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 of Skilarence, it is recommended to begin treatment with a low initial dose with subsequent gradual increases. In the first week, a 30 mg dose is taken once daily (1 tablet in the evening). In the second week, a 30 mg dose is taken twice daily (1 tablet in the morning and 1 in the evening). In the third week, a 30 mg dose 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 a 120 mg dose in the evening. This dose is then increased by one 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 (six 120 mg tablets).

Week

Number of tablets

Total daily dose (mg) of dimethyl fumarate

Morning

Midday

Evening

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.

Dose 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 children below the age of 18 years have not been established. There are no data available with Skilarence in paediatric population.

Method of administration

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 tablets should not be crushed, divided, dissolved or chewed.

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, 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 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 should only be initiated once the infection has resolved. If a patient develops an infection during treatment, suspension of treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving this medicinal product 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.

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 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. It 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 treatment and by taking the gastro-resistant tablet(s) with food (see sections 4.2 and 4.8).

Renal function

During the Phase III placebo-controlled clinical study, 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 dose 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) (see section 4.8). 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 treatment and every 3 months thereafter, since elevation of hepatic enzymes has been observed in some patients in the Phase III study (see section 4.8). 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 (see section 4.2).

Flushing

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

Excipients

Lactose

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

Sodium

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

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

Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs (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 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. Additional contraceptive methods in case of stomach and intestinal problems that could reduce the effectiveness of oral contraceptives could 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).

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

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 are gastrointestinal events followed by flushing and lymphopenia.

Tabulated list of adverse reactions

The following is a list of adverse reactions experienced by patients treated with Skilarence during the clinical development, post-marketing experience 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

Abdominal discomfort

Flatulence

Very common

Very common

Very common

Very common

Common

Common

Common

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).

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.

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 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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