Dimethyl fumarate
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIMETHYL FUMARATE (DIMETHYL FUMARATE)
Composition:
Active substance: dimethyl fumarate;
1 modified-release capsule contains 120 mg of dimethyl fumarate;
Excipients: microcrystalline cellulose, siliconized microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, methacrylate copolymer (type A), triethyl citrate, methacrylate copolymer dispersion (type C), talc, hard gelatin capsule*.
* Composition of the hard gelatin capsule: gelatin, sodium lauryl sulfate, titanium dioxide (E 171), quinoline yellow (E 104), indigo carmine FCF (E 133), purified water.
Pharmaceutical form. Modified-release capsules.
Main physicochemical properties: capsules with an opaque green cap printed with "AN" in black ink and an opaque white body printed with "1318" in black ink.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. ATC code L04A X07.
Pharmacological Properties.
Pharmacodynamics.
The mechanism of the therapeutic effect 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 effects. 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 toward anti-inflammatory production (TH2). Dimethyl fumarate 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 during the first year, followed by stabilization at a plateau level). In these studies, patients who discontinued dimethyl fumarate therapy when lymphocyte counts were below the lower limit of normal (LLN) of 910 cells/mm³ were monitored for lymphocyte count recovery.
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 has pharmacological activity. Since dimethyl fumarate is not detectable in plasma after oral administration, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate.
Absorption
The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the enteric-coated hard capsules contain mini-tablets protected by an enteric coating, absorption occurs only after gastric evacuation (typically within less than 1 hour). After administration of 240 mg twice daily with food, the mean maximum plasma concentration (Cmax) in patients with multiple sclerosis was 1.72 mg/L, and the total area under the concentration-time curve (AUC) was 8.02 h×mg/L. Overall, Cmax and AUC increased approximately proportionally with dose over 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, for twice- and thrice-daily dosing).
Administration of the drug 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 disturbances) (see section "Dosage and administration").
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 the primary metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. Further metabolism of fumaric acid proceeds through 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 administered 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 the drug is not detectable in blood in most patients within 24 hours. No accumulation of unchanged dimethyl fumarate or monomethyl fumarate occurs with repeated administration of dimethyl fumarate at therapeutic doses.
Linearity
Dimethyl fumarate concentrations increase approximately dose-proportionally over the range of 120 to 360 mg, following both single and multiple doses.
Pharmacokinetics in special patient populations
According to 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 studies.
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.
Pediatric population
The pharmacokinetic profile of dimethyl fumarate following 240 mg twice daily was evaluated in a small, open-label, uncontrolled study in patients aged 13 to 17 years with relapsing-remitting multiple sclerosis (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 h×mg/L, corresponding to a total daily AUC of 7.24 h×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 was not conducted.
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 was not conducted.
Clinical characteristics.
Indications.
The medicinal product is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
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.
Studies on the use of dimethyl fumarate in combination with antineoplastic or immunosuppressive agents have not been conducted; therefore, caution should be exercised when administering these agents concomitantly. Concomitant short-term intravenous administration of corticosteroids for the prevention of relapses in multiple sclerosis during clinical trials of dimethyl fumarate was not associated with a clinically significant increase in the frequency of infections.
Administration of inactivated vaccines according to national vaccination schedules may be considered during therapy with dimethyl fumarate. In a clinical study (involving a total of 71 patients with relapsing multiple sclerosis), comparable immune responses (defined as at least a 2-fold increase from pre-vaccination titer) were observed in patients receiving 240 mg of 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 conjugated meningococcal C polysaccharide vaccine (neoantigen). However, immune responses to various serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell-independent antigen) varied between treatment groups. A positive immune response, defined as a 4-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. Live vaccines may increase the risk of infectious diseases and therefore should not be administered to patients receiving dimethyl fumarate, except when the expected benefit of vaccination outweighs the potential risk.
During treatment with the medicinal product, concomitant use of other fumaric acid derivatives (for topical or systemic use) should be avoided.
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, nor any significant effect on P-glycoprotein, and studies on plasma protein binding of dimethyl fumarate and monomethyl fumarate (the main metabolite of dimethyl fumarate) showed no clinically relevant interactions.
Clinical studies have shown that medicinal products used to treat 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 mediated by prostaglandins. In two studies involving healthy volunteers, administration of acetylsalicylic acid at a dose of 325 mg (or equivalent) in non-enteric-coated formulation 30 minutes before dimethyl fumarate for more than 4 days and more than 4 weeks, respectively, did not alter the pharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acid therapy should be considered before prescribing 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 (see sections "Special precautions for use" and "Side effects").
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 "Side effects") in patients taking dimethyl fumarate (see subsection "Blood/laboratory tests" in section "Special precautions for use").
Moderate alcohol consumption did not affect dimethyl fumarate exposure and was not associated with an increased incidence of adverse reactions. Consumption of large amounts of strong alcoholic beverages (more than 30% alcohol by volume) should be avoided within one hour after administration of the medicinal product, as alcohol may increase the frequency of gastrointestinal adverse reactions.
In vitro studies on the potential induction of cytochrome P450 enzymes showed no interaction between dimethyl fumarate and oral contraceptives. An in vivo study with concomitant administration of dimethyl fumarate and combined oral contraceptives (norgestimate and ethinylestradiol) revealed no significant changes in exposure to the oral contraceptive. Studies on interactions with oral contraceptives containing other progestogens have not been conducted; however, an effect of dimethyl fumarate on contraceptive exposure is not expected.
Children
Interaction studies have been performed only in adults.
Special precautions for use.
Blood/laboratory tests
Changes in certain renal function parameters were observed in clinical trials in patients receiving dimethyl fumarate (see section "Adverse reactions"). The clinical significance of these changes is unknown. Renal function assessment (creatinine, blood urea nitrogen, and urinalysis) is recommended before starting treatment, at 3 and 6 months after initiation, and every 6–12 months thereafter, as clinically indicated.
Dimethyl fumarate may cause liver injury, including elevations in liver enzymes (≥ 3 × ULN [upper limit of normal]) and increased total bilirubin levels (≥ 2 × ULN). Hepatic dysfunction may occur immediately after starting the drug, within several weeks, or later. Resolution of adverse reactions was observed after discontinuation of dimethyl fumarate. Serum aminotransferase levels (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and total bilirubin levels should be assessed before starting dimethyl fumarate and during treatment, as clinically indicated.
Patients receiving dimethyl fumarate may develop severe, prolonged lymphopenia (see section "Adverse reactions"). A complete blood count, including lymphocyte count, should be performed before initiating treatment with dimethyl fumarate.
The effect of dimethyl fumarate has not been studied in patients who had reduced lymphocyte counts at the start of treatment; therefore, caution is advised when treating such patients. The medicinal product is contraindicated in patients with severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L).
After treatment initiation, 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 PML, and the following recommendations should be followed:
- The medicinal product should be discontinued in patients with prolonged severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L) lasting more than 6 months.
- In patients with persistent moderate reduction in absolute lymphocyte count (≥ 0.5 × 10⁹/L and < 0.8 × 10⁹/L) for more than six months, the benefit-risk balance of dimethyl fumarate treatment should be re-evaluated.
Patients with lymphocyte counts below the lower limit of normal (LLN), as defined by local laboratory reference values, should undergo regular monitoring of absolute lymphocyte count. Factors that may further increase individual risk of PML should be considered (see subsection "Progressive multifocal leukoencephalopathy (PML)" below).
Lymphocyte counts should be monitored until normalization. After lymphocyte counts have normalized and in the absence of alternative treatment options, the decision to resume dimethyl fumarate after discontinuation should be based on clinical assessment.
Magnetic resonance imaging (MRI)
An MRI should be performed before initiating treatment (typically within 3 months) and may serve as a baseline for comparison. The need for further MRI scans should be considered according to national and local guidelines. MRI may be considered as part of enhanced monitoring for patients at increased risk of PML. In case of clinical suspicion of PML, an MRI should be performed immediately for diagnostic purposes.
Progressive multifocal leukoencephalopathy (PML)
Cases of PML have occurred with the use of dimethyl fumarate (see section "Adverse reactions"). 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 prolonged lymphopenia (lymphocyte count below LLN). Prolonged moderate to severe lymphopenia increases the risk of PML with dimethyl fumarate; however, this risk cannot be excluded in patients with mild lymphopenia.
Additional risk factors for PML in the context of lymphopenia include:
- Longer duration of dimethyl fumarate therapy. Cases of PML have occurred approximately 1–5 years after treatment initiation, although the exact relationship with treatment duration is unknown.
- Marked reductions in CD4+ and especially CD8+ T-cells, which are important for immune defense (see section "Adverse reactions").
- Prior immunosuppressive or immunomodulatory therapy (see below).
Physicians should evaluate their patients for symptoms suggestive of neurological dysfunction and determine whether symptoms are typical of MS or possibly indicative of PML.
At the first sign or symptom suggestive of PML, the medicinal product should be discontinued and appropriate diagnostic investigations initiated, including testing for JCV DNA in cerebrospinal fluid (CSF) by quantitative polymerase chain reaction (PCR). PML symptoms may resemble those of a multiple sclerosis relapse. Typical PML symptoms are variable, progress over days or weeks, and include progressive weakness on one side of the body or limb clumsiness, visual disturbances, changes in thinking, memory and orientation, leading to confusion and 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 partner or caregiver 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 the serum JCV antibody test in patients treated with dimethyl fumarate has not been studied. A negative JCV antibody test (with normal lymphocyte count) does not exclude the possibility of subsequent JCV infection.
If a patient develops PML, dimethyl fumarate must be permanently discontinued.
Prior immunosuppressive or immunomodulatory therapy
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, in whom PML is a known risk. Physicians should be aware that PML cases occurring shortly after discontinuation of natalizumab may occur without lymphopenia.
Furthermore, most confirmed cases of PML with dimethyl fumarate occurred in patients who had prior immunomodulatory treatment.
When switching from 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 regularly during treatment (see subsection "Blood/laboratory tests" above).
Severe renal and hepatic impairment
The effect of 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 group (see section "Dosage and administration").
Active gastrointestinal disorders during flare-up
The effect of dimethyl fumarate has not been studied in patients with active gastrointestinal disorders during flare-up; therefore, the medicinal product should be used with caution in this patient group.
Flushing
During clinical trials, flushing occurred in 34 % of patients receiving dimethyl fumarate. In most cases, flushing intensity was mild or moderate. Data from studies 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 (see section "Interaction with other medicinal products and other forms of interaction"). In two studies involving healthy volunteers, the frequency and severity of flushing decreased over the treatment period.
During clinical trials, three out of 2560 patients receiving dimethyl fumarate experienced serious flushing symptoms, possibly due to hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but required hospitalization. Physicians and patients should be informed about the potential causes of severe flushing symptoms (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", and "Adverse reactions").
Anaphylactic reactions
Cases of anaphylaxis/anaphylactoid reactions have been reported during post-marketing surveillance of dimethyl fumarate treatment. Symptoms may include dyspnea, hypoxia, arterial hypotension, angioedema, rash, or urticaria. The mechanism of dimethyl fumarate-induced anaphylaxis is unknown. Reactions usually occur after the first dose but may also occur at any time during treatment and can be serious and life-threatening. Patients should discontinue dimethyl fumarate and seek immediate medical attention if they experience signs or symptoms of anaphylaxis. Re-initiation of treatment is not recommended (see section "Adverse reactions").
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. If a serious infection develops, treatment should be discontinued. The benefit-risk ratio should be evaluated before considering resumption of therapy.
Patients receiving dimethyl fumarate should report symptoms of infection to their physician. Patients with serious infections should not start dimethyl fumarate treatment until the infection has resolved.
No increase in the frequency of serious infections was observed in patients with lymphocyte counts < 0.8 × 10⁹/L or < 0.5 × 10⁹/L (see section "Adverse reactions").
If treatment continues in the presence of prolonged moderate or severe lymphopenia, the risk of opportunistic infections, including PML, cannot be excluded (see subsection "Progressive multifocal leukoencephalopathy (PML)" above).
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 shingles, shingles with ocular involvement, shingles with ear involvement, neurological herpesvirus infections, herpesvirus meningoencephalitis, and herpesvirus meningomyelitis. These adverse reactions may occur at any time during treatment. Signs and symptoms of shingles should be monitored, especially in patients with lymphocytopenia receiving dimethyl fumarate. If shingles occurs, appropriate treatment should be initiated. Discontinuation of the medicinal product should be considered in patients with serious infections until recovery (see section "Adverse reactions").
Initiation of treatment
Dimethyl fumarate treatment should be initiated gradually to reduce the risk of flushing and gastrointestinal adverse reactions (see section "Dosage and administration").
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), hyperaminoaciduria, and phosphaturia (possibly with hypophosphatemia). Progression may include symptoms such as 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 the presence of unexplained symptoms, Fanconi syndrome should be considered and appropriate investigations performed.
Pediatric population
Safety and efficacy in the pediatric population have not been established.
Hypersensitivity to excipients
The medicinal product contains more than 1 mmol (27.2 mg) of sodium per dose (1 capsule), which should be considered for patients on a sodium-controlled diet.
Use during pregnancy or breastfeeding.
Pregnancy
Data on the use of dimethyl fumarate in pregnant women are lacking. Reproductive toxicity has been observed in animal studies. Dimethyl fumarate is not recommended for use in pregnant women or in women of childbearing potential who are not using appropriate contraception (see section "Interaction with other medicinal products and other forms of interaction"). The medicinal product may be prescribed during pregnancy only if absolutely necessary, when the expected 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 dimethyl fumarate therapy 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 increases the risk of impaired fertility.
Ability to affect reaction speed when driving or operating machinery.
Dimethyl fumarate has no effect or a negligible effect on the ability to drive or operate machinery. Although no specific studies on driving or operating machinery have been conducted, clinical trials have not revealed any potential impact of dimethyl fumarate on this ability.
Dosage and Administration
Treatment with this medicinal product should be initiated under the supervision of a physician experienced in the management of multiple sclerosis.
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 mini-tablets prevents intestinal irritation.
Dosage
The initial dose of the medicinal product is 120 mg twice daily. After 7 days, the dose should be increased to the recommended maintenance dose of 240 mg twice daily (see section "Special Warnings and Precautions for Use").
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 until 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 one month.
Dimethyl fumarate should be taken with food (see section "Pharmacological Properties"). For patients who experience flushing or gastrointestinal adverse reactions, taking dimethyl fumarate with food may improve tolerability (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use", and "Undesirable Effects").
Special Populations
Elderly Patients
A limited number of patients aged 55 years and older participated in clinical studies with dimethyl fumarate, and an insufficient number of patients aged 65 years and older were included to draw conclusions about differences in tolerability between elderly and younger patients (see section "Pharmacological Properties"). 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
The effect of dimethyl fumarate has not been studied in patients with renal or hepatic impairment. Based on data from clinical pharmacology studies, dose adjustment in these patient groups is not required (see section "Pharmacological Properties"). Treatment of patients with severe renal or hepatic impairment should be undertaken with caution (see section "Special Warnings and Precautions for Use").
Children
Safety and efficacy in the paediatric population have not been established.
Overdose
Cases of dimethyl fumarate overdose have been reported. Symptoms described in these cases were consistent with the known adverse reaction profile of dimethyl fumarate. There are no known therapeutic measures to enhance elimination of dimethyl fumarate, and no known antidotes. In the event of overdose, symptomatic and supportive treatment should be initiated according to clinical indications.
Adverse Reactions
Summary of safety profile
In patients receiving dimethyl fumarate treatment, the most common adverse reactions (occurring in >10% of patients) were flushing and gastrointestinal disorders (diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal adverse reactions most commonly occurred at the beginning of therapy (primarily within the first month). These symptoms may recur intermittently throughout the entire treatment period. The most common adverse reactions leading to discontinuation of treatment (incidence >1%) in patients treated with dimethyl fumarate were flushing (3%) and gastrointestinal adverse reactions (4%).
Adverse reactions observed during clinical trials, post-marketing safety studies, and spontaneous reports are listed in the table below.
The frequency of adverse reactions is categorized as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (available data do not allow estimation of frequency).
| MedDRA System Organ Classes |
Adverse Reaction |
Frequency |
| Infections and infestations |
gastroenteritis |
common |
| progressive multifocal leukoencephalopathy (PML) |
frequency unknown |
|
| herpes zoster |
frequency unknown |
|
| Blood and lymphatic system disorders |
lymphopenia |
common |
| leukopenia |
common |
|
| thrombocytopenia |
uncommon |
|
| Immune system disorders |
hypersensitivity |
uncommon |
| anaphylaxis |
frequency unknown |
|
| dyspnea |
frequency unknown |
|
| hypoxia |
frequency unknown |
|
| arterial hypotension |
frequency unknown |
|
| angioedema |
frequency unknown |
|
| Nervous system disorders |
burning sensation |
common |
| Vascular disorders |
flushing |
very common |
| hot flush |
common |
|
| Respiratory, thoracic and mediastinal disorders |
rhinorrhea |
frequency unknown |
| 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 |
|
| acute pancreatitis |
frequency unknown |
|
| Hepatobiliary disorders |
elevation of AST levels |
common |
| elevation of ALT levels |
common |
|
| drug-induced liver injury |
frequency unknown |
|
| 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 sensation of warmth (7% vs 2%) was observed in patients treated with dimethyl fumarate compared to those receiving placebo. Flushing sensations are typically described as a rush of blood or warmth, but may also include other phenomena (e.g., feeling of heat, redness, itching, and burning sensation). Flushing usually begins early in dimethyl fumarate treatment (mostly within the first month) and may occur intermittently during therapy. In most patients, flushing events were of mild to moderate severity. Overall, 3% of patients treated with dimethyl fumarate discontinued treatment due to flushing. Severe flushing episodes, characterized by generalized erythema, rash, and/or pruritus, were observed in less than 1% of patients treated with dimethyl fumarate (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", and "Posology and method of administration").
Gastrointestinal disorders
The incidence of gastrointestinal adverse reactions (e.g., diarrhoea [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 treated with dimethyl fumarate compared to placebo. Gastrointestinal disturbances usually occur early in dimethyl fumarate treatment (mostly within the first month) and may recur intermittently during therapy. In most cases, the intensity of gastrointestinal symptoms was mild or moderate. Four percent (4%) of patients treated with dimethyl fumarate discontinued treatment due to gastrointestinal adverse reactions. Serious gastrointestinal adverse reactions, including gastroenteritis and gastritis, were observed in 1% of patients treated with dimethyl fumarate (see section "Posology and method of administration").
Liver function
In placebo-controlled studies, in most patients, elevations in liver transaminases did not exceed ULN by more than 3 times. An increased frequency of liver transaminase elevations in patients treated with dimethyl fumarate compared to placebo was observed mainly during the first 6 months of treatment. Elevations in ALT and AST activity of 3 times or more compared to 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 less than 1% of cases.
No cases of concurrent elevations in liver transaminases of 3 times or more and total bilirubin of 2 times or more compared to ULN were observed.
During the post-marketing period, elevations in liver transaminases and drug-induced liver injury (elevation in transaminases by 3 times and concomitant increase in total bilirubin by 2 times) were reported with dimethyl fumarate use, which resolved after discontinuation of treatment.
Lymphopenia
In placebo-controlled studies, the majority of patients (>98%) had normal lymphocyte counts prior to treatment initiation. Following dimethyl fumarate administration, a decrease in mean lymphocyte count was observed during the first year, followed by a plateau. On average, lymphocyte counts decreased by approximately 30% from baseline. Mean and median lymphocyte counts remained within the normal range. Lymphocyte counts < 0.5 × 10⁹/L were observed in less than 1% of placebo-treated patients and in 6% of patients treated with dimethyl fumarate. Lymphocyte counts < 0.2 × 10⁹/L were observed in one patient treated with dimethyl fumarate but not in placebo-treated patients.
In clinical studies (both controlled and uncontrolled), 41% of patients treated with dimethyl fumarate experienced lymphopenia (defined in these studies as < 0.91 × 10⁹/L). Mild lymphopenia (≥ 0.8 × 10⁹/L to < 0.91 × 10⁹/L) was observed in 28% of patients; moderate lymphopenia (≥ 0.5 × 10⁹/L to < 0.8 × 10⁹/L), persisting for at least six months, was observed in 11% of patients; severe lymphopenia (< 0.5 × 10⁹/L), persisting for at least six months, was observed in 2% of patients. In most patients with severe lymphopenia, lymphocyte counts 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), reductions in CD4+ T-cells were moderate (≥ 0.2 × 10⁹/L to < 0.4 × 10⁹/L) or marked (< 0.2 × 10⁹/L) in 37% and 6% of patients, respectively, while CD8+ T-cell counts decreased in 59% of patients to < 0.2 × 10⁹/L and in 25% of patients to < 0.1 × 10⁹/L.
Infections, including PML and opportunistic infections
Cases of John Cunningham virus (JCV) infection leading to PML have been reported during dimethyl fumarate treatment (see section "Special warnings and precautions for use"). PML can be fatal or lead to severe disability. In one clinical trial, a patient receiving dimethyl fumarate developed PML during prolonged severe lymphopenia (lymphocyte count predominantly < 0.5 × 10⁹/L for 3.5 years), resulting in death. In the post-marketing period, PML has also occurred in patients with moderate and mild lymphopenia (from < 0.5 × 10⁹/L to below LLN, as defined by the local laboratory).
In several PML cases with T-cell subset analysis at diagnosis, CD8+ T-cell counts decreased to < 0.1 × 10⁹/L, while reductions in CD4+ T-cell counts were variable (ranging from 0.05 to 0.5 × 10⁹/L) and more closely correlated with the overall severity of lymphopenia (from < 0.5 × 10⁹/L to below LLN). Thus, the CD4+/CD8+ ratio in these patients was increased.
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.
Cases of herpes zoster infection have been reported with dimethyl fumarate use. During a long-term study of 1736 patients with multiple sclerosis receiving dimethyl fumarate, approximately 5% experienced one or more episodes of herpes zoster, most of which were moderate or severe. In most patients, including those with severe herpes zoster infection, lymphocyte counts were above LLN. Grade 2 and 3 lymphopenia was predominant in patients with concurrent lymphocytopenia. In post-marketing observations, most herpes zoster cases were non-serious and responsive to treatment. Data from post-marketing surveillance on absolute lymphocyte count (ALC) in patients with herpes zoster are limited; however, most patients had Grade 2 (from < 0.8 × 10⁹/L to 0.5 × 10⁹/L) or Grade 3 (from < 0.5 × 10⁹/L to 0.2 × 10⁹/L) lymphopenia (see section "Special warnings and precautions for use").
Laboratory abnormalities
In placebo-controlled studies, urinary ketone levels (1+ or higher) were higher in patients treated with dimethyl fumarate (45%) compared to placebo (10%). No adverse clinical consequences of this phenomenon were observed.
Levels of 1,25-dihydroxyvitamin D decreased in patients treated with 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 treated with 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 two months of therapy.
Paediatric population
Safety and efficacy in the paediatric population have not been established.
In a small open-label, 24-week, uncontrolled study in paediatric patients with multiple sclerosis aged 13 to 17 years (120 mg twice daily for 7 days, then 240 mg twice daily until end of treatment; safety-evaluable population n = 22) followed by a 96-week extension study (240 mg twice daily; safety-evaluable population n = 20), the safety profile was similar to that observed in adult patients.
Reporting of adverse reactions
Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions.
Store at temperatures not exceeding 25°C in the original packaging.
Keep out of the reach and sight of children.
Packaging.
14 capsules in a bottle. 1 bottle in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Amneal Pharmaceuticals Private Limited.
Manufacturer's address and location of operations.
Survey No. 634, 637 to 641, Near Kanakwati Sarheda-Bavla Highway, Village Rajoda, Tal Bavla, Ahmedabad, Gujarat 382220, India (IN).