contains 171 mg of lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Otezla 10 mg film-coated tablets

Pink, diamond shaped 10 mg film-coated tablet of 8 mm length with “APR” engraved on one side and“10” on the opposite side.

Otezla 20 mg film-coated tablets

Brown, diamond shaped 20 mg film-coated tablet of 10 mm length with “APR” engraved on one sideand “20” on the opposite side.

Otezla 30 mg film-coated tablets

Beige, diamond shaped 30 mg film-coated tablet of 12 mm length with “APR” engraved on one sideand “30” on the opposite side.

Otezla, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), isindicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had aninadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1).

Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis (PSOR) in adultpatients who failed to respond to or who have a contraindication to, or are intolerant to other systemictherapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).

Paediatric psoriasis

Otezla is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescentsfrom the age of 6 years and weighing at least 20 kg who are candidates for systemic therapy.

Behçet’s disease

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s disease(BD) who are candidates for systemic therapy.

Treatment with Otezla should be initiated by specialists experienced in the diagnosis and treatment ofpsoriasis, psoriatic arthritis or Behçet’s disease.

Adult patients with psoriatic arthritis, psoriasis, or Behçet’s disease

The recommended dose of apremilast for adult patients is 30 mg taken orally twice daily. An initialtitration schedule is required as shown below in table 1.

Table 1. Dose titration schedule for adult patients

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 &thereafter

AM AM PM AM PM AM PM AM PM AM PM10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg

Paediatric patients with moderate to severe plaque psoriasis

The recommended dose of apremilast for paediatric patients 6 years of age and older with moderate tosevere plaque psoriasis is based on body weight. The recommended dose of apremilast is 20 mg takenorally twice daily for paediatric patients who weigh from 20 kg to less than 50 kg, and 30 mg takenorally twice daily for paediatric patients who weigh at least 50 kg, following the initial titrationschedule shown below in table 2.

Table 2. Dose titration schedule for paediatric patients

Day 6

Body Day 1 Day 2 Day 3 Day 4 Day 5& thereafterweight

AM AM PM AM PM AM PM AM PM AM PM20 kgto less10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 20 mg 20 mg 20 mgthan50 kg50 kgor 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mgmore

All indications (psoriasis in adults and children, psoriatic arthritis, Behçet’s disease)

No re-titration is required after initial titration.

The recommended twice daily apremilast dose should be taken approximately 12 hours apart (morningand evening), with no food restrictions.

If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time fortheir next dose, the missed dose should not be taken and the next dose should be taken at the regulartime.

During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment for

PsA and PSOR and within the first 12 weeks of treatment for BD. If a patient shows no evidence oftherapeutic benefit after this time period, treatment should be reconsidered. The patient's response totreatment should be evaluated on a regular basis.

No dose adjustment is required for this patient population (see sections 4.8 and 5.2).

Adult patients with psoriatic arthritis, psoriasis, or Behçet’s disease

No dose adjustment is needed in adult patients with mild and moderate renal impairment. The dose ofapremilast should be reduced to 30 mg once daily in adult patients with severe renal impairment(creatinine clearance of less than 30 mL per minute estimated by the Cockcroft-Gault equation). Forinitial dose titration in this group, it is recommended that apremilast be titrated using only the AMschedule listed in table 1 and the PM doses be skipped (see section 5.2).

Paediatric patients with moderate to severe psoriasis

No dose adjustment is needed in paediatric patients 6 years of age and older with mild or moderaterenal impairment. In paediatric patients 6 years of age and older with severe renal impairment(creatinine clearance of less than 30 mL per minute estimated by the Cockroft-Gault equation), doseadjustment is recommended. The apremilast dose should be reduced to 30 mg once daily for paediatricpatients who weigh at least 50 kg and to 20 mg once daily for paediatric patients who weigh 20 kg toless than 50 kg. For initial dose titration in these groups, it is recommended that apremilast be titratedusing only the AM schedule listed in table 2 above for the appropriate body weight category and the

PM doses be skipped.

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

The safety and efficacy of apremilast have not been established in children with moderate to severeplaque psoriasis below the age of 6 years or with a body weight less than 20 kg, or in other paediatricindications. No data are available.

Otezla is for oral use. The film-coated tablets should be swallowed whole, and can be taken either withor without food.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

Diarrhoea, nausea, and vomiting

There have been post-marketing reports of severe diarrhoea, nausea, and vomiting associated with theuse of apremilast. Most events occurred within the first few weeks of treatment. In some cases,patients were hospitalised. Patients 65 years of age or older may be at a higher risk of complications. Ifpatients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment with apremilastmay be necessary.

Apremilast is associated with an increased risk of psychiatric disorders such as insomnia anddepression. Instances of suicidal ideation and behaviour, including suicide, have been observed inpatients with or without history of depression (see section 4.8). The risks and benefits of starting orcontinuing treatment with apremilast should be carefully assessed if patients report previous orexisting psychiatric symptoms or if concomitant treatment with other medicinal products likely tocause psychiatric events is intended. Patients and caregivers should be instructed to notify theprescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered fromnew or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it isrecommended to discontinue treatment with apremilast.

The Otezla dose should be reduced to 30 mg once daily in adult patients with severe renal impairment(see sections 4.2 and 5.2).

In paediatric patients 6 years of age and older with severe renal impairment, the dose should bereduced to 30 mg once daily for paediatric patients who weigh at least 50 kg, and to 20 mg once dailyfor paediatric patients who weigh 20 kg to less than 50 kg (see sections 4.2 and 5.2).

Underweight patients

Patients who are underweight and paediatric patients who have a borderline to low body mass index atthe start of treatment should have their body weight monitored regularly. In the event of unexplainedand clinically significant weight loss, these patients should be evaluated by a medical practitioner anddiscontinuation of treatment should be considered.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted ina reduction of systemic exposure of apremilast, which may result in a loss of efficacy of apremilast.

Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine,phenytoin and St. John’s Wort) with apremilast is not recommended. Co-administration of apremilastwith multiple doses of rifampicin resulted in a decrease in apremilast area-under-the-concentrationtime curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%,respectively. Apremilast exposure is decreased when administered concomitantly with strong inducersof CYP3A4 (e.g. rifampicin) and may result in reduced clinical response.

In clinical studies, apremilast has been administered concomitantly with topical therapy (includingcorticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy.

There was no clinically meaningful interaction between ketoconazole and apremilast. Apremilast canbe co-administered with a potent CYP3A4 inhibitor such as ketoconazole.

There was no pharmacokinetic interaction between apremilast and methotrexate in psoriatic arthritispatients. Apremilast can be co-administered with methotrexate.

There was no pharmacokinetic interaction between apremilast and oral contraceptives containingethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives.

Pregnancy should be excluded before treatment can be initiated. Women of childbearing potentialshould use an effective method of contraception to prevent pregnancy during treatment.

There are limited data about the use of apremilast in pregnant women.

Apremilast is contraindicated during pregnancy (see section 4.3). Effects of apremilast on pregnancyincluded embryofoetal loss in mice and monkeys, and reduced foetal weights and delayed ossificationin mice at doses higher than the currently recommended highest human dose. No such effects wereobserved when exposure in animals was at 1.3-fold the clinical exposure (see section 5.3).

Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whetherapremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot beexcluded, therefore apremilast should not be used during breast-feeding.

No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility wereobserved in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-foldclinical exposure. For pre-clinical fertility data, see section 5.3.

Apremilast has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions with apremilast in adults with PsA and PSOR aregastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). The other mostcommonly reported adverse reactions include upper respiratory tract infections (8.4%), headache(7.9%), and tension headache (7.2%) and are mostly mild to moderate in severity.

The most commonly reported adverse drug reactions with apremilast in adults with BD are diarrhoea(41.3%), nausea (19.2%), headache (14.4%), upper respiratory tract infection (11.5%), upperabdominal pain (8.7%), vomiting (8.7%) and back pain (7.7%) and are mostly mild to moderate inseverity.

The gastrointestinal adverse reactions generally occurred within the first 2 weeks of treatment andusually resolved within 4 weeks.

Hypersensitivity reactions are uncommonly observed (see section 4.3).

The adverse reactions observed in adult patients treated with apremilast are listed below by systemorgan class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping,adverse reactions are presented in order of decreasing seriousness.

The adverse drug reactions were determined based on data from the apremilast clinical developmentprogramme and post-marketing experience in adult patients. The frequencies of adverse drug reactionsare those reported in the apremilast arms of the four Phase III studies in PsA (n = 1 945) or the two

Phase III studies in PSOR (n = 1 184), and in the phase III study in BD (n = 207). The highestfrequency from either data pool is represented in table 3.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); not known (cannot be estimated from theavailable data).

Table 3. Summary of adverse reactions in psoriatic arthritis (PsA), psoriasis (PSOR) and

Behçet’s disease (BD)

System Organ Class Frequency Adverse reaction

Very common Upper respiratory tract infectiona

Infections and

Bronchitisinfestations Common

Nasopharyngitis*

Immune system

Uncommon Hypersensitivitydisorders

Metabolism and

Common Decreased appetite*nutrition disorders

Insomnia

Common

Psychiatric disorders Depression

Uncommon Suicidal ideation and behaviour

System Organ Class Frequency Adverse reaction

Very common Headache*, a

Nervous system

Migraine*disorders Common

Tension headache*

Respiratory, thoracic,and mediastinal Common Coughdisorders

Diarrhoea*

Very Common

Nausea*

Vomiting*

Gastrointestinal Dyspepsiadisorders Common Frequent bowel movements

Upper abdominal pain*

Gastroesophageal reflux disease

Uncommon Gastrointestinal haemorrhage

Skin and Rash

Uncommonsubcutaneous tissue Urticariadisorders Not known Angioedema

Musculoskeletal andconnective tissue Common Back pain*disorders

General disorders andadministration site Common Fatigueconditions

Investigations Uncommon Weight decrease

*At least one of these adverse reactions was reported as seriousa Frequency reported as common in PSA and PSOR

In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour,were reported, while completed suicide was reported post-marketing. Patients and caregivers shouldbe instructed to notify the prescriber of any suicidal ideation (see section 4.4).

Body weight loss

Patient weight was measured routinely in clinical studies. The mean observed weight loss in adult PsAand PSOR patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% ofpatients receiving apremilast had observed weight loss between 5-10% while 5.7% of the patientsreceiving apremilast had observed weight loss greater than 10%. None of these patients had overtclinical consequences resulting from weight loss. A total of 0.1% of patients treated with apremilastdiscontinued due to adverse reaction of weight decreased. The mean observed weight loss in adult BDpatients treated with apremilast for 52 weeks was 0.52 kg. A total of 11.8% of patients recevingapremilast had observed weight loss between 5-10% while 3.8% of the patients receiving apremilasthad observed weight loss greater than 10%. None of these patients had overt clinical consequencesfrom weight loss. None of the patients discontinued the study due to adverse reaction of weightdecreased.

Please see additional warning in section 4.4 for patients who are underweight at beginning oftreatment.

From post-marketing experience, elderly patients ≥ 65 years of age may be at a higher risk ofcomplications of severe diarrhoea, nausea and vomiting (see section 4.4).

The safety of apremilast was not evaluated in PsA, PSOR or BD patients with hepatic impairment.

In the PsA, PSOR or BD clinical studies, the safety profile observed in patients with mild renalimpairment was comparable to patients with normal renal function. The safety of apremilast was notevaluated in PsA, PSOR or BD patients with moderate or severe renal impairment in the clinicalstudies.

The safety of apremilast was assessed in a 52-week clinical trial in paediatric patients 6 to 17 years ofage with moderate to severe plaque psoriasis (SPROUT study). The safety profile of apremilastobserved during the study was consistent with the safety profile previously established in adultpatients with moderate to severe plaque psoriasis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mgtwice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it isrecommended that the patient is monitored for any signs or symptoms of adverse effects andappropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportivecare is advised.

Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code:

L04AA32

Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly tomodulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosinemonophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibitionelevates intracellular cAMP levels, which in turn down-regulates the inflammatory response bymodulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMPalso modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatorymediators have been implicated in psoriatic arthritis and psoriasis.

In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did notfully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and

IL-23, and an increase in IL-10. In clinical studies in patients with psoriasis, apremilast decreasedlesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatorygenes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and

IL-8. In clinical studies in patients with Behçet Disease treated with apremilast, there was a significantpositive association between the change in plasma TNF-alpha and clinical efficacy as measured by thenumber of oral ulcers.

Apremilast administered at doses of up to 50 mg twice daily did not prolong the QT interval in healthysubjects.

Psoriatic Arthritis

The safety and efficacy of apremilast were evaluated in 3 multi-centre, randomised, double-blind,placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design inadult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment withsmall molecule or biologic DMARDs. A total of 1 493 patients were randomised and treated witheither placebo, apremilast 20 mg or apremilast 30 mg given orally twice daily.

Patients in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skinlesion (at least 2 cm in diameter) was also required in PALACE 3. Apremilast was used as amonotherapy (34.8%) or in combination with stable doses of small molecule DMARDs (65.2%).

Patients received apremilast in combination with one or more of the following: methotrexate (MTX,≤ 25 mg/week, 54.5%), sulfasalazine (SSZ, ≤ 2 g/day, 9.0%), and leflunomide (LEF; ≤ 20 mg/day,7.4%). Concomitant treatment with biologic DMARDs, including TNF blockers, was not allowed.

Patients with each subtype of PsA were enrolled in the 3 studies, including symmetric polyarthritis(62.0%), asymmetric oligoarthritis (26.9%), distal interphalangeal (DIP) joint arthritis (6.2%), arthritismutilans (2.7%), and predominant spondylitis (2.1%). Patients with pre-existing enthesopathy (63%)or pre-existing dactylitis (42%) were enrolled. A total of 76.4% of patients were previously treatedwith only small-molecule DMARDs and 22.4% of patients were previously treated with biologic

DMARDs, which includes 7.8% who had a therapeutic failure with a prior biologic DMARD. Themedian duration of PsA disease was 5 years.

Based on the study design, patients whose tender and swollen joint counts had not improved by at least20% were considered non-responders at week 16. Placebo patients who were considered non-responders were re-randomised 1:1 in a blinded fashion to either apremilast 20 mg twice daily or30 mg twice daily. At week 24, all remaining placebo-treated patients were switched to eitherapremilast 20 or 30 mg twice daily. Following 52 weeks of treatment, patients could continue on openlabel apremilast 20 mg or 30 mg within the long-term extension of the PALACE 1, PALACE 2, and

PALACE 3 studies for a total duration of treatment up to 5 years (260 weeks).

The primary endpoint was the percentage of patients achieving American College of Rheumatology(ACR) 20 response at week 16.

Treatment with apremilast resulted in significant improvements in the signs and symptoms of PsA, asassessed by the ACR 20 response criteria compared to placebo at weeks 16. The proportion of patientswith ACR 20/50/70 (responses in studies PALACE 1, PALACE 2 and PALACE 3, and the pooleddata for studies PALACE 1, PALACE 2 and PALACE 3) for apremilast 30 mg twice daily at week 16are shown in table 4. ACR 20/50/70 responses were maintained at week 24.

Among patients who were initially randomised to apremilast 30 mg twice daily treatment, ACR20/50/70 response rates were maintained through week 52 in the pooled studies PALACE 1,

PALACE 2 and PALACE 3 (figure 1).

Table 4. Proportion of patients with ACR responses in studies PALACE 1, PALACE 2 and

PALACE 3 and pooled studies at week 16

PALACE 1 PALACE 2 PALACE 3 POOLED

Placebo Apremilast Placebo Apremilast Placebo Apremilast Placebo Apremilast30 mg 30 mg 30 mg 30 mg+/- twice daily +/- twice daily +/- twice daily +/- twice daily

DMARDsN +/- DMARDsN +/- DMARDsN +/- DMARDsN +/-

Na = 168 DMARDsN = 159 DMARDsN = 169 DMARDsN = 496 DMARDsN= 168 = 162 = 167 = 497

ACRa

Week19.0% 38.1%** 18.9% 32.1%* 18.3% 40.7%** 18.8% 37.0%**

ACR

Week6.0% 16.1%* 5.0% 10.5% 8.3% 15.0% 6.5% 13.9%**

ACR

Week1.2% 4.2% 0.6% 1.2% 2.4% 3.6% 1.4% 3.0%

*p ≤ 0.01 for apremilast vs. placebo

**p ≤ 0.001 for apremilast vs. placeboa N is the number of patients as randomised and treated

Figure 1 Proportion of ACR 20/50/70 responders through week 52 in the pooled analysis ofstudies PALACE 1, PALACE 2 and PALACE 3 (NRI*)0 16 24 40 52

Study Week

Endpoint n/m (%) n/m (%) n/m (%) n/m (%)

ACR 20 184/497 (37.0) 196/497 (39.4) 222/497 (44.7) 209/497 (42.1)

ACR 50 69/497 (13.9) 93/497 (18.7) 102/497 (20.5) 90/497 (18.1)

ACR 70 15/497 ( 3.0) 33/497 ( 6.6) 44/497 ( 8.9) 38/497 ( 7.6)

Endpoint ACR 20 ACR 50 ACR 70

*NRI: None responder imputation. Subjects who discontinued early prior to the time point and subjects who did not have sufficient data for adefinitive determination of response status at the time point are counted as non-responders.

Among 497 patients initially randomised to apremilast 30 mg twice daily, 375 (75%) patients werestill on this treatment on week 52. In these patients, ACR 20/50/70 responses at week 52 were of 57%,25%, and 11% respectively. Among 497 patients initially randomised to apremilast 30 mg twice daily,

Response Rate +/- SE (%)375 (75%) patients entered the long term extension studies, and of these, 221 patients (59%) were stillon this treatment at week 260. ACR responses were maintained in the long-term open label extensionstudies for up to 5 years.

Responses observed in the apremilast treated group were similar in patients receiving and notreceiving concomitant DMARDs, including MTX. Patients previously treated with DMARDs orbiologics who received apremilast achieved a greater ACR 20 response at week 16 than patientsreceiving placebo.

Similar ACR responses were observed in patients with different PsA subtypes, including DIP. Thenumber of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allowmeaningful assessment.

In PALACE 1, PALACE 2 and PALACE 3, improvements in Disease Activity Scale (DAS) 28

C-reactive protein (CRP) and in the proportion of patients achieving a modified PsA response criteria(PsARC) were greater in the apremilast group, compared to placebo at week 16 (nominal p-valuep < 0.0004, p-value ≤ 0.0017, respectively). These improvements were maintained at week 24. Amongpatients who remained on the apremilast treatment to which they were randomised at study start,

DAS28 (CRP) score and PsARC response were maintained through week 52.

At weeks 16 and 24 improvements in parameters of peripheral activity characteristic of psoriaticarthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) andin the skin manifestations of psoriasis were seen in the apremilast-treated patients. Among patientswho remained on the apremilast treatment to which they were randomised at study start, theseimprovements were maintained through week 52.

The clinical responses were maintained in the same parameters of peripheral activity and in the skinmanifestations of psoriasis in the open-label extension studies for up to 5 years of treatment.

Apremilast-treated patients demonstrated statistically significant improvement in physical function, asassessed by the disability index of the health assessment questionnaire (HAQ-DI) change frombaseline, compared to placebo at weeks 16 in PALACE 1, PALACE 2 and PALACE 3 and in thepooled studies. Improvement in HAQ-DI scores was maintained at week 24.

Among patients who were initially randomised to apremilast 30 mg twice daily treatment, the changefrom baseline in the HAQ-DI score at week 52 was -0.333 in the apremilast 30 mg twice daily groupin a pooled analysis of the open label phase of studies PALACE 1, PALACE 2 and PALACE 3.

In studies PALACE 1, PALACE 2 and PALACE 3, significant improvements were demonstrated inhealth-related quality of life, as measured by the changes from baseline in the physical functioning(PF) domain of the Short Form Health Survey version 2 (SF-36v2), and in the Functional Assessmentof Chronic Illness Therapy - Fatigue (FACIT-fatigue) scores in patients treated with apremilastcompared to placebo at weeks 16 and 24. Among patients who remained on the apremilast treatment,to which they were initially randomised at study start, improvement in physical function and FACIT-fatigue was maintained through week 52.

Improved physical function as assessed by the HAQ-DI and the SF36v2PF domain, and the FACIT-fatigue scores were maintained in the open-label extension studies for up to 5 years of treatment.

The safety and efficacy of apremilast were evaluated in two multicentre, randomised, double-blind,placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of1 257 patients with moderate to severe plaque psoriasis who had a body surface area (BSA)involvement of ≥ 10%, Psoriasis Area and Severity Index (PASI) score ≥ 12, static Physician Global

Assessment (sPGA) of ≥ 3 (moderate or severe), and who were candidates for phototherapy orsystemic therapy.

These studies had a similar design through week 32. In both studies, patients were randomised 2:1 toapremilast 30 mg twice daily or placebo for 16 weeks (placebo-controlled phase) and fromweeks 16-32, all patients received apremilast 30 mg twice daily (maintenance phase). During the

Randomised Treatment Withdrawal Phase (weeks 32-52), patients originally randomised to apremilastwho achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reductionin their PASI score (PASI-50) (ESTEEM 2) were re-randomised at week 32 to either placebo orapremilast 30 mg twice daily. Patients who were re-randomised to placebo and who lost PASI-75response (ESTEEM 1) or lost 50% of the PASI improvement at week 32 compared to baseline(ESTEEM 2) were retreated with apremilast 30 mg twice daily. Patients who did not achieve thedesignated PASI response by week 32, or who were initially randomised to placebo, remained onapremilast until week 52. The use of low potency topical corticosteroids on the face, axillae, and groin,coal tar shampoo and/or salicylic acid scalp preparations was permitted throughout the studies. Inaddition, at week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy inaddition to apremilast 30 mg twice daily treatment.

Following 52 weeks of treatment, patients could continue on open-label apremilast 30 mg within thelong-term extension of the ESTEEM 1 and ESTEEM 2 studies for a total duration of treatment up to5 years (260 weeks).

In both studies, the primary endpoint was the proportion of patients who achieved PASI-75 atweek 16. The major secondary endpoint was the proportion of patients who achieved a sPGA score ofclear (0) or almost clear (1) at week 16.

The mean baseline PASI score was 19.07 (median 16.80), and the proportion of patients with sPGAscore of 3 (moderate) and 4 (severe) at baseline was 70.0% and 29.8%, respectively with a meanbaseline BSA involvement of 25.19% (median 21.0%). Approximately 30% of all patients hadreceived prior phototherapy and 54% had received prior conventional systemic and/or biologic therapyfor the treatment of psoriasis (including treatment failures), with 37% receiving prior conventionalsystemic therapy and 30% receiving prior biologic therapy. Approximately one-third of patients hadnot received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patientshad a history of psoriatic arthritis.

The proportion of patients achieving PASI-50, -75 and -90 responses, and sPGA score of clear (0) oralmost clear (1), are presented in table 5 below. Treatment with apremilast resulted in significantimprovement in moderate to severe plaque psoriasis as demonstrated by the proportion of patients with

PASI-75 response at week 16, compared to placebo. Clinical improvement measured by sPGA,

PASI-50 and PASI-90 responses were also demonstrated at week 16. In addition, apremilastdemonstrated a treatment benefit across multiple manifestations of psoriasis including pruritus, naildisease, scalp involvement and quality of life measures.

Table 5. Clinical response at week 16 in studies ESTEEM 1 and ESTEEM 2 (FASa, LOCFb)

ESTEEM 1 ESTEEM 2

Placebo 30 mg twice daily Placebo 30 mg twice daily

APR* APR*

N 282 562 137 274

PASIc 75, n (%) 15 (5.3) 186 (33.1) 8 (5.8) 79 (28.8)sPGAd of clear or11 (3.9) 122 (21.7) 6 (4.4) 56 (20.4)almost clear, n (%)

PASI 50, n (%) 48 (17.0) 330 (58.7) 27 (19.7) 152 (55.5)

PASI 90, n (%) 1 (0.4) 55 (9.8) 2 (1.5) 24 (8.8)

Percent change BSAe (%) -6.9 -47.8 -6.1 -48.4mean ± SD ± 38.95 ± 38.48 ± 47.57 ± 40.78

Change in pruritus VASf -7.3 -31.5 -12.2 -33.5(mm), mean ± SD ± 27.08 ± 32.43 ± 30.94 ± 35.46

Change in DLQIg, -2.1 -6.6 -2.8 -6.7mean ± SD ± 5.69 ± 6.66 ± 7.22 ± 6.95

Change in SF-36 MCS h, -1.02 2.39 0.00 2.58mean ± SD ± 9.161 ± 9.504 ± 10.498 ± 10.129

* p < 0.0001 for apremilast vs placebo, except for ESTEEM 2 PASI 90 and Change in SF-36 MCS wherep = 0.0042 and p = 0.0078, respectively.a FAS = Full Analysis Setb LOCF = Last Observation Carried Forwardc PASI = Psoriasis Area and Severity Indexd sPGA = Static Physician Global Assessmente BSA = Body Surface Areaf VAS = Visual Analog Scale; 0 = best, 100 = worstg DLQI = Dermatology Life Quality Index; 0 = best, 30 = worsth SF-36 MCS = Medical Outcome Study Short Form 36-Item Health Survey, Mental Component Summary

The clinical benefit of apremilast was demonstrated across multiple subgroups defined by baselinedemographics and baseline clinical disease characteristics (including psoriasis disease duration andpatients with a history of psoriatic arthritis). The clinical benefit of apremilast was also demonstratedregardless of prior psoriasis medication usage and response to prior psoriasis treatments. Similarresponse rates were observed across all weight ranges.

Response to apremilast was rapid, with significantly greater improvements in the signs and symptomsof psoriasis, including PASI, skin discomfort/pain and pruritus, compared to placebo by week 2. Ingeneral, PASI responses were achieved by week 16 and were maintained through week 32.

In both studies, the mean percent improvement in PASI from baseline remained stable during therandomised treatment withdrawal phase for patients re-randomised to apremilast at week 32 (table 6).

Table 6. Persistence of effect among subjects randomised to APR 30 twice daily at week 0and re-randomised to APR 30 twice daily at week 32 to week 52

ESTEEM 1 ESTEEM 2

Patients who achieved PASI-75 Patients who achieved

Time Pointat week 32 PASI-50 at week 32

Percent Change Week 16 -77.7 ± 20.30 -69.7 ± 24.23in PASI from Week 32 -88 ± 8.30 -76.7 ± 13.42baseline, meana Week 52 -80.5 ± 12.60 -74.4 ± 18.91(%) ± SD

ESTEEM 1 ESTEEM 2

Patients who achieved PASI-75 Patients who achieved

Time Pointat week 32 PASI-50 at week 32

Change in DLQI Week 16 -8.3 ± 6.26 -7.8 ± 6.41from baseline, Week 32 -8.9 ± 6.68 -7.7 ± 5.92mean ± SDa Week 52 -7.8 ± 5.75 -7.5 ± 6.27

Proportion of Week 16 40/48 (83.3) 21/37 (56.8)subjects with Week 32 39/48 (81.3) 27/37 (73.0)

Scalp Psoriasis

PGA (ScPGA) 0 Week 52 35/48 (72.9) 20/37 (54.1)or 1, n/N (%)ba Includes subjects re-randomised to APR 30 twice daily at week 32 with a baseline value and a post-baselinevalue at the evaluated study week.b N is based on subjects with moderate or greater scalp psoriasis at baseline who were re-randomised to APR 30twice daily at week 32. Subjects with missing data were counted as nonresponders.

In study ESTEEM 1, approximately 61% of patients re-randomised to apremilast at week 32 had a

PASI-75 response at week 52. Of the patients with at least a PASI-75 response who werere-randomised to placebo at week 32 during a randomised treatment withdrawal phase, 11.7% were

PASI-75 responders at week 52. The median time to loss of PASI-75 response among the patientsre-randomised to placebo was 5.1 weeks.

In study ESTEEM 2, approximately 80.3% of patients re-randomised to apremilast at week 32 had a

PASI-50 response at week 52. Of the patients with at least a PASI-50 response who were re-randomised to placebo at week 32, 24.2% were PASI-50 responders at week 52. The median time toloss of 50% of their week 32 PASI improvement was 12.4 weeks.

After randomised withdrawal from therapy at week 32, approximately 70% of patients in study

ESTEEM 1, and 65.6% of patients in study ESTEEM 2, regained PASI-75 (ESTEEM 1) or PASI-50(ESTEEM 2) responses after re-initiation of apremilast treatment. Due to the study design the durationof re-treatment was variable, and ranged from 2.6 to 22.1 weeks.

In study ESTEEM 1, patients randomised to apremilast at the start of the study who did not achieve a

PASI-75 response at week 32 were permitted to use concomitant topical therapies and/or UVBphototherapy between weeks 32 to 52. Of these patients, 12% achieved a PASI-75 response atweek 52 with apremilast plus topical and/or phototherapy treatment.

In studies ESTEEM 1 and ESTEEM 2, significant improvements (reductions) in nail psoriasis, asmeasured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, wereobserved in patients receiving apremilast compared to placebo-treated patients at week 16 (p < 0.0001and p = 0.0052, respectively). Further improvements in nail psoriasis were observed at week 32 inpatients continuously treated with apremilast.

In studies ESTEEM 1 and ESTEEM 2, significant improvements in scalp psoriasis of at least moderateseverity (≥ 3), measured by the proportion of patients achieving Scalp Psoriasis Physician’s Global

Assessment (ScPGA) of clear (0) or minimal (1) at week 16, were observed in patients receivingapremilast compared to placebo-treated patients (p < 0.0001 for both studies). The improvements weregenerally maintained in subjects who were re-randomised to apremilast at week 32 through week 52(table 6).

In studies ESTEEM 1 and ESTEEM 2, significant improvements in quality of life as measured by the

Dermatology Life Quality Index (DLQI) and the SF-36v2MCS were demonstrated in patientsreceiving apremilast compared with placebo-treated patients (table 5). Improvements in DLQI weremaintained through week 52 in subjects who were re-randomised to apremilast at week 32 (table 6). Inaddition, in study ESTEEM 1, significant improvement in the Work Limitations Questionnaire (WLQ-25) Index was achieved in patients receiving apremilast compared to placebo.

Among 832 patients initially randomised to apremilast 30 mg twice daily, 443 patients (53%) enteredthe open-label extension studies of ESTEEM 1 and ESTEEM 2, and of these 115 patients (26%) werestill on treatment at week 260. For patients who remained on apremilast in the open label extension of

ESTEEM 1 and ESTEEM 2 studies, improvements were generally maintained in PASI score, affected

BSA, itch, nail and quality of life measures for up to 5 years.

The long-term safety of apremilast 30 mg twice daily in patients with psoriatic arthritis and psoriasiswas assessed for a total duration of treatment up to 5 years. Long-term experience in open-labelextension studies with apremilast was generally comparable to the 52-week studies.

Paediatric psoriasis

A multicentre, randomised, double blind, placebo- controlled trial (SPROUT) was conducted in245 paediatric subjects 6 to 17 years of age (inclusive) with moderate to severe plaque psoriasis whowere candidates for phototherapy or systemic therapy. Enrolled subjects had an sPGA score of ≥ 3(moderate or severe disease), BSA involvement of ≥ 10%, and PASI score of ≥ 12, with psoriasis thatwas inadequately controlled by or inappropriate for topical therapy.

Subjects were randomised 2:1 to receive either apremilast (n = 163) or placebo (n = 82) for 16 weeks.

Subjects with a baseline weight of 20 kg to < 50 kg received apremilast 20 mg twice daily or placebotwice daily, and subjects with a baseline weight ≥ 50 kg received apremilast 30 mg twice daily orplacebo twice daily. At week 16, the placebo group was switched to receive apremilast (with dosebased on baseline weight) and the apremilast group remained on drug (according to their originaldosing assignment) through week 52. Subjects were allowed to use low-potency or weak topicalcorticosteroids on the face, axilla, and groin and unmedicated skin moisturizers for body lesions only.

The primary endpoint was the proportion of subjects who achieved an sPGA response (defined as ascore of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at week 16. Thekey secondary endpoint was the proportion of subjects who achieved a PASI-75 response (at least a75% reduction in PASI score from baseline) at week 16. Other endpoints at week 16 included theproportions of subjects who achieved a PASI-50 response (at least 50% reduction in PASI score frombaseline), PASI-90 response (at least 90% reduction in PASI score from baseline), and Children’s

Dermatology Life Quality Index (CDLQI) response (CDLQI total score of 0 or 1), percent changefrom baseline in affected BSA, change from baseline in PASI score, and change from baseline in the

CDLQI total score.

Enrolled subjects ranged in age from 6 to 17 years, with a median age of 13 years; 41.2% of subjectswere 6 to 11 years of age and 58.8% of subjects were 12 to 17 years of age. The mean baseline BSAinvolvement was 31.5% (median 26.0%), the mean baseline PASI score was 19.8 (median 17.2), andthe proportions of subjects with an sPGA score of 3 (moderate) and 4 (severe) at baseline were 75.5%and 24.5%, respectively. Of the enrolled subjects, 82.9% did not receive prior conventional systemictherapy, 82.4% did not receive prior phototherapy and 94.3% were biologic-naïve.

The efficacy results at week 16 are presented in table 7.

Table 7. Efficacy results at week 16 in paediatric subjects with moderate to severe plaquepsoriasis (ITT population)

SPROUT

Endpointa Placebo Apremilast

Number of subjects randomised N = 82 N = 163sPGA responseb 11.5% 33.1%

PASI-75 responseb 16.1% 45.4%

PASI-50 responseb 32.1% 70.5%

PASI-90 responseb 4.9% 25.2%

SPROUT

Endpointa Placebo Apremilast

Percent change from baseline in affected BSAc -21.82 ± 5.104 -56.59 ± 3.558

Change from baseline in CDLQI scorec, d -3.2 ± 0.45 -5.1 ± 0.31

Number of subjects with baseline CDLQI score ≥ 2 N=76 N=148

CDLQI responseb 31.3% 35.4%

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; ITT = intent to treat;; PASI = Psoriasis

Area and Severity Index; sPGA = Static Physician Global Assessment;a Apremilast 20 or 30 mg twice daily vs. placebo at week 16; p-value < 0.0001 for sPGA response and PASI-75 response,nominal p-value < 0.01 for all other end points except CDLQI response (nominal p-value 0.5616)b Proportion of subjects who achieved the responsec Least squares mean +/- standard errord 0 = best score, 30 = worst score

The mean percent change from baseline in total PASI score in apremilast-treated and placebo-treatedsubjects during the placebo-controlled phase is presented in figure 2.

Figure 2. Percent change from baseline in total PASI score through week 16 (ITT population;

MI)

Among patients originally randomised to apremilast, sPGA response, PASI-75 response, and the otherendpoints achieved at week 16 were maintained through week 52.

Behçet’s disease

The safety and efficacy of apremilast were evaluated in a phase 3, multicentre, randomised,placebo-controlled study (RELIEF) in adult patients with active Behçet’s Disease (BD) with oralulcers. Patients were previously treated with at least one non-biologic BD medication for oral ulcersand were candidates for systemic therapy. Concomitant treatment for BD was not allowed. Thepopulation studied met the International Study Group (ISG) criteria for BD with a history of skinlesions (98.6%), genital ulcers (90.3%), musculoskeletal (72.5%), ocular (17.4%), central nervoussystem (9.7%) or GI manifestations (9.2%), epididymitis (2.4%) and vascular involvement (1.4%).

Patients with severe BD, defined as those with active major organ involvement (for ex.

meningoencephalitis or pulmonary artery aneurysm) were excluded.

A total of 207 BD patients were randomised 1:1 to receive either apremilast 30 mg twice daily(n = 104) or placebo (n = 103) for 12-weeks (placebo-controlled phase) and from weeks 12 to 64, allpatients received apremilast 30 mg twice daily (active treatment phase). Patients ranged in age from19 to 72 years, with a mean age of 40 years. The mean duration of BD was 6.84 years. All patients hada history of recurrent oral ulcers with at least 2 oral ulcers at screening and randomisation: the meanbaseline oral ulcer counts were 4.2 and 3.9 in the apremilast and placebo groups, respectively.

The primary endpoint was the Area Under the Curve (AUC) for the number of oral ulcers frombaseline through week 12. Secondary endpoints included other measures of oral ulcers: oral ulcer pain

Visual Analog Scale (VAS), proportion of patients who are oral ulcer-free (complete response), timeto onset of oral ulcer resolution, and proportion of patients achieving resolution of oral ulcers by week6, and who remain oral ulcer free at every visit for at least 6 additional weeks during the 12-weekplacebo-controlled treatment phase. Other endpoints included Behçet’s Syndrome Activity Score(BSAS), BD Current Activity Form (BDCAF), including the BD Current Activity Index (BDCAI)score, the Patient’s Perception of Disease Activity, the Clinician’s Overall Perception of Disease

Activity and the BD Quality of Life Questionnaire (BD QoL).

Measure of oral ulcers

Apremilast 30 mg twice daily resulted in significant improvement in oral ulcers as demonstrated bythe AUC for the number of oral ulcers from baseline through week 12 (p < 0.0001), compared withplacebo.

Significant improvements in other measures of oral ulcers were demonstrated at week 12.

Table 8. Clinical response of oral ulcers at week 12 in RELIEF (ITT population)

Apremilast

Placebo30 mg BID

Endpointa N = 103

N = 104

AUCb for the number of oral ulcers from baseline through week 12 LS Mean LS Mean(MI) 222.14 129.54

Change from baseline in the pain of oral ulcers as measured by LS Mean LS Mean

VASc at week 12 (MMRM) -18.7 -42.7

Proportion of subjects achieving resolution of oral ulcers (oralulcer-free) by week 6, and who remain oral ulcer free at every visit4.9% 29.8%for at least 6 additional weeks during the 12-week placebo-controlled treatment phase

Median time (weeks) to oral ulcer resolution during the placebo-8.1 weeks 2.1 weekscontrolled treatment phase

Proportion of subjects with complete oral ulcer response at week 1222.3% 52.9%(NRI)

Proportion of subjects with partial oral ulcer responsed at week 1247.6% 76.0%(NRI)

ITT=intent to treat; LS=least squares; MI=multiple imputation; MMRM=mixed-effects model for repeatedmeasures; NRI=non-responder imputation; BID=twice daily.a p-value < 0.0001 for all apremilast vs. placebob AUC = Area Under the Curve.c VAS = Visual Analog Scale; 0 = no pain, 100 = worst possible pain.d Partial oral ulcer response = number of oral ulcers reduced by ≥ 50% post baseline (Exploratory analysis);nominal p-value - < 0.0001

Among 104 patients originally randomised to apremilast 30 mg twice daily, 75 patients(approximately 72%) remained on this treatment at week 64. A significant reduction in the meannumber of oral ulcers and oral ulcer pain was observed in the apremilast 30 mg twice daily treatmentgroup compared to the placebo treatment group at every visit, as early as week 1, through week 12 fornumber of oral ulcers (p ≤ 0.0015) and for oral ulcer pain (p ≤ 0.0035). Among patients who werecontinuously treated with apremilast and remained in the study, improvements in oral ulcers andreduction of oral ulcer pain were maintained through week 64 (figures 3 and 4).

Among patients originally randomised to apremilast 30 mg twice daily who remained in the study, theproportions of patients with a complete response and partial response of oral ulcers were maintainedthrough week 64 (53.3% and 76.0% respectively).

Figure 3. Mean number of oral ulcers by time point through week 64 (ITT population; DAO)

ITT = Intent To Treat; DAO = Data As Observed.

APR 30 BID = apremilast 30 mg twice daily.

Note: Placebo or APR 30 mg BID indicates the treatment group in which patients were randomised. Placebo treatment group patientsswitched to APR 30 BID at week 12.

The follow-up time point was 4 weeks after patients completed week 64 or 4 weeks after patients discontinued treatment before week 64.

Figure 4. Mean change from baseline in oral ulcer pain on a visual analog scale by time pointthrough week 64 (ITT Population; DAO)

APR 30 BID = apremilast twice daily; ITT = Intent-To-Treat; DAO = Data As Observed

Note: Placebo or APR 30 mg BID indicates the treatment group in which patients were randomised. Placebo treatment group patientsswitched to APR 30 BID at week 12.

The follow-up time point was 4 weeks after patients completed week 64 or 4 weeks after patients discontinued treatment before week 64.

Improvements in overall Behçet’s disease activity

Apremilast 30 mg twice daily, compared with placebo, resulted in significant reduction in overalldisease activity, as demonstrated by the mean change from baseline at week 12 in the BSAS(p < 0.0001) and the BDCAF (BDCAI, Patient’s Perception of Disease Activity, and the Clinician’s

Overall Perception of Disease Activity; p-values ≤ 0.0335 for all three components).

Among patients originally randomised to apremilast 30 mg twice daily who remained in the study,improvements (mean change from baseline) in both the BSAS and the BDCAF were maintained atweek 64.

Improvements in quality of life

Apremilast 30 mg twice daily, compared with placebo, resulted in significantly greater improvementin Quality of Life (QoL) at week 12, as demonstrated by the BD QoL Questionnaire (p = 0.0003).

Among patients originally randomised to apremilast 30 mg twice daily who remained in the study,improvement in BD QoL was maintained at week 64.

The European Medicines Agency has deferred the obligation to submit results of studies withapremilast in one or more subsets of the paediatric population with Behçet’s disease and psoriaticarthritis (see section 4.2 for information on paediatric use).

Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peakplasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilastpharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose rangeof 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily andapproximately 53% in healthy subjects and 68% in patients with psoriasis when administered twicedaily. Co-administration with food does not alter the bioavailability therefore, apremilast can beadministered with or without food.

Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume ofdistribution (Vd) is 87 L, indicative of extravascular distribution.

Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways includingoxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is notlikely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarilymediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the majorcirculating component following oral administration. Apremilast undergoes extensive metabolism withonly 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. Themajor circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast(M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreasedwhen administered concomitantly with rifampicin, a strong inducer of CYP3A4.

In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co-administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of activesubstances that are metabolised by CYP enzymes.

In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50 > 50 µM), howeverclinically relevant drug interactions mediated via P-gp are not expected to occur.

In vitro, apremilast has little to no inhibitory effect (IC50 > 10 µM) on Organic Anion Transporter(OAT)1 and OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide(OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP) and is not a substrate for thesetransporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast isco-administered with drugs that are substrates or inhibitors of these transporters.

The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminalelimination half-life of approximately 9 hours. Following oral administration of radiolabelledapremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, withabout 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively.

Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that inyoung subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 yearsof age in clinical trials. No dose adjustment is necessary for elderly patients.

The pharmacokinetics of apremilast were evaluated in a clinical trial in subjects 6 to 17 years of agewith moderate to severe plaque psoriasis at the recommended paediatric dose regimen (seesection 5.1). Population pharmacokinetic analysis indicated that steady-state exposure (AUC and Cmax)of apremilast in paediatric patients receiving the paediatric dose regimen (20 mg or 30 mg twice daily,based on body weight) was similar to steady-state exposure in adult patients at the 30 mg twice dailydose.

There is no meaningful difference in the PK of apremilast between mild or moderate renally impairedadult subjects and matched healthy subjects (N = 8 each). The results support that no dose adjustmentis needed in patients with mild and moderate renal impairment.

In 8 adult subjects with severe renal impairment to whom a single dose of 30 mg apremilast wasadministered, the AUC and Cmax of apremilast increased by approximately 89% and 42%,respectively. The dose of apremilast should be reduced to 30 mg once daily in adult patients withsevere renal impairment (eGFR less than 30 mL/min/1.73 m2 or CLcr < 30 mL/min). In paediatricpatients 6 years of age and older with severe renal impairment, the dose of apremilast should bereduced to 30 mg once daily for children who weigh at least 50 kg and to 20 mg once daily forchildren who weigh 20 kg to less than 50 kg (see section 4.2).

The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate orsevere hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity. There is no evidence of immunotoxic, dermal irritation, orphototoxic potential.

Fertility and early embryonic development

In a male mouse fertility study, apremilast at oral doses of 1, 10, 25, and 50 mg/kg/day produced noeffects on male fertility; the No Observed Adverse Effect Level (NOAEL) for male fertility wasgreater than 50 mg/kg/day 3-fold clinical exposure.

In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral dosesof 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating wereobserved at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates wereunaffected. The No Observed Effect Level (NOEL) for female fertility was 10 mg/kg/day (1.0-foldclinical exposure).

Embryo-foetal development

In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral dosesof 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals wereincreased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced numbers ofossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced foetal weights and retardedossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. Thematernal and developmental NOEL in the mouse was 10 mg/kg/day (1.3-fold clinical exposure).

In a monkey embryo-foetal developmental toxicity study, oral doses of 20, 50, 200, and1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at doses of50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day(1.4-fold clinical exposure).

Pre- and post-natal development

In a pre- and postnatal study, apremilast was administered orally to pregnant female mice at doses of10, 80 and 300 mg/kg/day from Gestation Day (GD) 6 to day 20 of lactation. Reductions in maternalbody weight and weight gain, and one death associated with difficulty in delivering pups wereobserved at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups werealso observed in one mouse at each of 80 and 300 mg/kg/day. Increased peri- and postnatal pup deathsand reduced pup body weights during the first week of lactation were observed at ≥ 80 mg/kg/day(≥ 4.0-fold clinical exposure). There were no apremilast-related effects on duration of pregnancy,number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, orany developmental effects in the pups beyond postnatal day 7. It is likely that pup developmentaleffects observed during the first week of the postnatal period were related to the apremilast-related puptoxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milkin the stomach of pups). All developmental effects were observed during the first week of thepostnatal period; no apremilast-related effects were seen during the remaining pre- and post-weaningperiods, including sexual maturation, behavioural, mating, fertility and uterine parameters. The NOELin the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-fold clinical AUC).

Carcinogenicity studies

Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatmentwith apremilast.

Genotoxicity studies

Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosomeaberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolicactivation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to2,000 mg/kg/day.

Other studies

There is no evidence of immunotoxic, dermal irritation, or phototoxic potential.

Cellulose microcrystalline

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Poly (vinyl alcohol)

Titanium dioxide (E171)

Macrogol (3350)

Talc

Iron oxide red (E172)

The 20 mg tablets also contain iron oxide yellow (E172).

The 30 mg tablets also contain iron oxide yellow (E172) and iron oxide black (E172).

Not applicable.

3 years.

Do not store above 30°C.

Otezla treatment initiation packs

PVC/aluminium foil blisters containing 27 film-coated tablets (4 × 10 mg, 23 × 20 mg).

PVC/aluminium foil blisters containing 27 film-coated tablets (4 × 10 mg, 4 × 20 mg, 19 × 30 mg).

Otezla 20 mg packs

PVC/aluminium foil blisters containing 14 film-coated tablets, in a pack size of 56 tablets.

Otezla 30 mg packs

PVC/aluminium foil blisters containing 14 film-coated tablets, in pack sizes of 56 tablets and168 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

Otezla 10 mg, 20 mg film-coated tablets (initiation pack)

EU/1/14/981/004

Otezla 10 mg, 20 mg, 30 mg film-coated tablets (initiation pack)

EU/1/14/981/001

Otezla 20 mg film-coated tablets

EU/1/14/981/005 - pack size of 56 tablets

Otezla 30 mg film-coated tablets

EU/1/14/981/002 - pack size of 56 tablets

EU/1/14/981/003 - pack size of 168 tablets

Date of first authorisation: 15 January 2015

Date of latest renewal: 23 August 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.