Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Almirall, S.A., Ronda General Mitre, 151, 08022, Barcelona, Spain
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.
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 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).
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 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.
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 with Skilarence should be stopped immediately and further appropriate neurological and radiological examinations performed.
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).
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).
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.
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.
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. 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.
Patients should be made aware that they are likely to experience flushing in the first few weeks of taking Skilarence (see section 4.8).
Skilarence contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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).
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).
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).
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 breastfeeding (see section 4.3).
There are no human or animal data on the effects of Skilarence on fertility.
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).
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.
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).
Very common: Lymphopenia, Leukopenia
Common: Eosinophilia, Leukocytosis
Very rare: Acute lymphatic leukaemia*, Irreversible pancytopenia*
Common: Decreased appetite
Common: Headache, Paraesthesia
Uncommon: Dizziness*
Not known: Progressive multifocal leukoencephalopathy*
Very common: Flushing
Very common: Diarrhoea, Abdominal distension*, Abdominal pain, Nausea
Common: Vomiting, Dyspepsia, Constipation, Abdominal discomfort, Flatulence
Common: Erythema, Skin burning sensation, Pruritus
Rare: Allergic skin reaction*
Uncommon: Proteinuria*
Not known: Renal failure*, Fanconi syndrome*
Common: Fatigue, Feeling hot, Asthenia
Common: Hepatic enzymes increased
Uncommon: Serum creatinine increased*
* Additional adverse reactions reported with Fumaderm, a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.
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).
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 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.
Not applicable.
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