Dimethylfumarate-vista
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dimethylfumarate-Vista (Dimethylfumarate-Vista)
Composition:
Active substance: dimethyl fumarate;
One modified-release capsule contains 120 mg or 240 mg of dimethyl fumarate;
Excipients:
Mini-tablet core: microcrystalline cellulose, sodium croscarmellose, talc, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating, organic layer: aqueous suspension with isopropyl alcohol consisting of methacrylic acid copolymer (type A), isopropyl alcohol, sodium lauryl sulfate, triethyl citrate;
Coating, aqueous layer: aqueous suspension consisting of methacrylic acid copolymer (type A), Tween 80, sodium lauryl sulfate, talc, simethicone, triethyl citrate, silicon dioxide.
Composition of the hard gelatin capsule containing 25 mini-tablets: gelatin, titanium dioxide (E 171), iron oxide yellow (E 172), brilliant blue FCF (E 133).
Composition of printing ink: shellac, iron oxide black (E 172), propylene glycol (E 1520), ammonium hydroxide (E 527).
Pharmaceutical form. Modified-release capsules.
Main physicochemical properties:
120 mg: capsule (size 0) with white body and light-green cap, radially printed «DFT 120» on the body. Capsule contents – white mini-tablets;
240 mg: capsule (size 0) with light-green body and cap, radially printed «DFT 240» on the body. Capsule contents – white mini-tablets.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Other immunosuppressants. Dimethyl fumarate. ATC code L04AX07.
Pharmacological Properties
Pharmacodynamics
The therapeutic mechanism of action of dimethyl fumarate in multiple sclerosis has not been fully elucidated. Preclinical studies have shown that the pharmacodynamic effects of dimethyl fumarate are primarily mediated through activation of the nuclear factor (erythroid-derived\ 2 (Nrf2) transcription pathway. Dimethyl fumarate has been shown to activate Nrf2-dependent antioxidant genes in patients (e.g., NAD(P)H dehydrogenase, quinone 1 [NQO1]).
Effect on the immune system
In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory activity. Dimethyl fumarate and its primary metabolite, monomethyl fumarate, have been shown to significantly reduce immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli. In clinical studies in patients with psoriasis, dimethyl fumarate affected lymphocyte phenotype by suppressing pro-inflammatory cytokine profiles (TH1, TH17) and shifting towards anti-inflammatory production (TH2). Dimethyl fumarate has demonstrated therapeutic activity in several models of inflammatory and neuroinflammatory injury. In a Phase III study in patients with multiple sclerosis, treatment with dimethyl fumarate resulted in a reduction in mean lymphocyte count (on average approximately 30% from baseline values during the first year, followed by stabilization at a plateau level).
Pharmacokinetics
The pharmacokinetics of dimethyl fumarate have been studied in patients with multiple sclerosis and in healthy volunteers. After oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted into its primary metabolite, monomethyl fumarate, which also possesses pharmacological activity. Since dimethyl fumarate is not detectable in plasma after oral administration, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate. Pharmacokinetic data were obtained in subjects with multiple sclerosis as well as in healthy volunteers.
Absorption
The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the enteric-coated hard capsules of Dimethylfumarate-Vista contain microtablets protected by an enteric coating, absorption occurs only after evacuation from the stomach (typically within less than 1 hour). Following administration of the 240 mg dose twice daily with food, the mean peak concentration (Cmax) in patients with multiple sclerosis was 1.72 mg/L, and the total area under the curve (AUC) was 8.02 hours×mg/L. Overall, Cmax and AUC increased approximately proportionally with dose within the studied dose range (120 to 360 mg). Administration of two 240 mg doses 4 hours apart as part of a three-times-daily regimen in patients with multiple sclerosis was associated with minimal accumulation of monomethyl fumarate in blood and did not affect the safety profile of the drug (median Cmax increased by 12% compared to twice-daily dosing (1.72 mg/L and 1.93 mg/L, respectively, with twice- and three-times-daily administration)).
Administration with food does not affect the plasma concentration of dimethyl fumarate. However, dimethyl fumarate should be administered with food to improve tolerability of adverse reactions (flushing or gastrointestinal adverse reactions).
Distribution
The apparent volume of distribution after oral administration of 240 mg dimethyl fumarate ranges from 60 to 90 L. Plasma protein binding of monomethyl fumarate in humans is typically between 27% and 40%.
Biotransformation
In humans, dimethyl fumarate is extensively metabolized, with less than 0.1% of the dose excreted unchanged in urine. It is initially metabolized by esterases in the gastrointestinal tract, blood, and tissues before reaching systemic circulation. Further metabolism occurs via the tricarboxylic acid (TCA) cycle without involvement of the cytochrome P450 (CYP) system. In one study using a 240 mg dose of 14C-dimethyl fumarate, glucose was identified as its primary metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. Further metabolism of fumaric acid proceeds via the TCA cycle, with CO2 release as the primary elimination pathway.
Excretion
Exhalation of CO2 is the primary route of elimination of dimethyl fumarate, accounting for 60% of the dose. Renal and fecal excretion are secondary elimination pathways, accounting for 15.5% and 0.9% of the dose, respectively.
The elimination half-life (T½) of monomethyl fumarate is short (approximately 1 hour), and it is not detectable in blood 24 hours after administration. No accumulation of unchanged dimethyl fumarate or monomethyl fumarate occurs with repeated administration of dimethyl fumarate under therapeutic dosing regimens.
Linearity
The concentration of dimethyl fumarate increases approximately proportionally with dose in the range of 120 to 360 mg, both after single and multiple doses.
Pharmacokinetics in special patient populations
Based on results from an analysis of variance (ANOVA), body weight is the main covariate influencing exposure (Cmax and AUC) in patients with relapsing-remitting multiple sclerosis, but it does not affect safety and efficacy outcomes as assessed in clinical trials.
Age and sex had no clinically significant effect on the pharmacokinetics of dimethyl fumarate. Pharmacokinetics in patients aged 65 years and older has not been studied.
Children
The pharmacokinetic profile of dimethyl fumarate at a dose of 240 mg twice daily was evaluated in a small open-label, uncontrolled study in patients with relapsing-remitting multiple sclerosis aged 13 to 17 years (n=21). The pharmacokinetics of dimethyl fumarate in adolescent patients were similar to those in adults (Cmax: 2.00±1.29 mg/L; AUC0–12h: 3.62±1.16 hours×mg/L, corresponding to total daily AUC of 7.24 hours×mg/L).
Renal impairment
Since renal excretion is a secondary elimination pathway for dimethyl fumarate and accounts for less than 16% of the administered dose, pharmacokinetic evaluation in patients with renal impairment has not been performed.
Hepatic impairment
Since dimethyl fumarate and monomethyl fumarate are metabolized by esterases without involvement of the CYP450 system, pharmacokinetic evaluation in individuals with hepatic impairment has not been performed.
Clinical Characteristics
Indications
The medicinal product Dimethyl fumarate-Vista is indicated for the treatment of adults and children aged 13 years and older with relapsing-remitting multiple sclerosis.
Contraindications
Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Suspected or confirmed progressive multifocal leukoencephalopathy (PML).
Interaction with other medicinal products and other forms of interaction
Antineoplastic, immunosuppressive, or corticosteroid agents
No studies have been conducted on the use of dimethyl fumarate in combination with antineoplastic or immunosuppressive agents; therefore, caution should be exercised when using them concomitantly. Concomitant short-term intravenous administration of corticosteroids for the prevention of relapses in multiple sclerosis during clinical trials with dimethyl fumarate was not associated with a clinically significant increase in the frequency of infections.
Vaccines
Administration of inactivated vaccines according to national vaccination schedules may be considered during dimethyl fumarate therapy. In a clinical study (involving a total of 71 patients with relapsing-remitting multiple sclerosis), comparable immune responses (defined as ≥ two-fold increase from pre-vaccination titer) were observed in patients receiving either 240 mg dimethyl fumarate twice daily for at least 6 months (n = 38) or non-pegylated interferon for at least 3 months (n = 33) to tetanus toxoid (T-cell-dependent antigen) and meningococcal C conjugate polysaccharide vaccine (neoantigen). However, immune responses to different serotypes of the 23-valent unconjugated pneumococcal polysaccharide vaccine (T-cell-independent antigen) varied between the two treatment groups. A positive immune response, defined as a four-fold increase in antibody titer to three vaccines, was achieved in fewer patients in both treatment groups. Small quantitative differences in response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were observed in favor of non-pegylated interferon.
There are no clinical data on the safety and efficacy of administering live attenuated vaccines to patients taking Dimethyl fumarate-Vista. Live vaccines may increase the risk of infectious diseases and therefore should not be administered to patients receiving Dimethyl fumarate-Vista, except when the potential benefit of vaccination outweighs the risk.
Other fumaric acid derivatives
Concomitant use of other fumaric acid derivatives (for topical or systemic use) should be avoided during treatment with Dimethyl fumarate-Vista.
In humans, dimethyl fumarate is extensively metabolized by esterases before reaching systemic circulation. Further metabolism occurs via the tricarboxylic acid cycle without involvement of the cytochrome P450 (CYP) enzyme system. In vitro studies showed no potential risk of inhibition or induction of cytochrome P450 enzymes, as well as no significant interaction with P-glycoprotein and no notable plasma protein binding of dimethyl fumarate and monomethyl fumarate.
Effect of other substances on dimethyl fumarate
Clinical studies have shown that medicinal products used for the treatment of multiple sclerosis (intramuscular interferon beta-1a and glatiramer acetate) did not interact with dimethyl fumarate and did not alter its pharmacokinetic profile.
Data from studies in healthy volunteers suggest that flushing associated with dimethyl fumarate is likely mediated by prostaglandins. Administration of acetylsalicylic acid 325 mg (or equivalent) in non-enteric-coated formulation 30 minutes before dimethyl fumarate for 4 days and for 4 weeks, respectively, did not alter the pharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acid therapy should be considered before concomitant use with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis. Long-term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied.
Concomitant therapy of dimethyl fumarate with nephrotoxic medicinal products (such as aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, or lithium) may increase the potential for adverse reactions affecting the kidneys and urinary system (e.g., proteinuria, see section "Adverse Reactions").
Moderate alcohol consumption did not affect the therapeutic effect of dimethyl fumarate and was not associated with an increased incidence of adverse reactions. However, consumption of large amounts of strong alcoholic beverages (more than 30% alcohol by volume) should be avoided within one hour after administration of Dimethyl fumarate-Vista, as alcohol may lead to an increased frequency of gastrointestinal adverse reactions.
Effect of dimethyl fumarate on other substances
In vitro studies on possible induction of cytochrome P450 enzymes showed no interaction between dimethyl fumarate and oral contraceptives. An in vivo study of concomitant administration of dimethyl fumarate with combined oral contraceptives (norgestimate and ethinylestradiol) revealed no clinically significant changes in exposure. Interaction studies with oral contraceptives containing other progestogens have not been conducted; however, an effect of dimethyl fumarate on their efficacy is not expected.
Children
Interaction studies have been conducted only in adult patients.
Special precautions for use
Blood / laboratory tests
Renal function
Alterations in individual renal function parameters have been observed in clinical studies in patients receiving dimethyl fumarate. The clinical significance of these changes is unknown. Assessment of renal function (serum creatinine, blood urea nitrogen, and urinalysis) is recommended prior to starting treatment, at 3 and 6 months of treatment, and every 6–12 months thereafter, as clinically indicated.
Hepatic function
Dimethyl fumarate may cause drug-induced liver injury, including elevations in liver enzymes (≥3 times the upper limit of normal) and increased total bilirubin levels (≥2 times the upper limit of normal). Hepatic dysfunction may occur immediately after starting treatment, after several weeks, or later. Resolution of adverse reactions has been observed after discontinuation of dimethyl fumarate therapy. Monitoring of serum aminotransferases (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels is recommended prior to starting dimethyl fumarate treatment and during treatment, as clinically indicated.
lymphocytes
Lymphopenia may develop in patients receiving dimethyl fumarate. A complete blood count, including lymphocyte count, should be performed before initiating dimethyl fumarate treatment. If a low lymphocyte count is detected, a thorough evaluation of possible causes should be completed before starting treatment with dimethyl fumarate.
The effect of dimethyl fumarate has not been studied in patients who had low lymphocyte counts at the start of treatment; therefore, caution should be exercised when treating such patients. The medicinal product should not be administered to patients with severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L).
After starting therapy, a complete blood count, including lymphocyte count, should be performed every 3 months.
Patients with lymphopenia should be closely monitored due to an increased risk of progressive multifocal leukoencephalopathy (PML), and the following recommendations should be followed:
- in patients with a lymphocyte count < 0.5 × 10⁹/L persisting for more than 6 months, consideration should be given to interrupting treatment;
- in patients with persistent moderate reduction in absolute lymphocyte count from ≥ 0.5 × 10⁹/L to < 0.8 × 10⁹/L for more than 6 months, a benefit-risk assessment of dimethyl fumarate treatment should be performed;
- for patients with lymphocyte counts below the lower limit of normal (LLN), as determined by laboratory testing, regular monitoring of absolute lymphocyte count is recommended. Additional factors that may further increase the individual risk of PML should also be considered (see the PML section below).
Lymphocyte counts should be monitored regularly until normalization. After lymphocyte counts have normalized and in the absence of alternative treatment options, the decision to resume dimethyl fumarate treatment after discontinuation should be based on clinical assessment.
Magnetic resonance imaging (MRI)
Prior to initiating treatment with Dimethyl fumarate-Vista, an MRI should be performed (typically within 3 months) for baseline comparison. The need for further MRI scans should be considered in accordance with national and local guidelines. MRI may be considered as part of enhanced monitoring in patients at increased risk of progressive multifocal leukoencephalopathy (PML). In case of clinical suspicion of PML, diagnostic MRI should be performed immediately.
Progressive multifocal leukoencephalopathy (PML)
Cases of PML have occurred with the use of dimethyl fumarate and other fumarate-containing medicinal products in patients with prolonged moderate to severe lymphopenia. PML is an opportunistic infection caused by the John Cunningham virus (JCV) that may lead to severe disability or death.
Cases of PML have been reported with dimethyl fumarate and other fumarate-containing medicinal products in patients with lymphopenia (lymphocyte count below LLN). Prolonged moderate to severe lymphopenia increases the risk of developing PML during dimethyl fumarate treatment; however, this risk cannot be excluded in patients with mild lymphopenia.
Additional factors that may contribute to an increased risk of PML in the context of lymphopenia include:
- duration of dimethyl fumarate therapy. Cases of PML have occurred approximately 1–5 years after starting treatment, although the exact relationship with treatment duration is unknown;
- significant reductions in CD4+ and especially CD8+ T-lymphocytes, which are important for immune defense (see section «Adverse reactions»);
- prior immunosuppressive or immunomodulatory therapy (see below).
Physicians should examine their patients to determine whether symptoms indicate neurological dysfunction and, if so, whether these symptoms are typical of multiple sclerosis or possibly suggestive of PML.
At the first signs or symptoms suggestive of PML, dimethyl fumarate should be withheld and appropriate diagnostic investigations initiated, including testing for JCV DNA in cerebrospinal fluid (CSF) by quantitative polymerase chain reaction (PCR).
Typical symptoms of PML are diverse, progress over days or weeks, and may include progressive weakness on one side of the body or limb clumsiness, blurred vision, changes in thinking, memory, and orientation, leading to personality changes.
Physicians should be particularly vigilant for symptoms suggestive of PML that the patient may not notice. Patients should also be advised to inform their family members or caregivers about their treatment, as they may observe symptoms the patient is unaware of.
PML can only occur in the presence of JCV infection. It should be noted that the impact of lymphopenia on the accuracy of serum JCV antibody testing has not been studied in patients receiving dimethyl fumarate. It should also be noted that a negative JCV antibody test (with normal lymphocyte count) does not exclude the possibility of JCV infection.
If a patient develops PML, dimethyl fumarate must be permanently discontinued.
Prior treatment with immunosuppressive or immunomodulatory agents
No studies have evaluated the efficacy and safety of switching from other medicinal products to dimethyl fumarate. Prior immunosuppressive therapy may influence the risk of PML in patients receiving dimethyl fumarate.
Cases of PML have occurred in patients previously treated with natalizumab, for which PML is an established risk. Physicians should be aware that cases of PML occurring after recent discontinuation of natalizumab may not be associated with lymphopenia. Furthermore, most confirmed cases of PML with dimethyl fumarate occurred in patients with prior immunomodulatory treatment.
When switching disease-modifying therapies to dimethyl fumarate, the half-life and mechanism of action of other agents should be considered to avoid additive immune effects while minimizing the risk of multiple sclerosis reactivation.
A complete blood count is recommended before starting dimethyl fumarate therapy and at regular intervals during treatment.
Severe renal and hepatic impairment
Dimethyl fumarate has not been studied in patients with severe renal or hepatic impairment; therefore, the medicinal product should be used with caution in this patient population.
Active gastrointestinal disorders
Dimethyl fumarate has not been studied in patients with active gastrointestinal disorders; therefore, the medicinal product should be used with caution in this patient population.
Flushing
During clinical trials, flushing was observed in 34% of patients receiving dimethyl fumarate. In most cases, flushing was mild to moderate in intensity. Clinical trial data suggest that dimethyl fumarate-associated flushing is likely mediated by prostaglandins. A short course of 75 mg of non-enteric-coated acetylsalicylic acid may be beneficial for patients experiencing flushing. In two studies in healthy volunteers, the frequency and intensity of flushing decreased over the treatment period.
During clinical trials, three out of 2,560 patients receiving dimethyl fumarate experienced serious flushing symptoms, possibly due to hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but led to hospitalization. Physicians and patients should be aware of the potential for severe flushing symptoms.
Anaphylactic reactions
Cases of anaphylaxis/anaphylactoid reactions have been reported during dimethyl fumarate treatment in post-marketing surveillance. Symptoms may include dyspnea, hypoxia, hypotension, angioedema, rash, or urticaria. The mechanism of dimethyl fumarate-induced anaphylaxis is unknown. Reactions typically occur after the first dose but may occur at any time during treatment and may be serious and life-threatening. Patients should discontinue dimethyl fumarate and seek immediate medical attention if they experience signs or symptoms of anaphylaxis and should not restart treatment.
Infections
In phase III placebo-controlled trials, the incidence of infections (60% vs. 58%) and serious infections (2% vs. 2%) was similar in patients receiving dimethyl fumarate and placebo, respectively. However, due to the immunomodulatory properties of dimethyl fumarate, if a patient develops a serious infection, treatment should be discontinued. The decision to resume treatment should be based on a benefit-risk assessment for the individual patient. Patients taking Dimethyl fumarate-Vista should inform their physician of any symptoms of infection. Patients with serious infections should not initiate treatment with Dimethyl fumarate-Vista until the infection has resolved.
No increased incidence of serious infections was observed in patients with lymphocyte counts < 0.8 × 10⁹/L or < 0.5 × 10⁹/L. However, when treatment continues in the presence of moderate or severe prolonged lymphopenia, the risk of opportunistic infections, including PML, cannot be excluded.
Herpes zoster infections
Cases of herpes zoster infections have been reported during dimethyl fumarate treatment. Most cases were non-serious; however, serious cases have been reported, including disseminated herpes zoster, herpes zoster with ocular and oral involvement, neurological herpesvirus infections, herpesvirus meningoencephalitis, and herpesvirus meningomyelitis.
These adverse reactions may occur at any time during treatment. Signs and symptoms of herpes zoster should be monitored, especially in patients with lymphocytopenia receiving dimethyl fumarate. If herpes zoster occurs, appropriate treatment should be initiated. Discontinuation of the medicinal product should be considered in patients with serious infections until they are resolved.
Initiation of treatment
Treatment with Dimethyl fumarate-Vista should be initiated gradually to reduce the risk of flushing and gastrointestinal adverse reactions.
Fanconi syndrome
Cases of Fanconi syndrome have been reported with dimethyl fumarate in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome and discontinuation of dimethyl fumarate treatment are important to prevent renal dysfunction and osteomalacia, as the syndrome is usually reversible. Key signs include proteinuria, glucosuria (with normal blood glucose levels), hyperaminoaciduria, and phosphaturia (possibly with hypophosphatemia). Progression may include polyuria, polydipsia, and proximal muscle weakness. In rare cases, hypophosphatemic osteomalacia may occur, characterized by non-localized bone pain, elevated serum alkaline phosphatase, and stress fractures. Importantly, Fanconi syndrome may occur without elevated creatinine or reduced glomerular filtration rate. In cases of unexplained symptoms, Fanconi syndrome should be considered and appropriate investigations performed.
Excipients
Sodium-containing compounds
This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Propylene glycol
Dimethyl fumarate-Vista contains propylene glycol, which may cause symptoms similar to those caused by alcohol consumption.
Use during pregnancy or breastfeeding
Pregnancy
A moderate amount of data is available from pregnant women (300 to 1,000 pregnancy outcomes), based on a pregnancy registry and post-marketing spontaneous reports. The pregnancy registry included 289 prospectively collected pregnancy outcomes in patients with multiple sclerosis exposed to dimethyl fumarate. Data from the pregnancy registry indicate that the average duration of exposure to dimethyl fumarate was 4.6 gestational weeks, with limited exposure beyond the sixth week of pregnancy (outcomes in 44 pregnancies). Exposure to dimethyl fumarate during these early stages of pregnancy did not indicate developmental abnormalities or fetal/neonatal toxicity compared to the general population. The risk of prolonged exposure to dimethyl fumarate or exposure during later stages of pregnancy is unknown.
Reproductive toxicity has been observed in animal studies. Dimethyl fumarate-Vista is not recommended during pregnancy.
The medicinal product may be prescribed during pregnancy only if clearly necessary, when the potential benefit to the mother outweighs the potential risk to the fetus.
breastfeeding
It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk; therefore, a risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue therapy with Dimethyl fumarate-Vista should be made after careful consideration of the benefit to the mother and the risk to the infant.
Fertility
There are no data on the effect of dimethyl fumarate on human fertility. Preclinical data do not suggest that dimethyl fumarate is associated with an increased risk of reduced fertility.
Ability to affect reaction speed when driving or operating machinery
Dimethyl fumarate-Vista has no or negligible influence on the ability to drive or operate machinery.
Method of Administration and Dosage
The use of the drug should be initiated under the supervision of a physician experienced in the treatment of multiple sclerosis.
Method of Administration
For oral use.
The capsule should be swallowed whole. The capsule or its contents should not be crushed, split, dissolved, sucked, or chewed, as the enteric coating of the microtablets prevents irritation of the intestinal tract.
Dosage
The initial dose of the drug is 120 mg twice daily. After 7 days, the dose should be increased to the recommended maintenance dose of 240 mg twice daily.
If a patient misses a dose, a double dose should not be taken. The patient may take the missed dose only if the interval between doses is at least 4 hours. Otherwise, the patient should wait for the next scheduled dose.
A temporary reduction in dose to 120 mg twice daily may reduce the likelihood of flushing and gastrointestinal adverse reactions. The recommended maintenance dose of 240 mg twice daily should be restored within 1 month. Dimethylfumarate-Vista should be taken with food. For patients who may experience flushing or gastrointestinal adverse reactions, taking dimethylfumarate with food may improve tolerability.
Special Populations
Elderly Patients
A limited number of patients aged 55 years and older participated in clinical studies of dimethylfumarate. The studies did not include a sufficient number of patients aged 65 years and older to determine differences in drug tolerability between elderly and younger patients. Based on the mechanism of action of the active substance, there are no theoretical grounds to justify dose adjustment in elderly patients.
Renal and Hepatic Impairment
Dimethylfumarate has not been studied in patients with renal or hepatic impairment. Based on data from clinical pharmacological studies, dose adjustment in these patient groups is not required. However, treatment of patients with severe renal or hepatic impairment should be conducted with caution.
Children
Dosage is the same for adults and children aged 13 years and older.
Data in children aged 10 to 12 years are limited. Available data are described in the section "Adverse Reactions", but dosage recommendations cannot be provided.
The safety and efficacy of dimethylfumarate in children under 10 years of age have not been established. No data are available.
Overdose
Symptoms. Cases of dimethylfumarate overdose have been reported. The symptoms described in these cases were consistent with the known adverse reaction profile of dimethylfumarate.
Treatment. There are no known therapeutic interventions to enhance elimination of dimethylfumarate, and no known antidotes. In case of overdose, symptomatic and supportive treatment should be initiated according to clinical indications.
Adverse Reactions
Summary of safety profile
The most common adverse reactions are flushing (35%) and gastrointestinal events (i.e., diarrhea (14%), nausea (12%), abdominal pain (10%), upper abdominal pain (10%)). Flushing and gastrointestinal adverse reactions occur more frequently at the beginning of therapy (mainly within the first month).
In such patients, these events may continue to occur intermittently during treatment with dimethyl fumarate.
The most common adverse reactions leading to discontinuation of treatment are flushing (3%) and gastrointestinal adverse reactions (4%).
In Phase 2 and 3 placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients received dimethyl fumarate for treatment periods of up to 12 years, with a total exposure equivalent to 11,318 patient-years. Overall, 1,169 patients received at least 5 years of treatment with dimethyl fumarate, and 426 patients received at least 10 years of treatment with dimethyl fumarate. The experience from uncontrolled clinical studies is consistent with that from placebo-controlled clinical studies.
List of adverse reactions in tabular form
Adverse reactions observed during clinical studies, post-marketing safety surveillance, and spontaneous reports are listed in the table below.
The frequency of adverse reactions is expressed according to the following categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (insufficient data available to estimate frequency).
| MedDRA System Organ Class |
Adverse reaction |
Frequency category |
| Infections and infestations |
gastroenteritis |
common |
| progressive multifocal leukoencephalopathy (PML) |
frequency not known |
|
| herpes zoster |
frequency not known |
|
| Blood and lymphatic system disorders |
lymphopenia |
common |
| leukopenia |
common |
|
| thrombocytopenia |
uncommon |
|
| Immune system disorders |
hypersensitivity |
uncommon |
| anaphylaxis |
frequency not known |
|
| dyspnea |
frequency not known |
|
| hypoxia |
frequency not known |
|
| hypotension |
frequency not known |
|
| angioneurotic edema |
frequency not known |
|
| Nervous system disorders |
burning sensation |
common |
| Vascular disorders |
flushing |
very common |
| hot flush |
common |
|
| Respiratory, thoracic and mediastinal disorders |
rhinorrhea |
not known |
| Gastrointestinal disorders |
diarrhea |
very common |
| nausea |
very common |
|
| upper abdominal pain |
very common |
|
| abdominal pain |
very common |
|
| vomiting |
common |
|
| dyspepsia |
common |
|
| gastritis |
common |
|
| gastrointestinal disorder |
common |
|
| Hepatobiliary disorders |
increased AST levels |
common |
| increased ALT levels |
common |
|
| drug-induced liver injury |
frequency not known |
|
| Skin and subcutaneous tissue disorders |
pruritus |
common |
| rash |
common |
|
| erythema |
common |
|
| alopecia |
common |
|
| Renal and urinary disorders |
proteinuria |
common |
| General disorders and administration site conditions |
sensation of heat |
common |
| Investigations |
ketonuria |
very common |
| albuminuria |
common |
|
| decreased white blood cell count |
common |
Description of individual adverse reactions
Flushing
In placebo-controlled studies, an increased frequency of flushing episodes (34% vs 4%) and hot flush sensation (7% vs 2%) was observed in patients receiving dimethyl fumarate compared to those receiving placebo. Flushing is typically described as a sensation of blood rush or warmth and may include other phenomena (e.g., feeling of warmth, redness, itching, and burning sensation). Flushing usually begins at the start of dimethyl fumarate treatment (mainly within the first month), and patients experiencing flushing may have recurrent episodes during therapy. In most patients, flushing events were of mild or moderate severity. Overall, 3% of patients receiving dimethyl fumarate discontinued treatment due to flushing. The frequency of severe flushing episodes characterized by generalized erythema, rash, and/or pruritus was observed in less than 1% of patients receiving dimethyl fumarate.
Gastrointestinal adverse reactions
The frequency of gastrointestinal adverse reactions (e.g., diarrhea [14% vs 10%], nausea [12% vs 9%], upper abdominal pain [10% vs 6%], abdominal pain [9% vs 4%], vomiting [8% vs 5%], and dyspepsia [5% vs 3%]) was higher in patients receiving dimethyl fumarate compared to placebo. Gastrointestinal adverse reactions usually begin at the start of dimethyl fumarate treatment (mainly within the first month) and may occur intermittently during therapy. In most cases, the intensity of gastrointestinal symptoms was reported by patients as mild or moderate. 4% of patients receiving dimethyl fumarate discontinued treatment due to gastrointestinal adverse events. The frequency of serious gastrointestinal adverse events, including gastroenteritis and gastritis, was observed in 1% of patients receiving dimethyl fumarate.
Liver function
Based on data from placebo-controlled studies, in most patients, elevations in liver transaminases did not exceed three times the upper limit of normal (ULN). An increased frequency of liver transaminase elevations in patients receiving dimethyl fumarate compared to placebo was observed mainly during the first 6 months of treatment. Elevations in ALT and AST activity to 3 or more times the ULN were recorded in 5% and 2% of patients receiving placebo, and in 6% and 2% of patients receiving dimethyl fumarate, respectively. Treatment with dimethyl fumarate was discontinued due to elevated liver transaminases in <1% of cases. This discontinuation rate was similar in patients receiving dimethyl fumarate and placebo.
No cases of concurrent elevations in liver transaminases ≥3 times ULN and total bilirubin ≥2 times ULN were observed in placebo-controlled studies. In the post-marketing period, with the use of dimethyl fumarate, increased liver transaminase levels and drug-induced liver injury (transaminase elevation ≥3 times ULN and concomitant increase in total bilirubin ≥2 times ULN) were reported, which resolved after discontinuation of treatment.
Lymphopenia
In placebo-controlled studies, the majority of patients (>98%) had normal lymphocyte counts before starting treatment. Following administration of dimethyl fumarate, a decrease in mean lymphocyte count was observed during the first year, followed by a plateau. On average, lymphocyte count decreased by approximately 30% from baseline. Mean and median lymphocyte counts remained within the normal range. Lymphocyte count <0.5×10⁹/L was observed in less than 1% of patients receiving placebo and in 6% of patients receiving dimethyl fumarate. Lymphocyte count <0.2×10⁹/L was observed in one patient receiving dimethyl fumarate but not in patients receiving placebo. In clinical studies (both controlled and uncontrolled), 41% of patients receiving dimethyl fumarate had lymphopenia (defined in these studies as <0.91×10⁹/L).
Mild lymphopenia (count from ≥0.8×10⁹/L to <0.91×10⁹/L) was observed in 28% of patients; moderate lymphopenia (lymphocyte count from ≥0.5×10⁹/L to <0.8×10⁹/L), persisting for at least 6 months, was observed in 11% of patients; severe lymphopenia (count <0.5×10⁹/L), persisting for at least six months, was observed in 2% of patients. In most patients with severe lymphopenia, lymphocyte count remained below <0.5×10⁹/L during continued therapy.
Additionally, in an uncontrolled prospective post-marketing study at week 48 of dimethyl fumarate treatment (n=185), CD4+ T-cell levels were moderately (count from ≥0.2×10⁹/L to <0.4×10⁹/L) or severely (<0.2×10⁹/L) reduced in 37% or 6% of patients, respectively, while CD8+ T-cells were more frequently reduced, with 59% of patients having counts <0.2×10⁹/L and 25% having counts <0.1×10⁹/L.
In controlled and uncontrolled clinical studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below the lower limit of normal (LLN) were monitored for lymphocyte count recovery to LLN.
Progressive multifocal leukoencephalopathy (PML)
Cases of John Cunningham virus (JCV) infection leading to progressive multifocal leukoencephalopathy (PML) have been reported with dimethyl fumarate use (see section «Special precautions»). PML may result in death or severe disability. In one clinical trial, a patient receiving dimethyl fumarate developed PML on the background of prolonged severe lymphopenia (lymphocyte count predominantly <0.5×10⁹/L over 3.5 years), resulting in death. In post-marketing settings, PML has also occurred with moderate and mild lymphopenia (from >0.5×10⁹/L to <LLN, as defined by laboratory standards).
In several PML cases with T-lymphocyte subset analysis performed at PML diagnosis, CD8+ T-cell counts were reduced to <0.1×10⁹/L, while CD4+ T-cell reductions varied (ranging from <0.05 to 0.5×10⁹/L) and correlated more with the overall severity of lymphopenia (from <0.5×10⁹/L to <LLN). Thus, in these patients, an elevated CD4+/CD8+ ratio was observed.
Prolonged moderate or severe lymphopenia is associated with an increased risk of PML with dimethyl fumarate use; however, PML has also occurred in patients with mild lymphopenia. Furthermore, most post-marketing PML cases occurred in patients aged 50 years or older.
Herpes zoster infections
Cases of herpes zoster infection have been reported with dimethyl fumarate use. In a long-term extension study where 1736 patients with multiple sclerosis received dimethyl fumarate, approximately 5% experienced one or more episodes of herpes zoster, of which 42% were mild, 55% moderate, and 3% severe.
The onset of the first dose of dimethyl fumarate varied from approximately 3 months to 10 years. Adverse reactions were reversible in four patients.
In most patients, including those who experienced severe herpes zoster infection, lymphocyte counts were above the lower limit of normal. In most patients with lymphocyte counts below LLN, lymphopenia was classified as moderate or severe. In post-marketing observations, most cases of herpes zoster infection were non-serious and resolved with treatment. Limited data are available on absolute lymphocyte count (ALC) in patients with herpes zoster infection in post-marketing settings. However, according to reports, most patients had moderate (from <0.8×10⁹/L to 0.5×10⁹/L) or severe (from <0.5×10⁹/L to 0.2×10⁹/L) lymphopenia (see section «Special precautions»).
Laboratory abnormalities
In placebo-controlled studies, urinary ketone levels (1+ or higher) were higher in patients receiving dimethyl fumarate (45%) compared to placebo (10%). No adverse clinical consequences of this finding were observed. Levels of 1,25-dihydroxyvitamin D decreased in patients receiving dimethyl fumarate compared to placebo (median percentage decrease from baseline at 2 years was 25% vs 15%, respectively), and parathyroid hormone levels increased in patients receiving dimethyl fumarate compared to placebo (mean percentage increase from baseline at 2 years was 29% vs 15%, respectively). Mean values for both parameters remained within normal ranges. A transient increase in mean eosinophil count was observed during the first 2 months of therapy.
Children
In a 96-week open-label, randomized, active-controlled study, children with multiple sclerosis (n=7 aged 10 to <13 years and n=71 aged 13 to <18 years) received 120 mg twice daily for 7 days, followed by 240 mg twice daily for the remainder of the treatment period. The safety profile in pediatric patients was similar to that previously observed in adult patients. The design of the pediatric clinical trial differed from placebo-controlled trials in adults; therefore, a contribution of trial design to numerical differences in adverse reactions between pediatric and adult patients cannot be excluded. Gastrointestinal disorders, respiratory, thoracic, and mediastinal disorders, as well as adverse reactions such as headache and dysmenorrhea, were more frequently observed (≥10%) in children than in adults. These adverse reactions were reported at the following rates in pediatric patients:
- Headache occurred in 28% of patients receiving dimethyl fumarate vs 36% of patients receiving interferon beta-1a;
- Gastrointestinal disorders were reported in 74% of patients receiving dimethyl fumarate vs 31% of patients receiving interferon beta-1a. Among these, abdominal pain and vomiting were most frequently reported with dimethyl fumarate;
- Respiratory, thoracic, and mediastinal disorders were recorded in 32% of patients receiving dimethyl fumarate vs 11% of patients receiving interferon beta-1a. Among these, oropharyngeal pain and cough were most frequently reported with dimethyl fumarate;
- Dysmenorrhea was reported in 17% of patients receiving dimethyl fumarate vs 7% of patients receiving interferon beta-1a.
In a small, open-label, 24-week uncontrolled study involving pediatric patients with multiple sclerosis aged 13 to 17 years (120 mg twice daily for 7 days, then 240 mg twice daily for the remainder of treatment; n=22), followed by a 96-week extension study (240 mg twice daily; n=20), the safety profile was similar to that observed in adult patients.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 30°C. Keep out of reach of children.
Packaging
10 capsules in a blister, 2 blisters in a cardboard pack (for 120 mg dosage).
10 capsules in a blister, 6 blisters in a cardboard pack (for 240 mg dosage).
Prescription status. Prescription only.
Manufacturers
Synthon Chile Ltda.
Synthon España, S.L.
Manufacturer locations and addresses of manufacturing sites
El Castaño No. 145, Lampa, Santiago, 0000, Chile.
C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.