Skilarence

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Skilarence 30 mg gastro-resistant tablets 
Skilarence 120 mg gastro-resistant tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Skilarence 30 mg 
Each gastro-resistant tablet contains 30 mg dimethyl fumarate. 
Skilarence 120 mg 
Each gastro-resistant tablet contains 120 mg dimethyl fumarate. 
 
Excipient with known effect 
Skilarence 30 mg 
Each gastro-resistant tablet contains 34.2 mg lactose (as monohydrate). 
Skilarence 120 mg 
Each gastro-resistant tablet contains 136.8 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Gastro-resistant tablet. 
Skilarence 30 mg 
White, film-coated, round, biconvex tablet with a diameter of approximately 6.8 mm. 
Skilarence 120 mg 
Blue, film-coated, round, biconvex tablet with a diameter of approximately 11.6 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Skilarence is indicated for the treatment of moderate to severe plaque psoriasis in adults in need of 
systemic medicinal therapy. 
 
4.2 Posology and method of administration 
 
Skilarence is intended for use under the guidance and supervision of a physician experienced in the 
diagnosis and treatment of psoriasis. 
 
Posology 
To improve tolerability, it is recommended to begin treatment with a low initial dose with subsequent 
gradual increases. In the first week, Skilarence 30 mg is taken once daily (1 tablet in the evening). In 
the second week, Skilarence 30 mg is taken twice daily (1 tablet in the morning and 1 in the evening). 
In the third week, Skilarence 30 mg is taken three times daily (1 tablet in the morning, 1 at midday, 
and 1 in the evening). From the fourth week, treatment is switched to only 1 tablet of 
Skilarence 120 mg in the evening. This dose is then increased by 1 Skilarence 120 mg tablet per week 
at different times of day for the subsequent 5 weeks, as shown in the table below. The maximum daily 
dose allowed is 720 mg (3 x 2 tablets of Skilarence 120 mg). 
 



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Week Number of tablets Total daily dose (mg) 
 Morning Midday Evening of dimethyl fumarate  

Skilarence 30 mg  
1 0 0 1 30 
2 1 0 1 60 
3 1 1 1 90 

Skilarence 120 mg  
4 0 0 1 120 
5 1 0 1 240 
6 1 1 1 360 
7 1 1 2 480 
8 2 1 2 600 
9+ 2 2 2 720 
 
If a particular dose increase is not tolerated, it may be temporarily reduced to the last tolerated dose. 
 
If treatment success is observed before the maximum dose is reached, no further increase of dose is 
necessary. After clinically relevant improvement of the skin lesions has been achieved, consideration 
should be given to gradual reduction of the daily dose of Skilarence to the maintenance dose required 
by the individual. 
 
Dosage modifications may also be necessary if abnormalities in laboratory parameters are observed 
(see section 4.4). 
 
Elderly patients 
Clinical studies of Skilarence did not include sufficient numbers of patients aged 65 years and above 
to determine whether they respond differently compared to patients under 65 years (see section 5.2). 
Based on the pharmacology of dimethyl fumarate, a need for dose adjustment in the elderly is not 
expected. 
 
Renal impairment 
No dose adjustment is needed in patients with mild to moderate renal impairment (see section 5.2). 
Skilarence has not been studied in patients with severe renal impairment, and use of Skilarence is 
contraindicated in these patients (see section 4.3). 
 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment (see section 5.2). 
Skilarence has not been studied in patients with severe hepatic impairment, and use of Skilarence is 
contraindicated in these patients (see section 4.3). 
 
Paediatric population 
The safety and efficacy of Skilarence in paediatric patients below the age of 18 years have not been 
established. There are no data available with Skilarence in paediatric patients. 
 
Method of administration 
Skilarence is for oral use. 
Skilarence tablets must be swallowed whole with fluid during or immediately after a meal. 
The coating of the gastro-resistant tablets is designed to prevent gastric irritation. Therefore, the tablets 
should not be crushed, divided, dissolved or chewed. 
 



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4.3 Contraindications 
 
‒ Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
‒ Severe gastrointestinal disorders. 
‒ Severe hepatic or renal impairment. 
‒ Pregnancy and breast-feeding. 
 
4.4 Special warnings and precautions for use 
 
Haematology 
Skilarence may decrease leukocyte and lymphocyte counts (see section 4.8). It has not been studied in 
patients with pre-existing low leukocyte or lymphocyte counts. 
 
Before treatment 
Prior to initiating treatment with Skilarence, a current complete blood count (including differential 
blood count and platelet count) should be available. Treatment should not be initiated if leukopenia 
below 3.0x109/L, lymphopenia below 1.0x109/L or other pathological results are identified. 
 
During treatment 
During treatment a complete blood count with differential should be performed every 3 months. 
Action is needed in the following circumstances: 
 
Leukopenia: If a marked decrease in the total number of white blood cells is found, the situation 
should be monitored carefully and treatment with Skilarence should be discontinued at levels below 
3.0x109/L. 
 
Lymphopenia: If the lymphocyte count falls below 1.0x109/L but is ≥0.7 x109/L, blood monitoring 
should be performed monthly until levels return to 1.0x109/L or higher for two consecutive blood tests 
at which point monitoring can again be performed every 3 months. 
If the lymphocyte count falls below 0.7x109/L, the blood test must be repeated and if the levels are 
confirmed to be below 0.7x109/L, then treatment must be stopped immediately. Patients developing 
lymphopenia should be monitored after stopping treatment until their lymphocyte count has returned 
to the normal range (see section 4.8). 
 
Other haematological disorders 
Therapy should be discontinued and caution is advised if other pathological results occur. In any case 
blood counts should be monitored until values have returned to the normal range. 
 
Infections 
Skilarence is an immunomodulator and may affect the way the immune system responds to infection. 
For patients with pre-existing infections of clinical relevance, the physician should decide if treatment 
with Skilarence should only be initiated once the infection has resolved. If a patient develops an 
infection during treatment with Skilarence, suspension of treatment should be considered and the 
benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Skilarence 
should be instructed to report symptoms of infection to a physician. 
 
Opportunistic infections/progressive multifocal leukoencephalopathy (PML) 
Cases of opportunistic infections, particularly of progressive multifocal leukoencephalopathy (PML) 
have been reported with other dimethyl fumarate-containing products (see section 4.8). PML is an 
opportunistic infection caused by the John-Cunningham virus (JCV) that can be fatal or cause severe 
disabilities. PML is probably caused by a combination of factors. 
 
A previous infection with JCV is considered a prerequisite for the development of PML. Risk factors 
can include previous immunosuppressive treatment and the existence of certain concomitant disorders 
(such as some autoimmune disorders or malignant haematological conditions). A modified or 
weakened immune system as well as genetic or environmental factors can also constitute risk factors. 
 



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Persistent moderate or severe lymphopenia during treatment with dimethyl fumarate is also considered 
a risk factor for PML. Patients who develop lymphopenia should be monitored for signs and 
symptoms of opportunistic infections, particularly for symptoms indicative of PML. Typical 
symptoms associated with PML are diverse, become worse over days to weeks and include 
progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision and 
changes in thinking, memory and orientation leading to confusion and personality changes. If PML is 
suspected, treatment with Skilarence should be stopped immediately and further appropriate 
neurological and radiological examinations performed. 
 
Prior and concomitant treatment with immunosuppressive or immunomodulating therapies 
Limited data are available on the efficacy and safety of Skilarence in patients who have been 
previously treated with other immunosuppressive or immunomodulating therapies. When switching 
patients from such therapies to Skilarence, the half-life and mode of action of the other therapy should 
be considered in order to avoid additive effects on the immune system. 
 
No data are available on the efficacy and safety of Skilarence when taken concomitantly with other 
immunosuppressive or immunomodulating therapies (see section 4.5). 
 
Pre-existing gastrointestinal disease 
Skilarence has not been studied in patients with pre-existing gastrointestinal disease. Skilarence is 
contraindicated in patients with severe gastrointestinal disease (see sections 4.3). Gastrointestinal 
tolerability can be improved by following the dose titration schedule on initiating Skilarence treatment 
and by taking Skilarence with food (see sections 4.2 and 4.8). 
 
Renal function 
Since renal elimination plays a minor role in the clearance of Skilarence from plasma, it is unlikely 
that renal impairment would affect the pharmacokinetic characteristics, and so a need for dose 
adjustment in patients with mild to moderate renal impairment is not expected (see sections 4.2 and 
5.2). 
 
During the Phase III placebo-controlled clinical trial, renal function was not seen to deteriorate during 
therapy across treatment groups. However, Skilarence has not been studied in patients with severe 
renal impairment, and some cases of renal toxicity have been reported during post-marketing 
surveillance with fumaric acid esters. Hence, Skilarence is contraindicated in patients with severe 
renal impairment (see section 4.3). 
 
Renal function (e.g. creatinine, blood urea nitrogen and urinalysis) should be checked prior to 
initiation of treatment and every 3 months thereafter. In the event of a clinically relevant change in 
renal function, particularly in the absence of alternative explanations, consideration should be given to 
dosage reduction or treatment discontinuation. 
 
Fanconi syndrome 
Early diagnosis of Fanconi syndrome and discontinuation of Skilarence treatment are important to 
prevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. The 
most important signs are: proteinuria, glucosuria (with normal blood sugar levels), 
hyperaminoaciduria and phosphaturia (possibly concurrent with hypophosphatemia). Progression 
might involve symptoms such as polyuria, polydipsia and proximal muscle weakness. In rare cases 
hypophosphataemic osteomalacia with non-localised bone pain, elevated alkaline phosphatase in 
serum and stress fractures may occur. Importantly, Fanconi syndrome can occur without elevated 
creatinine levels or low glomerular filtration rate. In case of unclear symptoms Fanconi syndrome 
should be considered and appropriate examinations should be performed. 
 
Hepatic function 
Skilarence has not been studied in patients with severe hepatic impairment and is contraindicated in 
these patients (see section 4.3).  
 
It is recommended to monitor hepatic function (SGOT, SGPT, gamma-GT, AP) prior to initiation of 



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treatment and every 3 months thereafter, since elevation of hepatic enzymes has been observed in 
some patients in the Phase III study. In the event of a clinically relevant change in hepatic parameters, 
particularly in the absence of alternative explanations, consideration should be given to dose reduction 
or treatment discontinuation. 
 
Flushing 
Patients should be made aware that they are likely to experience flushing in the first few weeks of 
taking Skilarence (see section 4.8). 
 
Lactose 
Skilarence contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
Skilarence should be used cautiously in combination with other systemic antipsoriatic therapy (e.g. 
methotrexate, retinoids, psoralens, ciclosporin, immunosuppressants or cytostatics) (see section 4.4). 
During treatment with Skilarence, simultaneous use of other fumaric acid derivatives (topical or 
systemic) should be avoided. 
 
Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides, 
diuretics, NSAIDs or lithium) may increase the potential for renal adverse reactions (e.g. proteinuria) 
in patients taking Skilarence. 
 
In cases of severe or prolonged diarrhoea during treatment with Skilarence, absorption of other 
medicinal products may be affected. Caution should be exercised when prescribing medicinal products 
with a narrow therapeutic index that require absorption in the intestinal tract. The efficacy of oral 
contraceptives may be reduced and the use of an alternative barrier contraceptive method is 
recommended to prevent possible failure of contraception (see the prescribing information of the oral 
contraceptive). 
 
Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should 
be avoided because it may lead to increased dissolution rates of Skilarence and, therefore, may 
increase the frequency of gastrointestinal adverse reactions. 
 
Vaccination during treatment with Skilarence has not been studied. Immunosuppression is a risk factor 
for the use of live vaccines. The risk of vaccination should be weighed against the benefit. 
 
There is no evidence for Skilarence interaction with cytochrome P450 and the most common efflux 
and uptake transporters, thus no interactions are expected with medicinal products metabolised or 
transported by these systems (see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of child-bearing potential 
Skilarence is not recommended in women of child-bearing potential not using appropriate 
contraception. In patients experiencing diarrhoea during Skilarence treatment, the effect of oral 
contraceptives may be reduced and additional barrier methods of contraception may be necessary (see 
section 4.5). 
 
Pregnancy 
There are limited data from the use of dimethyl fumarate in pregnant women. Animal studies have 
shown reproductive toxicity (see section 5.3). Skilarence is contraindicated during pregnancy (see 
section 4.3). 
 



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Breast-feeding 
It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to 
newborns or infants cannot be excluded. Therefore, Skilarence is contraindicated during breast-
feeding (see section 4.3). 
 
Fertility 
There are no human or animal data on the effects of Skilarence on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the ability to drive and use machines have been conducted. Skilarence may have a minor 
influence on the ability to drive and use machines. Dizziness and fatigue may occur following 
administration of Skilarence (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most common adverse reactions observed with Skilarence in the Phase III clinical study (1102) in 
psoriasis patients were gastrointestinal events (62.7%), flushing (20.8%) and lymphopenia (10.0%). 
Most adverse reactions were considered mild and did not lead to discontinuation of study treatment. 
The only adverse reactions that led to discontinuation of treatment in >5% of patients were 
gastrointestinal reactions. For monitoring recommendations and clinical management of adverse 
reactions, see section 4.4. 
 
Tabulated list of adverse reactions 
The following is a list of adverse reactions experienced by patients treated with Skilarence during the 
clinical study and with Fumaderm, a related medicinal product containing dimethyl fumarate along 
with other fumaric acid esters. 
 
The frequency of adverse reactions is defined using the following convention: 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); very rare 
(<1/10,000); and not known (cannot be estimated from available data). 
 
System organ class Adverse reactions Frequency 
Infections and infestations Herpes zoster Not known** 
Blood and lymphatic system 
disorders 

Lymphopenia 
Leukopenia 
Eosinophilia 
Leukocytosis 
Acute lymphatic leukaemia* 
Irreversible pancytopenia* 

Very common 
Very common 
Common 
Common 
Very rare 
Very rare 

Metabolism and nutrition 
disorders 

Decreased appetite Common 

Nervous system disorders Headache 

Paraesthesia 
Dizziness* 
Progressive multifocal leukoencephalopathy 

Common 
Common 
Uncommon 
Not known 

Vascular disorders Flushing Very common 
Gastrointestinal disorders Diarrhoea 

Abdominal distension 
Abdominal pain 
Nausea 
Vomiting 
Dyspepsia 
Constipation 

Very common 
Very common 
Very common 
Very common 
Common 
Common 
Common 



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System organ class Adverse reactions Frequency 
Abdominal discomfort 
Flatulence 

Common 
Common 

Skin and subcutaneous tissue 
disorders 

Erythema 
Skin burning sensation 
Pruritus 
Allergic skin reaction 

Common 
Common 
Common 
Rare 

Renal and urinary disorders Proteinuria 
Renal failure 
Fanconi syndrome* 

Uncommon 
Not known 
Not known 

General disorders and 
administration site conditions  

Fatigue 
Feeling hot 
Asthenia 

Common 
Common 
Common 

Investigations Hepatic enzymes increased 
Serum creatinine increased 

Common 
Uncommon 

*Additional adverse reactions reported with Fumaderm, a related medicinal product containing dimethyl fumarate along with 
other fumaric acid esters. 
**Adverse reactions reported during post marketing experience. 
 
Description of selected adverse reactions 
Gastrointestinal disturbances 
Data from the Phase III clinical study as well as from the literature show that gastrointestinal disorders 
with dimethyl fumarate-containing products are most likely to occur during the first 2 to 3 months 
after starting treatment. No apparent dose relationship and no risk factors for the occurrence of these 
adverse reactions could be identified. Diarrhoea was a common adverse reaction (36.9%) among 
patients taking Skilarence, leading to medicinal product withdrawal in about 10% of patients. More 
than 90% of these diarrhoea events were of mild to moderate severity (see section 4.4). 
 
Flushing 
Based on observations in the Phase III clinical study as well as on literature data, flushing is most 
likely to occur during the early weeks of treatment and tends to lessen with time. In the clinical study a 
total of 20.8% of patients receiving Skilarence experienced flushing, which was mild in the majority 
of cases (see section 4.4). Published clinical experience with dimethyl fumarate-containing products 
shows that individual episodes of flushing usually begin shortly after taking the tablets and resolve 
within a few hours. 
 
Haematological changes 
Data from the Phase III clinical study as well as from the literature show that changes in 
haematological parameters are most likely to occur during the first 3 months after starting treatment 
with dimethyl fumarate. In particular, in the clinical study there was a slight decrease in mean 
lymphocyte counts starting between weeks 3 and 5 and reaching a maximum in week 12 where 
approximately one third of patients had lymphocyte values below 1.0x109/L. The mean and median 
values of lymphocytes remained within the normal range during the clinical study. At week 16 (end of 
treatment), there was no further decline in lymphocyte counts. At week 16 of treatment, 13/175 (7.4%) 
of patients were noted to have lymphocyte levels <0.7x 109/L. Blood sampling for safety clinical 
laboratory tests at follow-up visits was only performed in case of abnormalities at the preceeding visit. 
During the treatment free follow up, lymphocyte levels of <0.7x 109/L were observed in 1/29 (3.5%) 
patient at 6 months and 0/28 (0%) at 12 months after stopping treatment. At 12 months after stopping 
treatment 3/28 (10.7%) of patients had lymphocyte values below 1.0x109/L, which would represent 
3/279 (1.1%) of the patients started on Skilarence. 
 
For the total leukocyte count, a decline became apparent at week 12 of treatment; it slowly increased 
again at week 16 (end of treatment); and 12 months after stopping treatment all patients had values 
above 3.0x109/L. 
 
A transient increase in mean values of eosinophils was noted as early as week 3, reached a maximum 



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at week 5 and 8, and had returned to baseline values at week 16.  
 
For monitoring recommendations and clinical management of haematological adverse reactions, see 
section 4.4. 
 
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 
 
Symptomatic treatment is indicated in the case of an overdose. No specific antidote is known. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other immunosuppressants, ATC code: L04AX07 
 
Mechanism of action 
The anti-inflammatory and immunomodulating effects of dimethyl fumarate and its metabolite 
monomethyl fumarate are not fully elucidated but are thought to be mainly due to the interaction with 
the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. This 
interaction with glutathione leads to the inhibition of translocation into the nucleus and the 
transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). 
 
The main activity of dimethyl fumarate and monomethyl fumarate is considered to be 
immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 
phenotype. The inflammatory cytokine production is reduced with induction of proapoptotic events, 
inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminished 
inflammatory infiltrate within psoriatic plaques. 
 
Clinical efficacy and safety 
The safety and efficacy of Skilarence was assessed in one double-blind, 3-arm, placebo- and active 
comparator-controlled Phase III study (1102) in patients with moderate to severe plaque psoriasis 
(Study 1102). 704 patients were randomised to receive Skilarence, an active comparator (Fumaderm, a 
combination product with the same content of dimethyl fumarate plus 3 monoethyl fumarate salts) and 
placebo in a ratio of 2:2:1. Patients began treatment with tablets containing 30 mg/day dimethyl 
fumarate or placebo, titrating up to a maximum of 720 mg/day in both active treatment arms as 
described in section 4.2. If treatment success was observed before the maximum dose of 720 mg/day 
of dimethyl fumarate was reached, no further increase of dosage was necessary and the dosage was to 
be steadily reduced to an individual maintenance dose. In case of individual intolerability of the 
increased dosage during weeks 4 to 16, the patient was to return to the last tolerated dose taken since 
the start of week 4, which was to be maintained until end of the treatment period (week 16). Patients 
received treatment for up to 16 weeks and follow-up visits were planned for up to 12 months after 
treatment was stopped. 
 
The demographic and baseline characteristics were well balanced between the treatment groups. Of 
the 699 patients, most were Caucasian (99%) and male (65%), and the mean age was 44 years. Most 
patients (91%) were <65 years of age. Most patients had moderate psoriasis based on Psoriasis Area 
and Severity Index (PASI) and Physician’s Global Assessment (PGA) scores at baseline: the mean 
PASI score at baseline was 16.35 and 60% of patients scored as moderate on the PGA. The majority of 
patients reported a “very large” or “extremely large” effect of psoriasis on their life based on the 
Dermatology Life Quality Index (DLQI), with a mean DLQI score of 11.5. 



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After 16 weeks of treatment, Skilarence was found to be superior to placebo (p<0.0001) based on 
PASI 75 and PGA score clear or almost clear and non-inferior (using a non-inferiority margin 
of -15%) to the active comparator (p<0.0003) based on PASI 75.  
 
Summary of clinical efficacy after 16 weeks treatment in Study 1102 
Assessment Skilarence Placebo Fumaderm 
 N=267 N=131 N=273 
Superiority testing vs placebo 
PASI 75, n (%) 100 (37.5) 20 (15.3) 110 (40.3) 

p-value <0.0001a <0.0001a 

Two-sided 99.24% CI 10.7, 33.7a 13.5, 36.6a 
PGA score clear or almost clear, n (%) 88 (33.0) 17 (13.0) 102 (37.4) 

p-value <0.0001a <0.0001a 
Two-sided 99.24% CI 9.0, 31.0 a 13.3, 35.5 a 

 Skilarence Fumaderm 
 N=267 N=273 
Non-inferiority of Skilarence vs. Fumaderm   
PASI 75, n (%) 100 (37.5) 110 (40.3) 

p-value 0.0003b 
One-sided 97.5% repeated CI (lower limit) -11.6b 

PGA score clear or almost clear, n (%) 88 (33.0) 102 (37.4) 
p-value 0.0007b 
One-sided 97.5% repeated CI (lower limit) -13.0b 

Fumaderm = Active comparator, a combination product with the same content of dimethyl fumarate plus 3 monoethyl 
hydrogen fumarate salts; n=number of patients with available data; N=number of patients in population; PASI=Psoriasis 
Area Severity Index; PGA=Physician’s Global Assessment; a Superiority of Skilarence vs. Placebo with a difference of 
22.2% for PASI 75 and 20.0% for PGA score clear or almost clear, superiority of Fumaderm vs Placebo with a difference of 
25.0% for PASI 75 and 24.4% for PGA score clear or almost clear; b Non-inferiority of Skilarence vs. Fumaderm with a 
difference of -2.8% for PASI 75 and -4.4% for PGA score clear or almost clear. 
 
There was a trend in the efficacy endpoint PASI score mean % change from baseline, indicating the 
onset of a clinical response to Skilarence as early as week 3 (-11.8%) which became statistically 
significant compared to placebo by week 8 (-30.9%). Further improvement was seen by week 16 
(-50.8%). 
 
The benefits of treatment with Skilarence were also supported by patient self-perceived improvements 
in their quality of life. At week 16, patients treated with Skilarence had a lower mean DLQI compared 
to placebo (5.4 vs 8.8).  
 
Rebound (defined as worsening of ≥125% of baseline PASI value) was assessed after 2 months off 
treatment and was shown not to be a clinical concern with fumaric acid esters, as it was documented in 
very few patients (Skilarence 1.1% and active comparator 2.2%, compared to 9.3% in the placebo 
group).  
 
Long-term efficacy data are currently not available for Skilarence, however, in the pharmacokinetic 
and clinical studies the systemic exposure, efficacy and safety of Skilarence were shown to be 
comparable to the active comparator containing dimethyl fumarate. Hence it is reasonable to expect 
the long-term efficacy of Skilarence to also be comparable to dimethyl fumarate-containing products. 
Maintenance of long term efficacy has been well described for other dimethyl fumarate-containing 
products, and therefore the treatment benefits seen with Skilarence at 16 weeks can be expected to be 
maintained in patients treated over the long term for at least 24 months. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 



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Skilarence in all subsets of the paediatric population in this indication (see section 4.2 for information 
on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
After oral administration, dimethyl fumarate is not detected in plasma because it is rapidly hydrolysed 
by esterases to its active metabolite monomethyl fumarate. After oral administration of a single 
Skilarence 120 mg tablet in healthy subjects, monomethyl fumarate reached plasma peak 
concentrations of around 1325 ng/mL and 1311 ng/mL under fasted or fed conditions, respectively. 
Taking Skilarence with food delayed the tmax of monomethyl fumarate from 3.5 to 9.0 hours. 
 
Distribution 
The plasma protein binding of monomethyl fumarate is around 50%. Dimethyl fumarate does not 
show any binding affinity to serum proteins which may further contribute to its rapid elimination from 
the circulation. 
 
Biotransformation 
The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes. In vitro 
studies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any of 
the cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not an 
inhibitor of the most common efflux and uptake transporters. In vitro studies have shown that dimethyl 
fumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoprotein 
inhibitor. 
 
In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occurs 
rapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach). A part of the total 
dimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while the 
remainder enters the portal vein blood. Further studies have shown that dimethyl fumarate (and to a 
lesser extent monomethyl fumarate) reacts partially with reduced glutathione forming a glutathione-
adduct. These adducts were detected in animal studies in the intestinal mucosa of rats and to a smaller 
extent in portal vein blood. Unconjugated dimethyl fumarate, however, cannot be detected in the 
plasma of animals or psoriatic patients following oral administration. By contrast, unconjugated 
monomethyl fumarate is detectable in plasma. Further metabolism occurs through oxidation via the 
tricarboxylic acid cycle forming carbon dioxide and water. 
 
Elimination 
Exhalation of CO2 resulting from the metabolism of monomethyl fumarate is the primary route of 
elimination; only small amounts of intact monomethyl fumarate are excreted through urine or faeces. 
The portion of dimethyl fumarate that reacts with glutathione, forming a glutathione-adduct, is 
metabolised further to its mercapturic acid, which is excreted in the urine. 
 
The apparent terminal elimination half-life of monomethyl fumarate is about 2 hours. 
 
Linearity/non-linearity 
Despite the high inter-subject variability, the exposure measured as AUC and Cmax was generally 
dose-proportional after single dose administration of 4 x 30 mg dimethyl fumarate tablets (total dose 
of 120 mg) and 2 x 120 mg dimethyl fumarate tablets (total dose of 240 mg). 
 
Renal impairment 
No specific studies have been performed in patients with renal impairment. However, because renal 
elimination plays a minor role in the total clearance from plasma, it is unlikely that renal impairment 
may affect the pharmacokinetic characteristics of Skilarence (see section 4.2). 
 
Hepatic impairment 
No specific studies have been performed in patients with hepatic impairment. However, as dimethyl 
fumarate is metabolised by esterases and the alkaline milieu of the small intestine without the 



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involvement of cytochrome P450, hepatic impairment is not expected to influence exposure (see 
section 4.2). 
 
5.3 Preclinical safety data 
 
Non-clinical safety pharmacology and genotoxicity data reveal no special hazard for humans. 
 
Toxicology 
The kidney was identified as a major target organ of toxicity in non-clinical studies. Renal findings in 
dogs included minimal to moderate tubular hypertrophy, increased incidence and severity of tubular 
vacuolation and minimal to slight tubular degeneration, which were considered toxicologically 
relevant. The no-observed adverse-effect-level (NOAEL) after 3 months of treatment was 
30 mg/kg/day, which corresponds to 2.9-fold and 9.5-fold the human systemic exposure at the highest 
recommended dose (720 mg/day), as AUC and Cmax values, respectively. 
 
Reproduction toxicity 
No fertility or pre- and post-natal development studies have been conducted with Skilarence. 
 
There were no effects on foetal body weights or malformations attributed to maternal administration of 
dimethyl fumarate during the embryo-foetal development study in rats. However, there was an 
increased number of foetuses with the variations “supernumerary liver lobe” and “abnormal iliac 
alignment” at maternally toxic doses. The NOAEL for maternal and embryo-foetal toxicity was 
40 mg/kg/day, corresponding to 0.2-fold and 2.0-fold the human systemic exposure at the highest 
recommended dose (720 mg/day), as AUC and Cmax values, respectively. 
 
Dimethyl fumarate has been shown to cross the placental membrane into foetal blood in rats. 
 
Carcinogenicity 
No carcinogenicity studies have been performed for Skilarence. Based on available data suggesting 
that fumaric acid esters may activate cellular pathways related to the development of renal tumours, a 
potential tumorigenic activity of exogenously administered dimethyl fumarate on the kidneys cannot 
be excluded.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Skilarence 30 mg and Skilarence 120 mg 
Core: 
Lactose monohydrate 
Cellulose microcrystalline 
Croscarmellose sodium 
Colloidal anhydrous silica 
Magnesium stearate 
 
Skilarence 30 mg 
Coating: 
Methacrylic acid-ethyl acrylate copolymer (1:1) 
Talc 
Triethyl citrate 
Titanium dioxide (E171) 
Simethicone 
 



13 

Skilarence 120 mg 
Coating: 
Methacrylic acid-ethyl acrylate copolymer (1:1) 
Talc 
Triethyl citrate 
Titanium dioxide (E171) 
Simethicone 
Indigo carmine (E132) 
Sodium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Skilarence 30 mg 
42, 70 and 210 gastro-resistant tablets in PVC/PVDC-aluminium blister packs. 
 
Skilarence 120 mg 
40, 70, 90, 100, 120, 180, 200, 240, 300, 360 and 400 gastro-resistant tablets in 
PVC/PVDC-aluminium blister packs. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Almirall, S.A. 
Ronda General Mitre, 151 
08022 Barcelona 
Spain 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/17/1201/001 
EU/1/17/1201/002 
EU/1/17/1201/003 
EU/1/17/1201/004 
EU/1/17/1201/005 
EU/1/17/1201/006 
EU/1/17/1201/007 
EU/1/17/1201/008 
EU/1/17/1201/009 



14 

EU/1/17/1201/010 
EU/1/17/1201/011 
EU/1/17/1201/012 
EU/1/17/1201/013 
EU/1/17/1201/014 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 june 2017 
 
 
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. 
 



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 

 
 



16 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Industrias Farmaceuticas Almirall, S.A. 
Ctra. Nacional II, Km. 593, Sant Andreu de la Barca, Barcelona,  
08740, Spain 
 
 
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  
 
The requirements for submission of periodic safety update reports 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. 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The 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.  

 
 
• Additional risk minimisation measures 
 
Prior to launch of Skilarence in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
 
The objectives of the educational programme are to inform health care professionals about the risk of 
serious infections, mainly opportunistic infections such as progressive multifocal leukoencephalopathy 
(PML), and to provide guidance on the monitoring of lymphocyte and leukocyte count abnormalities. 
 
The MAH shall ensure that in each Member State where Skilarence is marketed, healthcare 
professionals who are expected to prescribe and dispense Skilarence have access to the following 



17 

educational package.  
 

• The guide for healthcare professionals shall contain the following key elements: 
o Relevant information on PML (e.g. seriousness, severity, frequency, time to onset, 

reversibility of the AE as applicable) 
o Details of the population at higher risk for PML  
o Details on how to minimise the risk of PML through appropriate monitoring and 

management, including laboratory monitoring of lymphocyte and leukocyte prior to and 
during treatment, and criteria for treatment discontinuation  

o Key messages to convey in counselling of patients 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



20 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON - SKILARENCE 30 mg GASTRO RESISTANT TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Skilarence 30 mg gastro-resistant tablets 
dimethyl fumarate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each tablet contains 30 mg dimethyl fumarate. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
42 gastro-resistant tablets 
70 gastro-resistant tablets 
210 gastro-resistant tablets 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Do not crush, break, dissolve or chew the tablet. 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



21 

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 
 
Almirall, S.A. 
Ronda General Mitre, 151 
08022 Barcelona 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/17/1201/001 42 tablets 
EU/1/17/1201/013 70 tablets 
EU/1/17/1201/014 210 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Skilarence 30 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



22 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL - SKILARENCE 30 mg GASTRO RESISTANT TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Skilarence 30 mg gastro-resistant tablets 
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Almirall 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



23 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON - SKILARENCE 120 mg GASTRO RESISTANT TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Skilarence 120 mg gastro-resistant tablets 
dimethyl fumarate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each tablet contains 120 mg dimethyl fumarate. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
40 gastro-resistant tablets 
70 gastro-resistant tablets 
90 gastro-resistant tablets 
100 gastro-resistant tablets 
120 gastro-resistant tablets 
180 gastro-resistant tablets 
200 gastro-resistant tablets 
240 gastro-resistant tablets 
300 gastro-resistant tablets 
360 gastro-resistant tablets 
400 gastro-resistant tablets 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Do not crush, break, dissolve or chew the tablet. 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
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 
 
 



24 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Almirall, S.A. 
Ronda General Mitre, 151 
08022 Barcelona 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/17/1201/002 40 tablets 
EU/1/17/1201/003 70 tablets 
EU/1/17/1201/004 90 tablets 
EU/1/17/1201/005 100 tablets 
EU/1/17/1201/006 120 tablets 
EU/1/17/1201/007 180 tablets 
EU/1/17/1201/008 200 tablets 
EU/1/17/1201/009 240 tablets 
EU/1/17/1201/012 300 tablets 
EU/1/17/1201/010 360 tablets 
EU/1/17/1201/011 400 tablets 

 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Skilarence 120 mg 
 
 



25 

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



26 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL - SKILARENCE 120 mg GASTRO RESISTANT TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Skilarence 120 mg gastro-resistant tablets 
dimethyl fumarate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Almirall 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

 
Package leaflet: Information for the patient 

 
Skilarence 30 mg gastro-resistant tablets 

dimethyl fumarate 
 
 
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 or pharmacist. 
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Skilarence is and what it is used for 
2. What you need to know before you take Skilarence 
3. How to take Skilarence 
4. Possible side effects 
5. How to store Skilarence 
6. Contents of the pack and other information 
 
 
1. What Skilarence is and what it is used for 
 
What Skilarence is 
Skilarence is a medicine that contains the active substance dimethyl fumarate. Dimethyl fumarate 
works on cells of the immune system (the body's natural defences). It changes the activity of the 
immune system and reduces the production of substances involved in causing psoriasis. 
 
What Skilarence is used for 
Skilarence tablets are used to treat moderate to severe plaque psoriasis in adults. Psoriasis is a disease 
causing thickened, inflamed, red areas on the skin, often covered by silvery scales. 
 
Response to Skilarence can be generally seen as early as week 3 and improves over time. Experience 
with related products containing dimethyl fumarate shows treatment benefit for at least up to 
24 months. 
 
 
2. What you need to know before you take Skilarence 
 
Do not take Skilarence 
- if you are allergic to dimethyl fumarate or any of the other ingredients of this medicine (listed in 

section 6) 
- if you have severe problems with your stomach or intestines 
- if you have severe liver or kidney problems 
- if you are pregnant or breast-feeding 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Skilarence. 
 
Monitoring 
Skilarence may cause problems with your blood, liver or kidneys. You will have blood and urine tests 
before treatment and then regularly during your treatment to make sure that you are not getting these 



29 

complications and can continue to take this medicine. Depending on the results of these blood and 
urine tests, your doctor may reduce your dose of Skilarence or stop treatment. 
 
Infections 
White blood cells help your body to fight infections. Skilarence may reduce the number of your white 
blood cells. Talk to your doctor if you think you may have an infection. Symptoms include fever, pain, 
aching muscles, headache, loss of appetite and a general feeling of weakness. If you have a serious 
infection, either before starting treatment with Skilarence or during treatment, your doctor may advise 
you not to take Skilarence until the infection has resolved. 
 
Gastrointestinal disorders 
Tell your doctor if you have or have had problems with your stomach or intestines. Your doctor will 
advise you on what care you need to take during Skilarence treatment. 
 
Children and adolescents 
Children and adolescents below the age of 18 years should not take this medicine because it has not 
been studied in this age group. 
 
Other medicines and Skilarence 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
In particular, tell your doctor if you are taking the following: 
 
- Dimethyl fumarate or other fumarates. The active ingredient in Skilarence, dimethyl 

fumarate, is also used in other medicines such as tablets, ointments and baths. You must avoid 
using other products that contain fumarates to prevent taking too much. 

- Other medicines used to treat psoriasis, such as methotrexate, retinoids, psoralens, 
ciclosporin, or other immunosuppressants or cytostatics (medicines that affect the immune 
system). Taking these medicines with Skilarence could increase the risk of side effects on your 
immune system. 

- Other medicines that can affect your kidney function, such as methotrexate or ciclosporin 
(used to treat psoriasis), aminoglycosides (used to treat infections), diuretics (which increase 
urine), nonsteroidal anti-inflammatory drugs (used to treat pain) or lithium (used for bipolar 
disease and depression). These medicines taken together with Skilarence could increase the risk 
of side effects on your kidneys. 

 
If you get severe or prolonged diarrhoea with Skilarence, other medicines may not work as well as 
they should. Talk to your doctor if you have bad diarrhoea and are concerned that other medicines you 
are taking might not work. In particular, if you are taking a contraceptive medicine (the pill), the effect 
may be reduced and you may need to use other barrier methods to prevent pregnancy. See the 
instructions in the patient leaflet of the contraceptive you are taking. 
 
If you need a vaccination, talk to your doctor. Certain types of vaccines (live vaccines) may cause 
infection if used during treatment with Skilarence. Your doctor can advise you what would be best. 
 
Skilarence with alcohol 
Avoid strong alcoholic drinks (more than 50 ml of spirits containing more than 30% alcohol by 
volume) during treatment with Skilarence, as alcohol can interact with this medicine. This could cause 
stomach and intestinal problems. 
 
Pregnancy and breast-feeding 
Do not take Skilarence if you are pregnant or trying to become pregnant, as Skilarence may harm your 
baby. Use effective methods of contraception to avoid becoming pregnant during treatment with 
Skilarence (see also “Other medicines and Skilarence” above). 
Do not breast-feed during treatment with Skilarence. 
 



30 

Driving and using machines 
Skilarence may have a minor influence on the ability to drive and use machines. You may feel dizzy or 
tired after taking Skilarence. If you are affected, be careful when driving or using machines. 
 
Skilarence contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product. 
 
Skilarence contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Skilarence 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Dose 
Your doctor will start your treatment with a low dose (using 30 mg Skilarence tablets). This helps to 
reduce stomach problems and other side effects. Your dose will be increased every week as shown in 
the table below (switching to 120 mg Skilarence tablets from week 4 onwards). 
 

Treatment 
week 

Tablet 
strength 

How many tablets to take during the day  Number of 
tablets per day 

Total daily 
dose Breakfast Lunch Evening meal 

1 30 mg ‒ ‒ 1 1 30 mg 

2 30 mg 1 ‒ 1 2 60 mg 

3 30 mg 1 1 1 3 90 mg 

4 120 mg ‒ ‒ 1 1 120 mg 

5 120 mg 1 ‒ 1 2 240 mg 

6 120 mg 1 1 1 3 360 mg 

7 120 mg 1 1 2 4 480 mg 

8 120 mg 2 1 2 5 600 mg 

9+ 120 mg 2 2 2 6 720 mg 
 
Your doctor will check how well your condition is improving after you start taking Skilarence and will 
check for side effects. If you have severe side effects after an increase in dose, your doctor may 
recommend that you temporarily go back to the last dose. If the side effects are not troublesome, your 
dose will be increased until your condition is well controlled. You may not need the maximum dose of 
720 mg per day. After your condition has improved sufficiently, your doctor will consider how to 
gradually reduce the daily dose of Skilarence to what you need to maintain your improvement. 
 
Method of administration 
Swallow Skilarence tablets whole with liquid. Take your tablets during or immediately after a meal. 
Do not crush, break, dissolve or chew your tablets, as they have a special coating to help prevent 
irritation of your stomach. 
 



31 

If you take more Skilarence than you should 
If you think you have taken too many Skilarence tablets, talk to your doctor or pharmacist. 
 
If you forget to take Skilarence 
Do not take a double dose to make up for a forgotten dose. Take the next dose at the usual time and 
continue taking the medicine exactly as described in this leaflet or exactly as agreed with your doctor. 
Please ask your doctor or pharmacist if you are not sure. 
 
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. Some of 
these side effects, such as reddening of the face or body (flushing), diarrhoea, stomach problems and 
nausea usually improve as you continue treatment. 
 
The most serious side effects that may occur with Skilarence are allergic or hypersensitivity reactions; 
kidney failure or a kidney disease called Fanconi syndrome; or a severe brain infection called 
progressive multifocal leukoencephalopathy (PML). It is not known how commonly they occur. For 
symptoms see below. 
 
Allergic or hypersensitivity reactions 
Allergic or hypersensitivity reactions are rare but may be very serious. Reddening of the face or body 
(flushing) is a very common side effect which may affect more than 1 in 10 people. However, if you 
become flushed and get any of the following signs:  
- wheezing, difficulty breathing or shortness of breath, 
- swelling of the face, lips, mouth or tongue  
stop taking Skilarence and call a doctor straight away. 
 
Brain infection called PML 
Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection that can lead to 
severe disability or death. If you notice new or worsening weakness on one side of the body; 
clumsiness; changes in vision, thinking or memory; confusion; or personality changes lasting several 
days, stop taking Skilarence and talk to your doctor straight away. 
 
Fanconi syndrome 
Fanconi syndrome is a rare but serious kidney disorder which may occur with Skilarence. If you notice 
you are passing more urine, are more thirsty and drinking more than normal, your muscles seem 
weaker, you break a bone, or just have aches and pains, talk to your doctor as soon as possible so that 
this can be investigated further. 
 
Talk to your doctor if you get any of the following side effects. 
 
Very common side effects (may affect more than 1 in 10 people): 
- decrease in white blood cells called lymphocytes (lymphopenia) 
- decrease in all white blood cells (leukopenia) 
- reddening of the face or body (flushing) 
- diarrhoea 
- bloating, stomach pain or stomach cramps 
- feeling sick (nausea) 
 
Common side effects (may affect up to 1 in 10 people): 
- increase in all white blood cells (leukocytosis) 
- increase in specific white blood cells called eosinophils 
- increase in certain enzymes in the blood (used for checking the health of your liver) 
- being sick  



32 

- constipation 
- gas (flatulence), stomach discomfort, indigestion 
- decreased appetite 
- headache 
- feeling tired 
- weakness 
- feeling hot 
- abnormal sensations of the skin, such as itching, burning, stinging, tickling or tingling 
- pink or red blotches on the skin (erythema) 
 
Uncommon side effects (may affect up to 1 in 100 people): 
- dizziness 
- excess protein in the urine (proteinuria) 
- increase in serum creatinine (a substance in the blood used for measuring how well your 

kidneys are working) 
 
Rare side effects (may affect up to 1 in 1,000 people): 
- allergic skin reaction 
 
Very rare side effects (may affect up to 1 in 10,000 people): 
- acute lymphatic leukaemia (a type of blood cancer) 
- decrease in all types of blood cells (pancytopenia) 
 
Frequency not known (frequency cannot be estimated from the available data): 
- shingles 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. 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 Skilarence 
 
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 carton and the blister after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
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 Skilarence 30 mg contains 
- the active substance is dimethyl fumarate. One tablet contains 30 mg dimethyl fumarate. 
- the other ingredients are: lactose monohydrate, cellulose microcrystalline, croscarmellose 

sodium, colloidal anhydrous silica, magnesium stearate, methacrylic acid-ethyl acrylate 
copolymer (1:1), talc, triethyl citrate, titanium dioxide (E171) and simethicone. 

 
What Skilarence 30 mg looks like and contents of the pack 
Skilarence 30 mg is a white, round tablet with a diameter of approximately 6.8 mm. 
Skilarence 30 mg is available in packs containing 42, 70 and 210 gastro-resistant tablets. Not all pack 



33 

sizes may be marketed. The tablets are packed in PVC/PVDC-aluminium blisters. 
 
Marketing Authorisation Holder 
Almirall, S.A. 
Ronda General Mitre, 151 
E-08022 Barcelona 
Spain 
Tel. +34 93 291 30 00 
 
Manufacturer 
Industrias Farmacéuticas Almirall, S.A. 
Ctr. Nacional II, Km. 593 
E-08740 Sant Andreu de la Barca, Barcelona 
Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/ Luxembourg/Luxemburg 
Almirall N.V., Tél/Tel: +32 (0)2 771 86 37 
 
България/ Česká republika/ Eesti/ España/ Hrvatska/ Κύπρος/ Latvija/ Lietuva/ Magyarország/ 
Malta/ România/ Slovenija/ Slovenská republika 
Almirall, S.A., Teл./ Tel/ Τηλ: +34 93 291 30 00 
Tel (Česká republika / Slovenská republika): +420 220 990 139 
 
Danmark/ Norge/ Suomi/Finland/ Sverige 
Almirall ApS, Tlf/ Puh/Tel: +45 70 25 75 75 
 
Deutschland 
Almirall Hermal GmbH, Tel.: +49 (0)40 72704-0 
 
Ελλάδα 
Galenica A.E., Tηλ: +30 210 52 81 700 
 
France 
Almirall SAS, Tél.: +33(0)1 46 46 19 20 
 
Ireland 
Almirall Limited, Tel: +353 (0) 1431 9836 
 
Ísland 
Vistor hf., Sími: +354 535 70 00 
 
Italia 
Almirall SpA, Tel.: +39 02 346181 
 
Nederland 
Almirall B.V., Tel: +31 (0)30 799 1155 
 
Österreich 
Almirall GmbH, Tel.: +43 (0)1/595 39 60 
 
Polska 
Almirall Sp.z o. o., Tel.: +48 22 330 02 57 
 



34 

Portugal 
Almirall - Produtos Farmacêuticos, Lda., Tel.: +351 21 415 57 50 
 
United Kingdom 
Almirall Limited, Tel: +44 (0) 800 0087 399 
 
This leaflet was last revised in . 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 



35 

 
Package leaflet: Information for the patient 

 
Skilarence 120 mg gastro-resistant tablets 

dimethyl fumarate 
 
 
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 or pharmacist. 
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Skilarence is and what it is used for 
2. What you need to know before you take Skilarence 
3. How to take Skilarence 
4. Possible side effects 
5. How to store Skilarence 
6. Contents of the pack and other information 
 
 
1. What Skilarence is and what it is used for 
 
What Skilarence is 
Skilarence is a medicine that contains the active substance dimethyl fumarate. Dimethyl fumarate 
works on cells of the immune system (the body's natural defences). It changes the activity of the 
immune system and reduces the production of substances involved in causing psoriasis. 
 
What Skilarence is used for 
Skilarence tablets are used to treat moderate to severe plaque psoriasis in adults. Psoriasis is a disease 
causing thickened, inflamed, red areas on the skin, often covered by silvery scales. 
 
Response to Skilarence can be generally seen as early as week 3 and improves over time. Experience 
with related products containing dimethyl fumarate shows treatment benefit for at least up to 
24 months. 
 
 
2. What you need to know before you take Skilarence 
 
Do not take Skilarence 
- if you are allergic to dimethyl fumarate or any of the other ingredients of this medicine (listed in 

section 6) 
- if you have severe problems with your stomach or intestines  
- if you have severe liver or kidney problems 
- if you are pregnant or breast-feeding 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Skilarence. 
 
Monitoring 
Skilarence may cause problems with your blood, liver or kidneys. You will have blood and urine tests 
before treatment and then regularly during your treatment to make sure that you are not getting these 



36 

complications and can continue to take this medicine. Depending on the results of these blood and 
urine tests, your doctor may reduce your dose of Skilarence or stop treatment. 
 
Infections 
White blood cells help your body to fight infections. Skilarence may reduce the number of your white 
blood cells. Talk to your doctor if you think you may have an infection. Symptoms include fever, pain, 
aching muscles, headache, loss of appetite and a general feeling of weakness. If you have a serious 
infection, either before starting treatment with Skilarence or during treatment, your doctor may advise 
you not to take Skilarence until the infection has resolved.  
 
Gastrointestinal disorders 
Tell your doctor if you have or have had problems with your stomach or intestines. Your doctor will 
advise you on what care you need to take during Skilarence treatment. 
 
Children and adolescents 
Children and adolescents below the age of 18 years should not take this medicine because it has not 
been studied in this age group. 
 
Other medicines and Skilarence 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
In particular, tell your doctor if you are taking the following: 
 
- Dimethyl fumarate or other fumarates. The active ingredient in Skilarence, dimethyl 

fumarate, is also used in other medicines such as tablets, ointments and baths. You must avoid 
using other products that contain fumarates to prevent taking too much. 

- Other medicines used to treat psoriasis, such as methotrexate, retinoids, psoralens, 
ciclosporin, or other immunosuppressants or cytostatics (medicines that affect the immune 
system). Taking these medicines with Skilarence could increase the risk of side effects on your 
immune system. 

- Other medicines that can affect your kidney function, such as methotrexate or ciclosporin 
(used to treat psoriasis), aminoglycosides (used to treat infections), diuretics (which increase 
urine), nonsteroidal anti-inflammatory drugs (used to treat pain) or lithium (used for bipolar 
disease and depression). These medicines taken together with Skilarence could increase the risk 
of side effects on your kidneys. 

 
If you get severe or prolonged diarrhoea with Skilarence, other medicines may not work as well as 
they should. Talk to your doctor if you have bad diarrhoea and are concerned that other medicines you 
are taking might not work. In particular, if you are taking a contraceptive medicine (the pill), the effect 
may be reduced and you may need to use other barrier methods to prevent pregnancy. See the 
instructions in the patient leaflet of the contraceptive you are taking. 
 
If you need a vaccination, talk to your doctor. Certain types of vaccines (live vaccines) may cause 
infection if used during treatment with Skilarence. Your doctor can advise you what would be best. 
 
Skilarence with alcohol 
Avoid strong alcoholic drinks (more than 50 ml of spirits containing more than 30% alcohol by 
volume) during treatment with Skilarence, as alcohol can interact with this medicine. This could cause 
stomach and intestinal problems. 
 
Pregnancy and breast-feeding 
Do not take Skilarence if you are pregnant or trying to become pregnant, as Skilarence may harm your 
baby. Use effective methods of contraception to avoid becoming pregnant during treatment with 
Skilarence (see also “Other medicines and Skilarence” above). 
Do not breast-feed during treatment with Skilarence. 
 



37 

Driving and using machines 
Skilarence may have a minor influence on the ability to drive and use machines. You may feel dizzy or 
tired after taking Skilarence. If you are affected, be careful when driving or using machines. 
 
Skilarence contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product. 
 
Skilarence contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Skilarence 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Dose 
Your doctor will start your treatment with a low dose (using 30 mg Skilarence tablets). This helps to 
reduce stomach problems and other side effects. Your dose will be increased every week as shown in 
the table below (switching to 120 mg Skilarence tablets from week 4 onwards). 
 

Treatment 
week 

Tablet 
strength 

How many tablets to take during the day  Number of 
tablets per day 

Total daily 
dose Breakfast Lunch Evening meal 

1 30 mg ‒ ‒ 1 1 30 mg 

2 30 mg 1 ‒ 1 2 60 mg 

3 30 mg 1 1 1 3 90 mg 

4 120 mg ‒ ‒ 1 1 120 mg 

5 120 mg 1 ‒ 1 2 240 mg 

6 120 mg 1 1 1 3 360 mg 

7 120 mg 1 1 2 4 480 mg 

8 120 mg 2 1 2 5 600 mg 

9+ 120 mg 2 2 2 6 720 mg 
 
Your doctor will check how well your condition is improving after you start taking Skilarence and will 
check for side effects. If you have severe side effects after an increase in dose, your doctor may 
recommend that you temporarily go back to the last dose. If the side effects are not troublesome, your 
dose will be increased until your condition is well controlled. You may not need the maximum dose of 
720 mg per day. After your condition has improved sufficiently, your doctor will consider how to 
gradually reduce the daily dose of Skilarence to what you need to maintain your improvement. 
 
Method of administration 
Swallow Skilarence tablets whole with liquid. Take your tablets during or immediately after a meal. 
Do not crush, break, dissolve or chew your tablets, as they have a special coating to help prevent 
irritation of your stomach. 
 



38 

If you take more Skilarence than you should 
If you think you have taken too many Skilarence tablets, talk to your doctor or pharmacist. 
 
If you forget to take Skilarence 
Do not take a double dose to make up for a forgotten dose. Take the next dose at the usual time and 
continue taking the medicine exactly as described in this leaflet or exactly as agreed with your doctor. 
Please ask your doctor or pharmacist if you are not sure. 
 
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. Some of 
these side effects, such as reddening of the face or body (flushing), diarrhoea, stomach problems and 
nausea usually improve as you continue treatment. 
 
The most serious side effects that may occur with Skilarence are allergic or hypersensitivity reactions; 
kidney failure or a kidney disease called Fanconi syndrome; or a severe brain infection called 
progressive multifocal leukoencephalopathy (PML). It is not known how commonly they occur. For 
symptoms see below.  
 
Allergic or hypersensitivity reactions 
Allergic or hypersensitivity reactions are rare but may be very serious. Reddening of the face or body 
(flushing) is a very common side effect which may affect more than 1 in 10 people. However, if you 
become flushed and get any of the following signs:  
- wheezing, difficulty breathing or shortness of breath, 
- swelling of the face, lips, mouth or tongue  
stop taking Skilarence and call a doctor straight away. 
 
Brain infection called PML 
Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection that can lead to 
severe disability or death. If you notice new or worsening weakness on one side of the body; 
clumsiness; changes in vision, thinking or memory; confusion; or personality changes lasting several 
days, stop taking Skilarence and talk to your doctor straight away. 
 
Fanconi syndrome 
Fanconi syndrome is a rare but serious kidney disorder which may occur with Skilarence. If you notice 
you are passing more urine, are more thirsty and drinking more than normal, your muscles seem 
weaker, you break a bone, or just have aches and pains, talk to your doctor as soon as possible so that 
this can be investigated further. 
 
Talk to your doctor if you get any of the following side effects. 
 
Very common side effects (may affect more than 1 in 10 people): 
- decrease in white blood cells called lymphocytes (lymphopenia) 
- decrease in all white blood cells (leukopenia) 
- reddening of the face or body (flushing) 
- diarrhoea 
- bloating, stomach pain or stomach cramps 
- feeling sick (nausea) 
 
Common side effects (may affect up to 1 in 10 people): 
- increase in all white blood cells (leukocytosis) 
- increase in specific white blood cells called eosinophils 
- increase in certain enzymes in the blood (used for checking the health of your liver) 
- being sick  



39 

- constipation 
- gas (flatulence), stomach discomfort, indigestion 
- decreased appetite 
- headache 
- feeling tired 
- weakness 
- feeling hot 
- abnormal sensations of the skin, such as itching, burning, stinging, tickling or tingling 
- pink or red blotches on the skin (erythema) 
 
Uncommon side effects (may affect up to 1 in 100 people): 
- dizziness 
- excess protein in the urine (proteinuria) 
- increase in serum creatinine (a substance in the blood used for measuring how well your 

kidneys are working) 
 
Rare side effects (may affect up to 1 in 1,000 people): 
- allergic skin reaction 
 
Very rare side effects (may affect up to 1 in 10,000 people): 
- acute lymphatic leukaemia (a type of blood cancer) 
- decrease in all types of blood cells (pancytopenia) 
 
Frequency not known (frequency cannot be estimated from the available data): 
- shingles 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. 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 Skilarence 
 
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 carton and the blister after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
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 Skilarence 120 mg contains 
- the active substance is dimethyl fumarate. One tablet contains 120 mg dimethyl fumarate. 
- the other ingredients are: lactose monohydrate, cellulose microcrystalline, croscarmellose 

sodium, colloidal anhydrous silica, magnesium stearate, methacrylic acid-ethyl acrylate 
copolymer (1:1), talc, triethyl citrate, titanium dioxide (E171), simethicone, indigo carmine 
(E132) and sodium hydroxide. 

 



40 

What Skilarence 120 mg looks like and contents of the pack 
Skilarence 120 mg is a blue, round tablet with a diameter of approximately 11.6 mm. 
Pack sizes: 40, 70, 90, 100, 120, 180, 200, 240, 300, 360 and 400 gastro-resistant tablets. Not all pack 
sizes may be marketed. The tablets are packed in PVC/PVDC-aluminium blisters. 
 
Marketing Authorisation Holder 
Almirall, S.A. 
Ronda General Mitre, 151 
E-08022 Barcelona 
Spain 
Tel. +34 93 291 30 00 
 
Manufacturer 
Industrias Farmacéuticas Almirall, S.A. 
Ctr. Nacional II, Km. 593 
E-08740 Sant Andreu de la Barca, Barcelona 
Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/ Luxembourg/Luxemburg 
Almirall N.V., Tél/Tel: +32 (0)2 771 86 37 
 
България/ Česká republika/ Eesti/ España/ Hrvatska/ Κύπρος/ Latvija/ Lietuva/ Magyarország/ 
Malta/ România/ Slovenija/ Slovenská republika 
Almirall, S.A., Teл./ Tel/ Τηλ: +34 93 291 30 00 
Tel (Česká republika / Slovenská republika): +420 220 990 139 
 
Danmark/ Norge/ Suomi/Finland/ Sverige 
Almirall ApS, Tlf/ Puh/Tel: +45 70 25 75 75 
 
Deutschland 
Almirall Hermal GmbH, Tel.: +49 (0)40 72704-0 
 
Ελλάδα 
Galenica A.E., Tηλ: +30 210 52 81 700 
 
France 
Almirall SAS, Tél.: +33(0)1 46 46 19 20 
 
Ireland 
Almirall Limited, Tel: +353 (0) 1431 9836 
 
Ísland 
Vistor hf., Sími: +354 535 70 00 
 
Italia 
Almirall SpA, Tel.: +39 02 346181 
 
Nederland 
Almirall B.V., Tel: +31 (0)30 799 1155 
 
Österreich 
Almirall GmbH, Tel.: +43 (0)1/595 39 60 
 



41 

Polska 
Almirall Sp.z o. o., Tel.: +48 22 330 02 57 
 
Portugal 
Almirall - Produtos Farmacêuticos, Lda., Tel.: +351 21 415 57 50 
 
United Kingdom 
Almirall Limited, Tel: +44 (0) 800 0087 399 
 
This leaflet was last revised in . 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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
	A. LABELLING
	B. PACKAGE LEAFLET