SKILARENCE 30mg gastro-resistant tablets medication leaflet

Skilarence 30 mg gastro-resistant tablets

Skilarence 120 mg gastro-resistant tablets

Skilarence 30 mg gastro-resistant tablets

Each gastro-resistant tablet contains 30 mg dimethyl fumarate.

Each gastro-resistant tablet contains 34.2 mg lactose (as monohydrate).

Skilarence 120 mg gastro-resistant tablets

Each gastro-resistant tablet contains 120 mg dimethyl fumarate.

Each gastro-resistant tablet contains 136.8 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Gastro-resistant tablet

Skilarence 30 mg gastro-resistant tablets

White, film-coated, round, biconvex tablet with a diameter of approximately 6.8 mm.

Skilarence 120 mg gastro-resistant tablets

Blue, film-coated, round, biconvex tablet with a diameter of approximately 11.6 mm.

Skilarence is indicated for the treatment of moderate to severe plaque psoriasis in adults in need ofsystemic medicinal therapy.

Skilarence is intended for use under the guidance and supervision of a physician experienced in thediagnosis and treatment of psoriasis.

To improve tolerability of Skilarence, it is recommended to begin treatment with a low initial dosewith subsequent gradual increases. In the first week, a 30 mg dose is taken once daily (1 tablet in theevening). In the second week, a 30 mg dose is taken twice daily (1 tablet in the morning and 1 in theevening). In the third week, a 30 mg dose is taken three times daily (1 tablet in the morning, 1 atmidday, and 1 in the evening). From the fourth week, treatment is switched to only 1 tablet ofa 120 mg dose in the evening. This dose is then increased by one 120 mg tablet per week at differenttimes of day for the subsequent 5 weeks, as shown in the table below.

The maximum daily dose allowed is 720 mg (six 120 mg tablets).

Week Number of tablets Total daily dose (mg)

Morning Midday Evening of dimethyl fumarate

Skilarence 30 mg1 0 0 1 302 1 0 1 603 1 1 1 90

Skilarence 120 mg4 0 0 1 1205 1 0 1 2406 1 1 1 3607 1 1 2 4808 2 1 2 6009+ 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 isnecessary. After clinically relevant improvement of the skin lesions has been achieved, considerationshould be given to gradual reduction of the daily dose of Skilarence to the maintenance dose requiredby the individual.

Dose modifications may also be necessary if abnormalities in laboratory parameters are observed (seesection 4.4).

Clinical studies of Skilarence did not include sufficient numbers of patients aged 65 years and aboveto 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 notexpected.

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 iscontraindicated in these patients (see section 4.3).

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 iscontraindicated in these patients (see section 4.3).

The safety and efficacy of Skilarence in children below the age of 18 years have not been established.

There are no data available with Skilarence in paediatric population.

For oral use.

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 tabletsshould not be crushed, divided, dissolved or chewed.

‒ 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.

Skilarence may decrease leukocyte and lymphocyte counts (see section 4.8). It has not been studied inpatients with pre-existing low leukocyte or lymphocyte counts.

Prior to initiating treatment, a current complete blood count (including differential blood count andplatelet 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, 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 bemonitored carefully and treatment 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 beperformed monthly until levels return to 1.0x109/L or higher for two consecutive blood tests at whichpoint 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 areconfirmed to be below 0.7x109/L, then treatment must be stopped immediately. Patients developinglymphopenia should be monitored after stopping treatment until their lymphocyte count has returnedto 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.

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 treatmentshould only be initiated once the infection has resolved. If a patient develops an infection duringtreatment, suspension of treatment should be considered and the benefits and risks should bereassessed prior to re-initiation of therapy. Patients receiving this medicinal product should beinstructed 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 anopportunistic infection caused by the John-Cunningham virus (JCV) that can be fatal or cause severedisabilities. PML is probably caused by a combination of factors.

A previous infection with JCV is considered a prerequisite for the development of PML. Risk factorscan include previous immunosuppressive treatment and the existence of certain concomitant disorders(such as some autoimmune disorders or malignant haematological conditions). A modified orweakened immune system as well as genetic or environmental factors can also constitute risk factors.

Persistent moderate or severe lymphopenia during treatment with dimethyl fumarate is also considereda risk factor for PML. Patients who develop lymphopenia should be monitored for signs andsymptoms of opportunistic infections, particularly for symptoms indicative of PML. Typicalsymptoms associated with PML are diverse, become worse over days to weeks and includeprogressive weakness on one side of the body or clumsiness of limbs, disturbance of vision andchanges in thinking, memory and orientation leading to confusion and personality changes. If PML issuspected, treatment should be stopped immediately and further appropriate neurological andradiological 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 beenpreviously treated with other immunosuppressive or immunomodulating therapies. When switchingpatients from such therapies to Skilarence, the half-life and mode of action of the other therapy shouldbe 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 otherimmunosuppressive or immunomodulating therapies (see section 4.5).

Pre-existing gastrointestinal disease

Skilarence has not been studied in patients with pre-existing gastrointestinal disease. It iscontraindicated in patients with severe gastrointestinal disease (see sections 4.3). Gastrointestinaltolerability can be improved by following the dose titration schedule on initiating treatment and bytaking the gastro-resistant tablet(s) with food (see sections 4.2 and 4.8).

During the Phase III placebo-controlled clinical study, renal function was not seen to deteriorateduring therapy across treatment groups. However, Skilarence has not been studied in patients withsevere renal impairment, and some cases of renal toxicity have been reported during post-marketingsurveillance with fumaric acid esters. Hence, Skilarence is contraindicated in patients with severerenal impairment (see section 4.3).

Renal function (e.g. creatinine, blood urea nitrogen and urinalysis) should be checked prior toinitiation of treatment and every 3 months thereafter. In the event of a clinically relevant change inrenal function, particularly in the absence of alternative explanations, consideration should be given todose reduction or treatment discontinuation.

Fanconi syndrome

Early diagnosis of Fanconi syndrome and discontinuation of Skilarence treatment are important toprevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. Themost important signs are: proteinuria, glucosuria (with normal blood sugar levels),hyperaminoaciduria and phosphaturia (possibly concurrent with hypophosphatemia) (see section 4.8).

Progression might involve symptoms such as polyuria, polydipsia and proximal muscle weakness. Inrare cases hypophosphataemic osteomalacia with non-localised bone pain, elevated alkalinephosphatase in serum and stress fractures may occur. Importantly, Fanconi syndrome can occurwithout 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 inthese patients (see section 4.3).

It is recommended to monitor hepatic function (SGOT, SGPT, gamma-GT, AP) prior to initiation oftreatment and every 3 months thereafter, since elevation of hepatic enzymes has been observed insome patients in the Phase III study (see section 4.8). In the event of a clinically relevant change inhepatic parameters, particularly in the absence of alternative explanations, consideration should begiven to dose reduction or treatment discontinuation (see section 4.2).

Flushing

Patients should be made aware that they are likely to experience flushing in the first few weeks oftreatment (see section 4.8).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium free’.

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, simultaneous use of other fumaric acid derivatives (topical or systemic) should beavoided.

Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides,diuretics, non-steroidal anti-inflammatory drugs (NSAIDs) or lithium) may increase the potential forrenal adverse reactions (e.g. proteinuria) in patients taking Skilarence.

In cases of severe or prolonged diarrhoea during treatment with Skilarence, absorption of othermedicinal products may be affected. Caution should be exercised when prescribing medicinal productswith a narrow therapeutic index that require absorption in the intestinal tract. The efficacy of oralcontraceptives may be reduced and the use of an alternative barrier contraceptive method isrecommended to prevent possible failure of contraception (see the prescribing information of the oralcontraceptive).

Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) shouldbe avoided because it may lead to increased dissolution rates of Skilarence and, therefore, mayincrease the frequency of gastrointestinal adverse reactions.

Vaccination during treatment with Skilarence has not been studied. Immunosuppression is a risk factorfor the use of live vaccines. The risk of vaccination should be weighed against the benefit.

There is no evidence for interaction with cytochrome P450 and the most common efflux and uptaketransporters, thus no interactions are expected with medicinal products metabolised or transported bythese systems (see section 5.2).

Skilarence is not recommended in women of child-bearing potential not using appropriatecontraception. Additional contraceptive methods in case of stomach and intestinal problems that couldreduce the effectiveness of oral contraceptives could be necessary (see section 4.5).

There are limited data from the use of dimethyl fumarate in pregnant women. Animal studies haveshown reproductive toxicity (see section 5.3). Skilarence is contraindicated during pregnancy (seesection 4.3).

It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk tonewborns or infants cannot be excluded. Therefore, Skilarence is contraindicated during breast-feeding (see section 4.3).

There are no human or animal data on the effects of Skilarence on fertility.

Skilarence may have a minor influence on the ability to drive and use machines. Dizziness and fatiguemay occur following administration of Skilarence (see section 4.8).

The most common adverse reactions observed with Skilarence are gastrointestinal events followed byflushing and lymphopenia.

The following is a list of adverse reactions experienced by patients treated with Skilarence during theclinical development, post-marketing experience and with Fumaderm, a related medicinal productcontaining 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 Lymphopenia Very commondisorders Leukopenia Very common

Eosinophilia Common

Leukocytosis Common

Acute lymphatic leukaemia* Very rare

Irreversible pancytopenia* Very rare

Metabolism and nutrition Decreased appetite Common

System organ class Adverse reactions Frequencydisorders

Nervous system disorders Headache Common

Paraesthesia Common

Dizziness* Uncommon

Progressive multifocal leukoencephalopathy Not known

Vascular disorders Flushing Very common

Gastrointestinal disorders Diarrhoea Very common

Abdominal distension Very common

Abdominal pain Very common

Nausea Very common

Vomiting Common

Dyspepsia Common

Constipation Common

Abdominal discomfort Common

Flatulence Common

Skin and subcutaneous tissue Erythema Commondisorders Skin burning sensation Common

Pruritus Common

Allergic skin reaction Rare

Renal and urinary disorders Proteinuria Uncommon

Renal failure Not known

Fanconi syndrome* Not known

General disorders and Fatigue Commonadministration site conditions Feeling hot Common

Asthenia Common

Investigations Hepatic enzymes increased Common

Serum creatinine increased Uncommon

*Additional adverse reactions reported with Fumaderm, a related medicinal product containing dimethyl fumarate alongwith other fumaric acid esters.

**Adverse reactions reported during post marketing experience.

Gastrointestinal disturbances

Data from the Phase III clinical study as well as from the literature show that gastrointestinal disorderswith dimethyl fumarate-containing products are most likely to occur during the first 2 to 3 monthsafter starting treatment. No apparent dose relationship and no risk factors for the occurrence of theseadverse reactions could be identified. Diarrhoea was a common adverse reaction (36.9%) amongpatients taking Skilarence, leading to medicinal product withdrawal in about 10% of patients. Morethan 90% of these diarrhoea events were of mild to moderate severity (see section 4.4).

The only adverse reactions that led to discontinuation of treatment in >5% of patients weregastrointestinal reactions. For monitoring recommendations and clinical management of adversereactions, see section 4.4.

Flushing

Based on observations in the Phase III clinical study as well as on literature data, flushing is mostlikely to occur during the early weeks of treatment and tends to lessen with time. In the clinical study atotal of 20.8% of patients receiving Skilarence experienced flushing, which was mild in the majorityof cases (see section 4.4). Published clinical experience with dimethyl fumarate-containing productsshows that individual episodes of flushing usually begin shortly after taking the tablets and resolvewithin a few hours.

Haematological changes

Data from the Phase III clinical study as well as from the literature show that changes inhaematological parameters are most likely to occur during the first 3 months after starting treatmentwith dimethyl fumarate. In particular, in the clinical study there was a slight decrease in meanlymphocyte counts starting between weeks 3 and 5 and reaching a maximum in week 12 whereapproximately one third of patients had lymphocyte values below 1.0x109/L. The mean and medianvalues of lymphocytes remained within the normal range during the clinical study. At week 16 (end oftreatment), 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 clinicallaboratory 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 stoppingtreatment 3/28 (10.7%) of patients had lymphocyte values below 1.0x109/L, which would represent3/279 (1.1%) of the patients started on Skilarence.

For the total leukocyte count, a decline became apparent at week 12 of treatment; it slowly increasedagain at week 16 (end of treatment); and 12 months after stopping treatment all patients had valuesabove 3.0x109/L.

A transient increase in mean values of eosinophils was noted as early as week 3, reached a maximumat week 5 and 8, and had returned to baseline values at week 16.

For monitoring recommendations and clinical management of haematological adverse reactions, seesection 4.4.

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

Symptomatic treatment is indicated in the case of an overdose. No specific antidote is known.

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX07

The anti-inflammatory and immunomodulating effects of dimethyl fumarate and its metabolitemonomethyl fumarate are not fully elucidated but are thought to be mainly due to the interaction withthe intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. Thisinteraction with glutathione leads to the inhibition of translocation into the nucleus and thetranscriptional 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 beimmunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2phenotype. The inflammatory cytokine production is reduced with induction of proapoptotic events,inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminishedinflammatory infiltrate within psoriatic plaques.

The safety and efficacy of Skilarence was assessed in one double-blind, 3-arm, placebo- and activecomparator-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, acombination product with the same content of dimethyl fumarate plus 3 monoethyl fumarate salts) andplacebo in a ratio of 2:2:1. Patients began treatment with tablets containing 30 mg/day dimethylfumarate or placebo, titrating up to a maximum of 720 mg/day in both active treatment arms asdescribed in section 4.2. If treatment success was observed before the maximum dose of 720 mg/dayof dimethyl fumarate was reached, no further increase of dose was necessary and the dose was to besteadily reduced to an individual maintenance dose. In case of individual intolerability of the increaseddose during weeks 4 to 16, the patient was to return to the last tolerated dose taken since the start ofweek 4, which was to be maintained until end of the treatment period (week 16). Patients receivedtreatment for up to 16 weeks and follow-up visits were planned for up to 12 months after treatmentwas stopped.

The demographic and baseline characteristics were well balanced between the treatment groups. Ofthe 699 patients, most were Caucasian (99%) and male (65%), and the mean age was 44 years. Mostpatients (91%) were <65 years of age. Most patients had moderate psoriasis based on Psoriasis Areaand 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 ofpatients 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.

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 marginof -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 monoethylhydrogen 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 of22.2% for PASI 75 and 20.0% for PGA score clear or almost clear, superiority of Fumaderm vs Placebo with a difference of25.0% for PASI 75 and 24.4% for PGA score clear or almost clear; b Non-inferiority of Skilarence vs. Fumaderm with adifference 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 theonset of a clinical response to Skilarence as early as week 3 (-11.8%) which became statisticallysignificant 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 improvementsin their quality of life. At week 16, patients treated with Skilarence had a lower mean DLQI comparedto placebo (5.4 vs 8.8).

Rebound (defined as worsening of ≥125% of baseline PASI value) was assessed after 2 months offtreatment and was shown not to be a clinical concern with fumaric acid esters, as it was documented invery few patients (Skilarence 1.1% and active comparator 2.2%, compared to 9.3% in the placebogroup).

Maintenance of efficacy has been observed during long-term treatment with dimethyl fumarate-containing products. In the pharmacokinetic and clinical studies the systemic exposure, efficacy andsafety of Skilarence were shown to be comparable to the active comparator containing dimethylfumarate. Hence it is reasonable to expect the long-term efficacy of Skilarence to also be comparableto dimethyl fumarate-containing products.

The European Medicines Agency has waived the obligation to submit the results of studies with

Skilarence in all subsets of the paediatric population in psoriasis (see section 4.2 for information onpaediatric use).

After oral administration, dimethyl fumarate is not detected in plasma because it is rapidly hydrolysedby esterases to its active metabolite monomethyl fumarate. After oral administration of a single

Skilarence 120 mg tablet in healthy subjects, monomethyl fumarate reached plasma peakconcentrations 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.

The plasma protein binding of monomethyl fumarate is around 50%. Dimethyl fumarate does notshow any binding affinity to serum proteins which may further contribute to its rapid elimination fromthe circulation.

The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes. In vitrostudies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any ofthe cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not aninhibitor of the most common efflux and uptake transporters. In vitro studies have shown that dimethylfumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoproteininhibitor.

In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occursrapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach). A part of the totaldimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while theremainder enters the portal vein blood. Further studies have shown that dimethyl fumarate (and to alesser 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 smallerextent in portal vein blood. Unconjugated dimethyl fumarate, however, cannot be detected in theplasma of animals or psoriatic patients following oral administration. By contrast, unconjugatedmonomethyl fumarate is detectable in plasma. Further metabolism occurs through oxidation via thetricarboxylic acid cycle forming carbon dioxide and water.

Exhalation of CO2 resulting from the metabolism of monomethyl fumarate is the primary route ofelimination; 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, ismetabolised further to its mercapturic acid, which is excreted in the urine.

The apparent terminal elimination half-life of monomethyl fumarate is about 2 hours.

Despite the high inter-subject variability, the exposure measured as AUC and Cmax was generallydose-proportional after single dose administration of 4 x 30 mg dimethyl fumarate tablets (total doseof 120 mg) and 2 x 120 mg dimethyl fumarate tablets (total dose of 240 mg).

No specific studies have been performed in patients with renal impairment. However, because renalelimination plays a minor role in the total clearance from plasma, it is unlikely that renal impairmentmay affect the pharmacokinetic characteristics of Skilarence (see section 4.2).

No specific studies have been performed in patients with hepatic impairment. However, as dimethylfumarate is metabolised by esterases and the alkaline milieu of the small intestine without theinvolvement of cytochrome P450, hepatic impairment is not expected to influence exposure (seesection 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and genotoxicity.

The kidney was identified as a major target organ of toxicity in non-clinical studies. Renal findings indogs included minimal to moderate tubular hypertrophy, increased incidence and severity of tubularvacuolation and minimal to slight tubular degeneration, which were considered toxicologicallyrelevant. The no-observed adverse-effect-level (NOAEL) after 3 months of treatment was30 mg/kg/day, which corresponds to 2.9-fold and 9.5-fold the human systemic exposure at the highestrecommended 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 ofdimethyl fumarate during the embryo-foetal development study in rats. However, there was anincreased number of foetuses with the variations “supernumerary liver lobe” and “abnormal iliacalignment” at maternally toxic doses. The NOAEL for maternal and embryo-foetal toxicity was40 mg/kg/day, corresponding to 0.2-fold and 2.0-fold the human systemic exposure at the highestrecommended 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.

No carcinogenicity studies have been performed for Skilarence. Based on available data suggestingthat fumaric acid esters may activate cellular pathways related to the development of renal tumours, apotential tumorigenic activity of exogenously administered dimethyl fumarate on the kidneys cannotbe excluded.

Skilarence 30 mg and 120 mg gastro-resistant tablets

Core

Lactose monohydrate

Cellulose microcrystalline

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Skilarence 30 mg gastro-resistant tablets

Methacrylic acid-ethyl acrylate copolymer (1:1)

Talc

Triethyl citrate

Titanium dioxide (E171)

Simethicone

Skilarence 120 mg gastro-resistant tablets

Methacrylic acid-ethyl acrylate copolymer (1:1)

Talc

Triethyl citrate

Titanium dioxide (E171)

Simethicone

Indigo carmine (E132)

Sodium hydroxide

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Skilarence 30 mg gastro-resistant tablets42, 70 and 210 gastro-resistant tablets in PVC/PVDC-aluminium blister packs.

Skilarence 120 mg gastro-resistant tablets40, 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.

No special requirements for disposal.

Almirall, S.A.

Ronda General Mitre, 15108022 Barcelona

Spain

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

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

Date of first authorisation: 23 June 2017

Date of latest renewal: 21 February 2022

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

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