Otezla

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Otezla 10 mg film-coated tablets 
Otezla 20 mg film-coated tablets 
Otezla 30 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Otezla 10 mg film-coated tablets  
 
Each film-coated tablet contains 10 mg of apremilast. 
 
Excipient(s) with known effect 
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. 
 
Excipient(s) with known effect 
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. 
 
Excipient(s) with known effect 
Each film-coated tablet contains 171 mg of lactose (as lactose monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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 side 
and “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 side 
and “30” on the opposite side. 
 
 



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4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Psoriatic arthritis 
 
Otezla, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is 
indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an 
inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1).  
 
Psoriasis 
 
Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients 
who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy 
including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).  
 
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. 
 
4.2 Posology and method of administration 
 
Treatment with Otezla should be initiated by specialists experienced in the diagnosis and treatment of 
psoriasis, psoriatic arthritis or Behçet’s disease. 
 
Posology 
 
The recommended dose of apremilast is 30 mg taken orally twice daily, approximately 12 hours apart 
(morning and evening), with no food restrictions. An initial titration schedule is required as shown 
below in Table 1. No re-titration is required after initial titration. 
 
Table 1. Dose titration schedule 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & 

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
 
If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for 
their next dose, the missed dose should not be taken and the next dose should be taken at the regular 
time. 
 
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 of 
therapeutic benefit after this time period, treatment should be reconsidered. The patient's response to 
treatment should be evaluated on a regular basis. 
 
Special populations 
 
Elderly patients 
No dose adjustment is required for this patient population (see sections 4.8 and 5.2). 
 
Patients with renal impairment 
No dose adjustment is needed in patients with mild and moderate renal impairment. The dose of 
apremilast should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine 
clearance of less than 30 mL per minute estimated by the Cockcroft-Gault equation). For initial dose 



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titration in this group, it is recommended that apremilast be titrated using only the AM schedule listed 
in Table 1 and the PM doses be skipped (see section 5.2). 
 
Patients with hepatic impairment 
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).  
 
Paediatric population 
The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. No data 
are available. 
 
Method of administration  
 
Otezla is for oral use. The film-coated tablets should be swallowed whole, and can be taken either with 
or without food.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 
 
Pregnancy (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Diarrhoea, nausea, and vomiting 
 
There have been post-marketing reports of severe diarrhoea, nausea, and vomiting associated with the 
use 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. If 
patients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment with apremilast 
may be necessary. 
 
Psychiatric disorders 
 
Apremilast is associated with an increased risk of psychiatric disorders such as insomnia and 
depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in 
patients with or without history of depression (see section 4.8). The risks and benefits of starting or 
continuing treatment with apremilast should be carefully assessed if patients report previous or 
existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to 
cause psychiatric events is intended. Patients and caregivers should be instructed to notify the 
prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from 
new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is 
recommended to discontinue treatment with apremilast.  
 
Severe renal impairment 
 
Otezla should be dose reduced to 30 mg once daily in patients with severe renal impairment (see 
sections 4.2 and 5.2). 
 
Underweight patients 
 
Patients who are underweight at the start of treatment should have their body weight monitored 
regularly. In the event of unexplained and clinically significant weight loss, these patients should be 
evaluated by a medical practitioner and discontinuation of treatment should be considered. 
 



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Lactose content 
 
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in 
a 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 apremilast 
with multiple doses of rifampicin resulted in a decrease in apremilast area-under-the-concentration 
time curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%, 
respectively. Apremilast exposure is decreased when administered concomitantly with strong inducers 
of CYP3A4 (e.g. rifampicin) and may result in reduced clinical response.  
 
In clinical studies, apremilast has been administered concomitantly with topical therapy (including 
corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy. 
 
There was no clinically meaningful interaction between ketoconazole and apremilast. Apremilast can 
be co-administered with a potent CYP3A4 inhibitor such as ketoconazole.  
 
There was no pharmacokinetic interaction between apremilast and methotrexate in psoriatic arthritis 
patients. Apremilast can be co-administered with methotrexate. 
 
There was no pharmacokinetic interaction between apremilast and oral contraceptives containing 
ethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Pregnancy should be excluded before treatment can be initiated. Women of childbearing potential 
should use an effective method of contraception to prevent pregnancy during treatment. 
 
Pregnancy 
 
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 pregnancy 
included embryofoetal loss in mice and monkeys, and reduced foetal weights and delayed ossification 
in mice at doses higher than the currently recommended highest human dose. No such effects were 
observed when exposure in animals was at 1.3-fold the clinical exposure (see section 5.3). 
 
Breast-feeding 
 
Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whether 
apremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot be 
excluded, therefore apremilast should not be used during breast-feeding. 
 
Fertility 
 
No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility were 
observed in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-fold 
clinical exposure. For pre-clinical fertility data, see section 5.3. 
 



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4.7 Effects on ability to drive and use machines 
 
Apremilast has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The most commonly reported adverse reactions with apremilast in PsA and PSOR are gastrointestinal 
(GI) disorders including diarrhoea (15.7%) and nausea (13.9%). The other most commonly 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 BD are  diarrhoea (41.3%), 
nausea (19.2%), headache (14.4%), upper respiratory tract infection (11.5%), upper abdominal pain 
(8.7%), vomiting (8.7%) and back pain (7.7%) and are mostly mild to moderate in severity. 
 
The gastrointestinal adverse reactions generally occurred within the first 2 weeks of treatment and 
usually resolved within 4 weeks.  
 
Hypersensitivity reactions are uncommonly observed (see section 4.3). 
 
Tabulated list of adverse reactions 
 
The adverse reactions observed in patients treated with apremilast are listed below by system organ 
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 development 
programme and post-marketing experience. The frequencies of adverse drug reactions are 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 = 1184), and in the phase III study in BD (n = 207) the highest frequency from 
either data pool is represented in table 2).  
 
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 the 
available data). 
 
Table 2. Summary of adverse reactions in psoriatic arthritis (PsA), psoriasis (PSOR) and 

Behçet’s disease (BD) 

System Organ Class Frequency Adverse reaction 

Infections and 
infestations 

Very common Upper respiratory tract infectiona

Common 
Bronchitis
 
Nasopharyngitis* 

Immune system 
disorders Uncommon Hypersensitivity 

Metabolism and 
nutrition disorders Common Decreased appetite* 

Psychiatric disorders 
Common InsomniaDepression
Uncommon Suicidal ideation and behaviour 



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System Organ Class Frequency Adverse reaction 

Nervous system 
disorders 

Very common Headache*, a 

Common 
Migraine* 

Tension headache* 

Respiratory, thoracic, 
and mediastinal 
disorders 

Common Cough 

Gastrointestinal 
disorders 

Very Common 
Diarrhoea* 
Nausea* 

Common 

Vomiting*  
Dyspepsia 
Frequent bowel movements 
Upper abdominal pain* 
Gastroesophageal reflux disease  

Uncommon Gastrointestinal haemorrhage 

Skin and 
subcutaneous tissue 
disorders 

Uncommon RashUrticaria
Not known Angioedema 

Musculoskeletal and 
connective tissue 
disorders 

Common Back pain* 

General disorders and 
administration site 
conditions 

Common Fatigue 

Investigations Uncommon Weight decrease 
*At least one of these adverse reactions was reported as serious 
a Frequency reported as common in PSA and PSOR  
 
Description of selected adverse reactions 
 
Psychiatric disorders 
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 should 
be 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 PsA and 
PSOR patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% of patients 
receiving apremilast had observed weight loss between 5-10% while 5.7% of the patients receiving 
apremilast had observed weight loss greater than 10%. None of these patients had overt clinical 
consequences resulting from weight loss. A total of 0.1% of patients treated with apremilast 
discontinued due to adverse reaction of weight decreased. The mean observed weight loss in BD 
patients treated with apremilast for 52 weeks was 0.52 kg. A total of 11.8% of patients receving 
apremilast had observed weight loss between 5-10% while 3.8% of the patients receiving apremilast 
had observed weight loss greater than 10%.  None of these patients had overt clinical consequences 
from weight loss. None of the patients discontinued the study due to adverse reaction of weight 
decreased. 
 
Please see additional warning in section 4.4 for patients who are underweight at beginning of 
treatment.  



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Special populations 
 
Elderly patients 
From post-marketing experience, elderly patients ≥ 65 years of age may be at a higher risk of 
complications of severe diarrhoea, nausea and vomiting (see section 4.4). 
 
Patients with hepatic impairment 
The safety of apremilast was not evaluated in PsA, PSOR or BD patients with hepatic impairment. 
 
Patients with renal impairment  
In the PsA, PSOR or BD clinical studies, the safety profile observed in patients with mild renal 
impairment was comparable to patients with normal renal function. The safety of apremilast was not 
evaluated in PsA, PSOR or BD patients with moderate or severe renal impairment in the clinical 
studies. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg 
twice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is 
recommended that the patient is monitored for any signs or symptoms of adverse effects and 
appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive 
care is advised. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code: 
L04AA32 
 
Mechanism of action 
 
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to 
modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine 
monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition 
elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by 
modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP 
also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory 
mediators have been implicated in psoriatic arthritis and psoriasis. 
 
Pharmacodynamic effects 
 
In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not 
fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 
40 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 decreased lesional 
skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, 
including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8. 



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In clinical studies in patients with Behçet Disease treated with apremilast, there was a significant 
positive association between the change in plasma TNF-alpha and clinical efficacy as measured by the 
number of oral ulcers. 
 
Apremilast administered at doses of up to 50 mg twice daily did not prolong the QT interval in healthy 
subjects. 
 
Clinical efficacy and safety 
 
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 in 
adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with 
small molecule or biologic DMARDs. A total of 1,493 patients were randomised and treated with 
either 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 skin 
lesion (at least 2 cm in diameter) was also required in PALACE 3. Apremilast was used as a 
monotherapy (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%), arthritis 
mutilans (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 treated 
with 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. The 
median duration of PsA disease was 5 years.  
 
Based on the study design, patients whose tender and swollen joint counts had not improved by at least 
20% 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 or 
30 mg twice daily. At week 24, all remaining placebo-treated patients were switched to either 
apremilast 20 or 30 mg twice daily. Following 52 weeks of treatment, patients could continue on open 
label 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, as 
assessed by the ACR 20 response criteria compared to placebo at weeks 16. The proportion of patients 
with ACR 20/50/70 (responses in studies PALACE 1, PALACE 2 and PALACE 3, and the pooled 
data for studies PALACE 1, PALACE 2 and PALACE 3) for apremilast 30 mg twice daily at week 16 
are shown in table 3. ACR 20/50/70 responses were maintained at week 24. 
 
Among patients who were initially randomised to apremilast 30 mg twice daily treatment, ACR 
20/50/70 response rates were maintained through week 52 in the pooled studies PALACE 1, 
PALACE 2 and PALACE 3 (figure 1). 
 



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Table 3. Proportion of patients with ACR responses in studies PALACE 1, PALACE 2 and 
PALACE 3 and pooled studies at week 16  

*p ≤ 0.01 for apremilast vs. placebo 
**p ≤ 0.001 for apremilast vs. placebo 
a 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 of 

studies PALACE 1, PALACE 2 and PALACE 3 (NRI*) 

R
es

po
ns

e 
R

at
e 

+/
- S

E 
(%

)

0

10

20

30

40

50

0 16 24 40 52

Endpoint ACR 20 ACR 50 ACR 70

Study Week
Endpoint
ACR 20

Study Week
Endpoint n/m (%)
ACR 20 184/497 (37.0)

Study Week
Endpoint n/m (%)
ACR 20 196/497 (39.4)

Study Week
Endpoint n/m (%)
ACR 20 222/497 (44.7)

Study Week
Endpoint n/m (%)
ACR 20 209/497 (42.1)

Study Week
Endpoint

ACR 50

Study Week
Endpoint n/m (%)

ACR 50 69/497 (13.9)

Study Week
Endpoint n/m (%)

ACR 50 93/497 (18.7)

Study Week
Endpoint n/m (%)

ACR 50 102/497 (20.5)

Study Week
Endpoint n/m (%)

ACR 50 90/497 (18.1)

Study Week
Endpoint

ACR 70

Study Week
Endpoint n/m (%)

ACR 70 15/497 ( 3.0)

Study Week
Endpoint n/m (%)

ACR 70 33/497 ( 6.6)

Study Week
Endpoint n/m (%)

ACR 70 44/497 ( 8.9)

Study Week
Endpoint n/m (%)

ACR 70 38/497 ( 7.6)

 
*NRI: None responder imputation. Subjects who discontinued early prior to the time point and subjects who did not have sufficient data for a 
definitive 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 were 
still 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, 
375 (75%) patients entered the long term extension studies, and of these, 221 patients (59%) were still 
on this treatment at week 260. ACR responses were maintained in the long-term open label extension 
studies for up to 5 years. 
 
Responses observed in the apremilast treated group were similar in patients receiving and not 
receiving concomitant DMARDs, including MTX. Patients previously treated with DMARDs or 

 PALACE 1 PALACE 2 PALACE 3 POOLED 
 
 
 
 

Na 

Placebo  
 

+/- 
DMARDs
N = 168 

Apremilast 
30 mg 

twice daily 
+/- 

DMARDs
N = 168 

Placebo  
 

+/- 
DMARDs
N = 159 

Apremilast 
30 mg 

twice daily
+/- 

DMARDs
N = 162 

Placebo  
 

+/- 
DMARDs
N = 169 

Apremilast 
30 mg 

twice daily 
+/- 

DMARDs
N = 167 

Placebo  
 

+/- 
DMARDs
N = 496 

Apremilast 
30 mg 

twice daily
+/- 

DMARDs
N = 497 

ACR 
20a         

Week 
16 19.0% 38.1%** 18.9% 32.1%* 18.3% 40.7%** 18.8% 37.0%** 

ACR 50         
Week 
16 6.0% 16.1%* 5.0% 10.5% 8.3% 15.0% 6.5% 13.9%** 

ACR 70         
Week 
16 1.2% 4.2% 0.6% 1.2% 2.4% 3.6% 1.4% 3.0% 



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biologics who received apremilast achieved a greater ACR 20 response at week 16 than patients 
receiving placebo.  
 
Similar ACR responses were observed in patients with different PsA subtypes, including DIP. The 
number of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allow 
meaningful 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-value 
p < 0.0004, p-value ≤ 0.0017, respectively). These improvements were maintained at week 24. Among 
patients 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 psoriatic 
arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) and 
in the skin manifestations of psoriasis were seen in the apremilast-treated patients. Among patients 
who remained on the apremilast treatment to which they were randomised at study start, these 
improvements were maintained through week 52.  
 
The clinical responses were maintained in the same parameters of peripheral activity and in the skin 
manifestations of psoriasis in the open-label extension studies for up to 5 years of treatment. 
 
Physical function and health-related quality of life  
 
Apremilast-treated patients demonstrated statistically significant improvement in physical function, as 
assessed by the disability index of the health assessment questionnaire (HAQ-DI) change from 
baseline, compared to placebo at weeks 16 in PALACE 1, PALACE 2 and PALACE 3 and in the 
pooled 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 change 
from baseline in the HAQ-DI score at week 52 was -0.333 in the apremilast 30 mg twice daily group 
in 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 in 
health-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 Assessment 
of Chronic Illness Therapy – Fatigue (FACIT-fatigue) scores in patients treated with apremilast 
compared 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. 
 
Psoriasis 
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 of 
1,257 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 or 
systemic therapy. 
 
These studies had a similar design through week 32. In both studies, patients were randomised 2:1 to 
apremilast 30 mg twice daily or placebo for 16 weeks (placebo-controlled phase) and from weeks 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 apremilast who 



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achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reduction in 
their PASI score (PASI-50) (ESTEEM 2) were re-randomised at week 32 to either placebo or 
apremilast 30 mg twice daily. Patients who were re-randomised to placebo and who lost PASI-75 
response (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 the 
designated PASI response by week 32, or who were initially randomised to placebo, remained on 
apremilast 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. In 
addition, at week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50 
response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy in 
addition to apremilast 30 mg twice daily treatment. 
 
Following 52 weeks of treatment, patients could continue on open-label apremilast 30 mg within the 
long-term extension of the ESTEEM 1 and ESTEEM 2 studies for a total duration of treatment up to 5 
years (260 weeks). 
 
In both studies, the primary endpoint was the proportion of patients who achieved PASI-75 at 
week 16. The major secondary endpoint was the proportion of patients who achieved a sPGA score of 
clear (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 sPGA 
score of 3 (moderate) and 4 (severe) at baseline was 70.0% and 29.8%, respectively with a mean 
baseline BSA involvement of 25.19% (median 21.0%). Approximately 30% of all patients had 
received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy 
for the treatment of psoriasis (including treatment failures), with 37% receiving prior conventional 
systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of patients had 
not received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patients 
had a history of psoriatic arthritis. 
 
The proportion of patients achieving PASI-50, -75 and -90 responses, and sPGA score of clear (0) or 
almost clear (1), are presented in table 4 below. Treatment with apremilast resulted in significant 
improvement 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, apremilast demonstrated a 
treatment benefit across multiple manifestations of psoriasis including pruritus, nail disease, scalp 
involvement and quality of life measures. 



13 

 
Table 4. Clinical response at week 16 in studies ESTEEM 1 and ESTEEM 2 (FAS a, LOCFb) 
 ESTEEM 1 ESTEEM 2 
 Placebo 30 mg twice daily 

APR* 
Placebo 30 mg twice daily 

APR* 
N 282 562 137 274 
PASIc 75, n (%) 15 (5.3) 186 (33.1) 8 (5.8) 79 (28.8) 
sPGAd of clear or  
almost clear, n (%) 11 (3.9) 122 (21.7) 6 (4.4) 56 (20.4) 

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 (%) 
mean ± SD 

-6.9 
± 38.95

-47.8 
± 38.48

-6.1 
± 47.57

-48.4 
± 40.78

Change in pruritus VASf 
(mm), mean ± SD 

-7.3 
± 27.08

-31.5 
± 32.43

-12.2 
± 30.94

-33.5 
± 35.46

Change in DLQIg, mean ± 
SD  

-2.1 
± 5.69

-6.6 
± 6.66

-2.8 
± 7.22

-6.7 
± 6.95 

Change in SF-36 MCS h, 
mean ± SD 

-1.02 
± 9.161

2.39 
± 9.504

0.00 
± 10.498

2.58 
± 10.129

* p < 0.0001 for apremilast vs placebo, except for ESTEEM 2 PASI 90 and Change in SF-36 MCS where p = 
0.0042 and p = 0.0078, respectively. 
a FAS = Full Analysis Set  
b LOCF = Last Observation Carried Forward  
c PASI = Psoriasis Area and Severity Index 
d sPGA = Static Physician Global Assessment  
e BSA = Body Surface Area  
f VAS = Visual Analog Scale; 0 = best, 100 = worst  
g DLQI = Dermatology Life Quality Index; 0 = best, 30 = worst  
h 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 baseline 
demographics and baseline clinical disease characteristics (including psoriasis disease duration and 
patients with a history of psoriatic arthritis). The clinical benefit of apremilast was also demonstrated 
regardless of prior psoriasis medication usage and response to prior psoriasis treatments. Similar 
response rates were observed across all weight ranges. 
 
Response to apremilast was rapid, with significantly greater improvements in the signs and symptoms 
of psoriasis, including PASI, skin discomfort/pain and pruritus, compared to placebo by week 2. In 
general, 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 the 
randomised treatment withdrawal phase for patients re-randomised to apremilast at week 32 (table 5).  
 
Table 5. Persistence of effect among subjects randomised to APR 30 twice daily at week 0 

and re-randomised to APR 30 twice daily at week 32 to week 52  
  

Time Point 

ESTEEM 1 ESTEEM 2 
Patients who achieved PASI-75 

at week 32 
Patients who achieved 

PASI-50 at week 32 
Percent Change 
in PASI from 
baseline, mean 
(%) ± SDa 

Week 16 -77.7 ± 20.30 -69.7 ± 24.23 
Week 32 -88 ± 8.30 -76.7 ± 13.42 

Week 52 -80.5 ± 12.60 -74.4 ± 18.91 

Change in DLQI 
from baseline, 
mean ± SDa 

Week 16 -8.3 ± 6.26 -7.8 ± 6.41 
Week 32 -8.9 ± 6.68 -7.7 ± 5.92 
Week 52 -7.8 ± 5.75 -7.5 ± 6.27 



14 

  
Time Point 

ESTEEM 1 ESTEEM 2 
Patients who achieved PASI-75 

at week 32 
Patients who achieved 

PASI-50 at week 32 
Proportion of 
subjects with 
Scalp Psoriasis 
PGA (ScPGA) 0 
or 1, n/N (%)b 

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

Week 52 35/48 (72.9) 20/37 (54.1) 

a Includes subjects re-randomised to APR 30 twice daily at week 32 with a baseline value and a post-baseline 
value 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 30 
twice 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 were re-
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 patients re-
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 to 
loss 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 duration 
of 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 UVB 
phototherapy between weeks 32 to 52. Of these patients, 12% achieved a PASI-75 response at 
week 52 with apremilast plus topical and/or phototherapy treatment.  
 
In studies ESTEEM 1 and ESTEEM 2, significant improvements (reductions) in nail psoriasis, as 
measured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, were 
observed in patients receiving apremilast compared to placebo-treated patients at week 16 (p < 0.0001 
and p = 0.0052, respectively). Further improvements in nail psoriasis were observed at week 32 in 
patients continuously treated with apremilast.  
 
In studies ESTEEM 1 and ESTEEM 2, significant improvements in scalp psoriasis of at least moderate 
severity (≥ 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 receiving 
apremilast compared to placebo-treated patients (p < 0.0001 for both studies). The improvements were 
generally maintained in subjects who were re-randomised to apremilast at week 32 through week 52 
(table 5). 
 
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 patients 
receiving apremilast compared with placebo-treated patients (table 4). Improvements in DLQI were 
maintained through week 52 in subjects who were re-randomised to apremilast at week 32 (table 5). In 
addition, 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%) entered 
the open-label extension studies of ESTEEM 1 and ESTEEM 2, and of these 115 patients (26%) were 
still on treatment at week 260. For patients who remained on apremilast in the open label extension of 



15 

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 psoriasis 
was assessed for a total duration of treatment up to 5 years. Long-term experience in open-label 
extension studies with apremilast was generally comparable to the 52-week studies. 
 
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 oral ulcers. 
Patients were previously treated with at least one non-biologic BD medication for oral ulcers and were 
candidates for systemic therapy. Concomitant treatment for BD was not allowed. The population 
studied met the International Study Group (ISG) criteria for BD with a history of skin lesions (98.6%), 
genital ulcers (90.3%), musculoskeletal (72.5%), ocular (17.4%), central nervous system (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, all 
patients received apremilast 30 mg twice daily (active treatment phase). Patients ranged in age from 19 
to 72 years, with a mean age of 40 years. The mean duration of BD was 6.84 years. All patients had a 
history of recurrent oral ulcers with at least 2 oral ulcers at screening and randomization: the mean 
baseline 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 from 
baseline 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), time 
to onset of oral ulcer resolution, and proportion of patients achieving resolution of oral ulcers by week 
6, and who remain oral ulcer free at every visit for at least 6 additional weeks during the 12-week 
placebo-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 by 
the AUC for the number of oral ulcers from baseline through week 12 (p < 0.0001), compared with 
placebo.   
Significant improvements in other measures of oral ulcers were demonstrated at week 12. 
 
Table 6.  Clinical response of oral ulcers at week 12 in RELIEF (ITT population) 

Endpointa 
Placebo 
N = 103 

Apremilast 
30 mg BID 

N = 104 

AUCb for the number of oral ulcers from baseline through week 12 
(MI) 

LS Mean 
222.14 

LS Mean 
129.54 

Change from baseline in the pain of oral ulcers as measured by 
VASc at week 12 (MMRM) 

LS Mean 
-18.7 

LS Mean 
-42.7 

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

4.9% 29.8% 



16 

Endpointa 
Placebo 
N = 103 

Apremilast 
30 mg BID 

N = 104 

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

Proportion of subjects with complete oral ulcer response at week 12 
(NRI) 22.3% 52.9% 

Proportion of subjects with partial oral ulcer responsed at week 12 
(NRI) 47.6% 76.0% 

ITT=intent to treat; LS=least squares; MI=multiple imputation; MMRM=mixed-effects model for repeated 
measures; NRI=non-responder imputation; BID=twice daily. 
a p-value < 0.0001 for all apremilast vs. placebo 
b 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 mean 
number of oral ulcers and oral ulcer pain was observed in the apremilast 30 mg twice daily treatment 
group compared to the placebo treatment group at every visit, as early as week 1, through week 12 for 
number of oral ulcers (p ≤ 0.0015) and for oral ulcer pain (p ≤ 0.0035). Among patients who were 
continuously treated with apremilast and remained in the study, improvements in oral ulcers and 
reduction of oral ulcer pain were maintained through week 64 (figures 2 and 3).  
 
Among patients originally randomised to apremilast 30 mg twice daily who remained in the study, the 
proportions of patients with a complete response and partial response of oral ulcers were maintained 
through week 64 (53.3% and 76.0% respectively).  
 
 
 
Figure 2. 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 patients 
switched 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.  
 



17 

Figure 3. Mean change from baseline in oral ulcer pain on a visual analog scale by time point 
through 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 patients 
switched 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 overall 
disease 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 at 
week 64. 
 
Improvements in quality of life 
 
Apremilast 30 mg twice daily, compared with placebo, resulted in significantly greater improvement 
in 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. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak 
plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast 
pharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose range 
of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and 
approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice 
daily. Co-administration with food does not alter the bioavailability therefore, apremilast can be 
administered with or without food. 
 



18 

Distribution 
 
Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume of 
distribution (Vd) is 87 L, indicative of extravascular distribution. 
 
Biotransformation 
 
Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including 
oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not 
likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily 
mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major 
circulating component following oral administration. Apremilast undergoes extensive metabolism with 
only 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. The 
major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast 
(M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased 
when 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 active 
substances that are metabolised by CYP enzymes. 
 
In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50 > 50 µM), however 
clinically 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 these 
transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co-
administered with drugs that are substrates or inhibitors of these transporters. 
 
Elimination 
 
The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal 
elimination half-life of approximately 9 hours. Following oral administration of radiolabelled 
apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with 
about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively. 
 
Elderly patients 
 
Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 
85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that in 
young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years 
of age in clinical trials. No dosage adjustment is necessary for elderly patients. 
 
Renal impairment 
 
There is no meaningful difference in the PK of apremilast between mild or moderate renally impaired 
subjects and matched healthy subjects (N = 8 each). The results support that no dose adjustment is 
needed in patients with mild and moderate renal impairment. Apremilast dose should be reduced to 
30 mg once daily in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 or 
CLcr < 30 mL/min). In 8 subjects with severe renal impairment to whom a single dose of 30 mg 
apremilast was administered, the AUC and Cmax of apremilast increased by approximately 89% and 
42%, respectively. 
 



19 

Hepatic impairment 
 
The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate or 
severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology and repeated dose toxicity. There is no evidence of immunotoxic, dermal irritation, or 
phototoxic potential. 
 
Fertility and early embryonic development 
 
In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no 
effects on male fertility; the No Observed Adverse Effect Level (NOAEL) for male fertility was 
greater than 50 mg/kg/day 3-fold clinical exposure.  
 
In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral 
dosages of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to 
mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates 
were unaffected. The No Observed Effect Level (NOEL) for female fertility was 10 mg/kg/day (1.0-
fold clinical exposure). 
 
Embryo-foetal development 
 
In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral 
dosages of 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals 
were increased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced 
numbers of ossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced foetal weights and 
retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. 
The maternal 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 dosages of 20, 50, 200, and 
1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at dosages of 
50 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 dosages 
of 10, 80 and 300 mg/kg/day from Gestation Day (GD) 6 to day 20 of lactation. Reductions in 
maternal body weight and weight gain, and one death associated with difficulty in delivering pups 
were observed at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups 
were also observed in one mouse at each of 80 and 300 mg/kg/day. Increased peri- and postnatal pup 
deaths and 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, or any developmental effects in the pups beyond postnatal day 7. It is likely that pup 
developmental effects observed during the first week of the postnatal period were related to the 
apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care 
(higher incidence of no milk in the stomach of pups). All developmental effects were observed during 
the first week of the postnatal period; no apremilast-related effects were seen during the remaining 
pre- and post-weaning periods, including sexual maturation, behavioural, mating, fertility and uterine 
parameters. The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-
fold clinical AUC). 
 



20 

Carcinogenicity studies 
 
Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatment 
with apremilast.  
 
Genotoxicity studies 
 
Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome 
aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic 
activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 
2,000 mg/kg/day. 
 
Other studies 
 
There is no evidence of immunotoxic, dermal irritation, or phototoxic potential.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Cellulose microcrystalline 
Lactose monohydrate 
Croscarmellose sodium 
Magnesium stearate 
 
Film-coating 
 
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).  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30ºC. 
 
6.5 Nature and contents of container  
 
Otezla 10 mg, 20 mg, 30 mg film-coated tablets (initiation pack) 
 
PVC/aluminium foil blisters containing 27 film-coated tablets (4 x 10 mg, 4 x 20 mg, 19 x 30 mg).  



21 

 
Otezla 30 mg film-coated tablets 
 
PVC/aluminium foil blisters containing 14 film-coated tablets, in pack sizes of 56 tablets and 
168 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Otezla 10 mg, 20 mg, 30 mg film-coated tablets (initiation pack) 
 
EU/1/14/981/001 
 
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 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 January 2015 
Date of latest renewal: 23 August 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE  
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



23 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturers responsible for batch release 
 
Celgene Distribution B.V. 
Winthontlaan 6 N  
3526 KV Utrecht  
Netherlands 

 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
Amgen NV 
Telecomlaan 5-7 
1831 Diegem 
Belgium 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 
 Periodic safety update reports (PSURs) 

 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 

 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



26 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Wallet card containing 2-week treatment initiation pack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Otezla 10 mg film-coated tablets 
Otezla 20 mg film-coated tablets 
Otezla 30 mg film-coated tablets 
apremilast  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg, 20 mg or 30 mg of apremilast. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet  
Treatment initiation pack 
 
Each pack of 27 film-coated tablets for a 2 week treatment schedule contains: 
4 film-coated tablets of 10 mg 
4 film-coated tablets of 20 mg 
19 film-coated tablets of 30 mg 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
Week 1  
Week 2 
Day 1 - Day 7  
Day 8 - Day 14 
Sun as symbol for morning dose 
Moon as symbol for evening dose 
Refer to the wallet card for daily dose 
 
QR code to be included 
www.otezla-eu-pil.com 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 



27 

 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/981/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Otezla 10 mg 
Otezla 20 mg 
Otezla 30 mg  
 
 



28 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2 D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



29 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister (Particulars printed directly onto the wallet card with the blank blister sealed inside)  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Otezla 10 mg tablets 
Otezla 20 mg tablets 
Otezla 30 mg tablets 
 
apremilast  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



30 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Otezla 30 mg film–coated tablets  
apremilast  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 30 mg of apremilast. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet  
56 film-coated tablets  
168 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
 
QR code to be included 
www.otezla-eu-pil.com 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



31 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/981/002 56 film-coated tablets 
EU/1/14/981/003 168 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Otezla 30 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2 D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



32 

 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Otezla 30 mg tablets 
apremilast  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



34 

 
Package leaflet: Information for the patient 

 
Otezla 10 mg film-coated tablets 
Otezla 20 mg film-coated tablets 
Otezla 30 mg film-coated tablets 

apremilast 
 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Otezla is and what it is used for 
2. What you need to know before you take Otezla 
3. How to take Otezla 
4. Possible side effects 
5. How to store Otezla 
6. Contents of the pack and other information 
 
 
1. What Otezla is and what it is used for 
 
What Otezla is 
 
Otezla contains the active substance ‘apremilast’. This belongs to a group of medicines called 
phosphodiesterase 4 inhibitors, which help to reduce inflammation. 
 
What Otezla is used for 
 
Otezla is used to treat adults with the following conditions: 
 Active psoriatic arthritis - if you cannot use another type of medicine called 

‘Disease-Modifying Antirheumatic Drugs’ (DMARDs) or when you have tried one of these 
medicines and it did not work.  

 Moderate to severe chronic plaque psoriasis - if you cannot use one of the following 
treatments or when you have tried one of these treatments and it did not work: 
- phototherapy - a treatment where certain areas of skin are exposed to ultraviolet light 
- systemic therapy - a treatment that affects the entire body rather than just one local area, 

such as ‘ciclosporin’, ‘methotrexate’ or ‘psoralen ’. 
 Behçet’s disease (BD) - to treat the mouth ulcers which is a common problem for people with 

this illness. 
 
What psoriatic arthritis is 
 
Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis, an 
inflammatory disease of the skin.  
 



35 

What plaque psoriasis is 
 
Psoriasis is an inflammatory disease of the skin, which can cause red, scaly, thick, itchy, painful 
patches on your skin and can also affect your scalp and nails.  
 
What Behçet’s disease is 
 
Behçet’s disease is a rare type of inflammatory disease which affects many parts of the body. The 
most common problem is mouth ulcers. 
 
How Otezla works 
 
Psoriatic arthritis, psoriasis and Behçet’s disease are usually lifelong conditions and there is currently 
no cure. Otezla works by reducing the activity of an enzyme in the body called ‘phosphodiesterase 4’, 
which is involved in the process of inflammation. By reducing the activity of this enzyme, Otezla can 
help to control the inflammation associated with psoriatic arthritis, psoriasis and Behçet’s disease, and 
thereby reduce the signs and symptoms of these conditions. 
 
In psoriatic arthritis, treatment with Otezla results in an improvement in swollen and painful joints, 
and can improve your general physical function. 
 
In psoriasis, treatment with Otezla results in a reduction in psoriatic skin plaques and other signs and 
symptoms of the disease. 
 
In Behçet’s disease, treatment with Otezla reduces the number of mouth ulcers and can stop them 
completely. It can also reduce the associated pain. 
 
Otezla has also been shown to improve the quality of life in patients with psoriasis, psoriatic arthritis 
or Behçet’s disease. This means that the impact of your condition on daily activities, relationships and 
other factors should be less than it was before.  
 
 
2. What you need to know before you take Otezla 
 
Do not take Otezla: 
 
 if you are allergic to apremilast or any of the other ingredients of this medicine (listed in 

section 6).  
 if you are pregnant or think you may be pregnant. 
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Otezla. 
 
Depression and suicidal thoughts 
 
Tell your doctor before starting Otezla if you have depression which is getting worse with thoughts of 
suicide.  
 
You or your caregiver should also tell your doctor straight away of any changes in behaviour or mood, 
feelings of depression and of any suicidal thoughts you may have after taking Otezla. 
 
Severe kidney problems 
 
If you have severe kidney problems, your dose will be different – see section 3. 
 



36 

If you are underweight 
 
Talk to your doctor while taking Otezla if you lose weight without meaning to. 
 
Gut problems 
 
If you experience severe diarrhoea, nausea, or vomiting, you should talk to your doctor. 
 
Children and adolescents 
 
Otezla has not been studied in children and adolescents, therefore it is not recommended for use in 
children and adolescents aged 17 years and under.  
 
Other medicines and Otezla 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
This includes medicines obtained without a prescription and herbal medicines. This is because Otezla 
can affect the way some other medicines work. Also some other medicines can affect the way Otezla 
works.  
 
In particular, tell your doctor or pharmacist before taking Otezla if you are taking any of the following 
medicines: 
 
 rifampicin – an antibiotic used for tuberculosis  
 phenytoin, phenobarbital and carbamazepine - medicines used in the treatment of seizures or 

epilepsy 
 St John’s Wort – a herbal medicine for mild anxiety and depression. 
 
Pregnancy and breast-feeding  
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
There is little information about the effects of Otezla in pregnancy. You should not become pregnant 
while taking this medicine and should use an effective method of contraception during treatment with 
Otezla.  
It is not known if this medicine passes into human milk. You should not use Otezla while breast-
feeding.  
 
Driving and using machines 
 
Otezla has no effect on the ability to drive and use machines. 
 
Otezla contains lactose  
 
Otezla contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Otezla  
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 



37 

How much to take 
 
 When you first start taking Otezla, you will receive a ‘treatment initiation pack’ which contains 

all the doses as listed in the table below. 
 The ‘treatment initiation pack’ is clearly labelled to make sure you take the correct tablet at the 

correct time. 
 Your treatment will start at a lower dose and will gradually be increased over the first 6 days of 

treatment. 
 The ‘treatment initiation pack’ will also contain enough tablets for another 8 days at the 

recommended dose (days 7 to 14). 
 The recommended dose of Otezla is 30 mg twice a day after the titration phase is complete - one 

30 mg dose in the morning and one 30 mg dose in the evening, approximately 12 hours apart, 
with or without food. 

 This is a total daily dose of 60 mg. By the end of day 6 you will have reached this recommended 
dose.  

 Once the recommended dose has been reached, you will only get the 30 mg tablet strength in 
your prescribed packs. You will only ever need to go through this stage of gradually increasing 
your dose once even if you re-start treatment.  

 

 
People with severe kidney problems 
 
If you have severe kidney problems then the recommended dose of Otezla is 30 mg once a day 
(morning dose). Your doctor will talk to you about how to increase your dose when you first start 
taking Otezla. 
 
How and when to take Otezla  
 
 Otezla is for oral use. 
 Swallow the tablets whole, preferably with water. 
 You can take the tablets either with or without food. 
 Take Otezla at about the same time each day, one tablet in the morning and one tablet in the 

evening. 
 
If your condition has not improved after six months of treatment, you should talk to your doctor.  
 
If you take more Otezla than you should 
 
If you take more Otezla than you should, talk to a doctor or go to a hospital straight away. Take the 
medicine pack and this leaflet with you. 
 
If you forget to take Otezla 
 
 If you miss a dose of Otezla, take it as soon as you remember. If it is close to the time for your 

next dose, just skip the missed dose. Take the next dose at your regular time.  
 Do not take a double dose to make up for a forgotten dose. 
 

Day Morning Dose Evening Dose Total Daily Dose 
Day 1 10 mg (pink) Do not take a dose 10 mg 
Day 2 10 mg (pink) 10 mg (pink) 20 mg 
Day 3 10 mg (pink) 20 mg (brown) 30 mg 
Day 4 20 mg (brown) 20 mg (brown) 40 mg 
Day 5 20 mg (brown) 30 mg (beige) 50 mg 
Day 6 onwards 30 mg (beige) 30 mg (beige) 60 mg 



38 

If you stop taking Otezla 
 
 You should continue taking Otezla until your doctor tells you to stop.  
 Do not stop taking Otezla without talking to your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Serious side effects – depression and suicidal thoughts 
 
Tell your doctor straight away about any changes in behaviour or mood, feelings of depression, 
thoughts of suicide or suicidal behaviour (this is uncommon).  
 
Very common side effects (may affect more than 1 in 10 people) 
 diarrhoea 
 nausea 
 headaches, migraines or tension headaches 
 upper respiratory tract infections such as cold, runny nose, sinus infection 
 
Common side effects (may affect up to 1 in 10 people) 
 cough 
 back pain 
 vomiting 
 feeling tired 
 stomach pain  
 loss of appetite 
 frequent bowel movements 
 difficulty sleeping (insomnia) 
 indigestion or heartburn 
 inflammation and swelling of the tubes in your lungs (bronchitis) 
 common cold (nasopharyngitis) 
 depression 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 rash 
 hives (urticaria) 
 weight loss 
 allergic reaction 
 bleeding in the bowel or in the stomach 
 suicidal ideation or behaviour 
 
Not known side effects (frequency cannot be estimated from the available data): 
 severe allergic reaction (may include swelling of the face, lips, mouth, tongue, or throat that 

may lead to difficulty breathing or swallowing) 
 
If you are 65 years of age or older, you might have a higher risk of complications of severe diarrhoea, 
nausea and vomiting. If your gut problems become severe, you should talk to your doctor. 
 



39 

Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Otezla 
 
 Keep this medicine out of the sight and reach of children. 
 Do not use this medicine after the expiry date which is stated on the blister or on the wallet or 

on the carton after EXP. The expiry date refers to the last day of that month. 
 Do not store above 30°C. 
 Do not use this medicine if you notice any damage or signs of tampering to the medicine 

packaging. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.  
 
 
6. Contents of the pack and other information 
 
What Otezla contains  
 
The active substance is apremilast. 
 Otezla 10 mg film-coated tablets: each film-coated tablet contains 10 mg of apremilast.  
 Otezla 20 mg film-coated tablets: each film-coated tablet contains 20 mg of apremilast.  
 Otezla 30 mg film-coated tablets: each film-coated tablet contains 30 mg of apremilast.  
 
The other ingredients in the tablet core are cellulose microcrystalline, lactose monohydrate, 
croscarmellose sodium and magnesium stearate.  
 The film-coating contains poly (vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, 

iron oxide red (E172). 
 The 20 mg film-coated tablet also contains iron oxide yellow (E172).  
 The 30 mg film-coated tablet also contains iron oxide yellow (E172) and iron oxide black 

(E172). 
 
What Otezla looks like and contents of the pack 
 
The Otezla 10 mg film-coated tablet is a pink, diamond shaped film-coated tablet with “APR” 
engraved on one side and “10” on the opposite side. 
The Otezla 20 mg film-coated tablet is a brown, diamond shaped film-coated tablet with “APR” 
engraved on one side and “20” on the opposite side. 
The Otezla 30 mg film-coated tablet is a beige, diamond shaped film-coated tablet with “APR” 
engraved on one side and “30” on the opposite side. 
 
Pack sizes 
 The treatment initiation pack is a folding wallet containing 27 film-coated tablets: 4 x 10 mg 

tablets, 4 x 20 mg tablets and 19 x 30 mg tablets.  
 The one-month standard pack contains 56 x 30 mg film-coated tablets.  
 The three-month standard pack contains 168 x 30 mg film-coated tablets.  
 



40 

Marketing Authorisation Holder and Manufacturer 
Amgen Europe B.V. 
Minervum 7061  
4817 ZK Breda 
The Netherlands 
 
Marketing Authorisation Holder 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands  
 
Manufacturer 
Celgene Distribution B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
Manufacturer 
Amgen NV 
Telecomlaan 5-7 
1831 Diegem 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
s.a. Amgen n.v. 
Tel/Tél: +32 (0)2 7752711 
 

Lietuva 
Amgen Switzerland AG Vilniaus filialas 
Tel: +370 5 219 7474  

България 
Амджен България ЕООД 
Тел.: +359 (0)2 424 7440  

Luxembourg/Luxemburg 
s.a. Amgen  
Belgique/Belgien 
Tel/Tél: +32 (0)2 7752711 

Česká republika 
Amgen s.r.o. 
Tel: +420 221 773 500  

Magyarország 
Amgen Kft. 
Tel.: +36 1 35 44 700  

Danmark 
Amgen, filial af Amgen AB, Sverige 
Tlf: +45 39617500 
 

Malta 
Amgen B.V. 
The Netherlands 
Tel: +31 (0)76 5732500 
 

Deutschland 
AMGEN GmbH 
Tel.: +49 89 1490960 
 

Nederland 
Amgen B.V. 
Tel: +31 (0)76 5732500 

Eesti 
Amgen Switzerland AG Vilniaus filialas 
Tel: +372 586 09553  

Norge 
Amgen AB 
Tel: +47 23308000 



41 

Ελλάδα 
Genesis Pharma SA 
Τηλ: +30 210 8771500 
 
 

Österreich 
Amgen GmbH  
Tel: +43 (0)1 50 217 
 

España 
Amgen S.A. 
Tel: +34 93 600 18 60  
 

Polska 
Amgen Biotechnologia Sp. z o.o. 
Tel.: +48 22 581 3000  

France 
Amgen S.A.S. 
Tél: +33 (0)9 69 363 363  

Portugal 
Amgen Biofarmacêutica, Lda. 
Tel: +351 21 4220606 
 

Hrvatska 
Amgen d.o.o. 
Tel: +385 (0)1 562 57 20  

România 
Genesis Biopharma România SRL 
Tel: +40 21 403 4074   

Ireland 
Amgen Ireland Limited 
Tel: +353 1 8527400 
 

Slovenija 
AMGEN zdravila d.o.o. 
Tel: +386 (0)1 585 1767 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
Amgen Slovakia s.r.o. 
Tel: +421 2  321 114 49 

Italia 
Amgen S.r.l. 
Tel: +39 02 6241121  

Suomi/Finland 
Amgen AB, sivuliike Suomessa/Amgen AB, filial 
i Finland 
Puh/Tel: +358 (0)9 54900500 
 

Kύπρος 
Genesis Pharma (Cyprus) Ltd 
Τηλ: +357 22765735  

Sverige 
Amgen AB  
Tel: +46 (0)8 6951100 

Latvija 
Amgen Switzerland AG Rīgas filiāle 
Tel: +371 257 25888 
 

United Kingdom 
Amgen Limited 
Tel: +44 (0)1223 420305  

 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed and updated information on this medicine is available by scanning the QR code on the outer 
packaging with a smartphone. The same information is also available on the following URL:  
www.otezla-eu-pil.com. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET