Dimethylfumarate-pharmak
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dimethylfumarate-Farmak (Dimethylfumarate-Farmak)
Composition:
Active substance: dimethyl fumarate;
One gastro-resistant hard capsule contains 120 mg or 240 mg of dimethyl fumarate;
Excipients in the core of mini-tablets: microcrystalline cellulose, povidone K-30, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating composition of mini-tablets: SheffCoat Clear ASA 5X00294 (hydroxypropyl methylcellulose, triacetin, talc); SheffCoat White ENT TEC 5X00273 (methacrylic acid copolymer (type A), talc, titanium dioxide (E 171), triethyl citrate);
Coating composition of hard capsule size № 0 or № 00: gelatin, titanium dioxide (E 171), iron oxide yellow (E 172), diamond blue (FCF-FD&C Blue 1 (E 133));
*Composition of black printing ink (capsule marking): shellac (E 904), anhydrous ethanol (E 1510), isopropyl alcohol, butyl alcohol, propylene glycol (E 1520), purified water, concentrated ammonia solution (E 527), potassium hydroxide (E 525), iron oxide black (E 172).
Pharmaceutical form. Gastro-resistant hard capsules.
Main physicochemical properties:
Gastro-resistant hard capsules of 120 mg: green opaque cap and white opaque body, capsule size № 0, marked with black ink «DMF 120» on the body, containing mini-tablets of white to almost white color;
Gastro-resistant hard capsules of 240 mg: green opaque cap and body, capsule size № 00, marked with black ink «DMF 240» on the body, containing mini-tablets of white to almost white color.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Other immunosuppressants.
ATC code L04A X07.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
The mechanism of the therapeutic effect of dimethyl fumarate in multiple sclerosis is not fully understood. Preclinical studies have shown that the pharmacodynamic effect of dimethyl fumarate is primarily mediated through activation of nuclear factor (erythroid-derived 2) (Nrf2) transcription. 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 has demonstrated anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical studies. In clinical studies involving patients with psoriasis, dimethyl fumarate affected lymphocyte phenotypes, reducing levels of pro-inflammatory cytokines (TH1, TH17), and induced a shift towards anti-inflammatory production (TH2). Dimethyl fumarate demonstrated therapeutic activity in several models of inflammatory and neuroinflammatory injury. In Phase III trials in patients with multiple sclerosis (DEFINE, CONFIRM, and ENDORSE), treatment with dimethyl fumarate resulted in a mean reduction in lymphocyte count of approximately 30% from baseline during the first year, followed by stabilization at a lower level. In these studies, patients who discontinued dimethyl fumarate treatment and whose lymphocyte counts were below the LLN (910 cells/mm³) were monitored until lymphocyte counts returned to the LLN.
Paediatric Patients
The safety and efficacy of dimethyl fumarate in paediatric patients with multiple sclerosis were evaluated in a randomized, open-label, active-controlled, parallel-group study in patients with multiple sclerosis aged 10 to 17 years. A total of 150 patients were randomized to receive either dimethyl fumarate (240 mg orally twice daily) or interferon beta-1a (30 mcg intramuscularly once weekly) for 96 weeks. The primary endpoint was the percentage of patients without new or newly enlarged T2 hyperintense lesions on brain MRI at week 96. The key secondary endpoint was the number of new or newly enlarged T2 hyperintense lesions on brain MRI at week 96. Descriptive statistics were used, as no confirmatory hypothesis was defined for the primary endpoint.
The percentage of patients in the ITT population without new or newly enlarged T2 lesions on MRI at week 96 compared to baseline was 12.8% for dimethyl fumarate versus 2.8% for the interferon beta-1a group. The mean number of new or newly enlarged T2 lesions at week 96 compared to baseline, adjusted for baseline T2 lesion count and age (ITT population excluding patients without MRI data), was 12.4 for dimethyl fumarate and 32.6 for interferon beta-1a.
The probability of clinical relapse was 34% in the dimethyl fumarate group and 48% in the interferon beta-1a group over the 96-week open-label study period.
The safety profile in paediatric patients (aged 13 to 17 years) receiving dimethyl fumarate treatment was quantitatively similar to the safety profile previously observed in adult patients.
Pharmacokinetics
Following oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted into its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is not quantitatively detectable in plasma after oral administration of dimethyl fumarate. Therefore, all pharmacokinetic analyses related to dimethyl fumarate were conducted using plasma concentrations of monomethyl fumarate. Pharmacokinetic data were obtained from patients with multiple sclerosis and healthy volunteers.
Absorption
The time to maximum concentration (Tmax) of monomethyl fumarate is 2 to 2.5 hours. Since the Dimethylfumarate-Pharmak solid gastro-resistant capsules contain microtablets coated with a gastro-resistant layer, absorption does not begin until the capsules have left the stomach (typically within less than 1 hour). After administration of 240 mg twice daily with food, the mean maximum concentration (Cmax) was 1.72 mg/L, and the total exposure, expressed as area under the concentration-time curve (AUC), was 8.02 mg·h/L in patients with multiple sclerosis. In general, Cmax and AUC increased approximately dose-proportionally over the studied dose range (120 mg to 360 mg). Patients with multiple sclerosis received two 240 mg doses administered 4 hours apart under a three-times-daily dosing regimen. This resulted in minimal accumulation, increasing median Cmax by 12% compared to twice-daily dosing (1.72 mg/L with twice-daily dosing versus 1.93 mg/L with three-times-daily dosing), with no safety consequences.
Food intake does not have a clinically significant effect on the exposure of dimethyl fumarate. Dimethyl fumarate should be taken with food to improve tolerability regarding gastrointestinal adverse effects.
Distribution
The predicted volume of distribution after oral administration of 240 mg dimethyl fumarate ranges from 60 L to 90 L. The extent of plasma protein binding of monomethyl fumarate in humans typically ranges from 27% to 40%.
Biotransformation
In humans, dimethyl fumarate undergoes extensive metabolism, and less than 0.1% of the dose is excreted unchanged in urine. Initially, the compound is metabolized by esterases, which are widely distributed in the gastrointestinal tract, blood, and tissues, prior to entering systemic circulation. Further metabolism occurs via the tricarboxylic acid (TCA) cycle without involvement of the cytochrome P450 (CYP) system. A study using a single 240 mg dose of 14C-dimethyl fumarate showed that glucose is the primary metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. The metabolism of fumaric acid occurs through the TCA cycle, with the primary route of elimination being exhalation of CO2.
Elimination
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 terminal half-life of monomethyl fumarate is short (approximately 1 hour), and in most individuals, monomethyl fumarate is not present in plasma 24 hours after administration. No accumulation of the parent drug or monomethyl fumarate occurs with repeated dosing of dimethyl fumarate under the recommended treatment regimen.
Linearity
The exposure of dimethyl fumarate increases approximately dose-proportionally after single and multiple doses within the studied dose range of 120 mg to 360 mg.
Pharmacokinetics in Special Patient Populations
According to results from an analysis of variance (ANOVA), body weight is a significant covariate affecting exposure (Cmax and AUC) in patients with relapsing-remitting multiple sclerosis; however, this does not impact the safety and efficacy outcomes studied in clinical trials.
Gender and age had no clinically significant effect on the pharmacokinetics of dimethyl fumarate. Pharmacokinetics in patients aged 65 years and older have not been studied.
Paediatric Patients
The pharmacokinetic profile of dimethyl fumarate 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 these adolescent patients were consistent with those previously observed in adult patients (Cmax: 2.00 ± 1.29 mg/L; AUC0–12h: 3.62 ± 1.16 mg·h/L, corresponding to a total daily AUC of 7.24 mg·h/L).
Renal Impairment
Since the renal system is a secondary elimination pathway for dimethyl fumarate, accounting for less than 16% of the administered dose, pharmacokinetics have not been studied in patients with renal impairment.
Hepatic Impairment
Since dimethyl fumarate and monomethyl fumarate are metabolized by esterases without involvement of the CYP450 system, pharmacokinetics have not been studied in individuals with hepatic impairment.
Clinical characteristics.
Indications.
The medicinal product Dimethylfumarate-Pharmak is indicated for the treatment of adult patients and children aged 13 years and older with relapsing-remitting multiple sclerosis (RRMS).
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.
Dimethylfumarate has not been studied in combination with antineoplastic or immunosuppressive therapies; 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 dimethylfumarate clinical trials was not associated with a clinically significant increase in the frequency of infections.
Concomitant administration of inactivated vaccines according to national vaccination schedules may be considered during dimethylfumarate therapy. In a clinical study involving 71 patients with relapsing-remitting multiple sclerosis who received either 240 mg dimethylfumarate (n=38) twice daily for at least 6 months or non-pegylated interferon (n=33) for at least 3 months, patients achieved the following immunological response rates: similar immune responses (defined as ≥two-fold increase in titer pre- and post-vaccination) to tetanus toxoid (a T-cell-dependent antigen) and conjugated meningococcal C-polysaccharide vaccine (a neoantigen), whereas immune responses to various serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (a T-cell-independent antigen) differed between the two treatment groups. A smaller proportion of individuals in both treatment groups achieved a positive immune response defined as ≥four-fold increase in antibody titer to three vaccines. Small quantitative differences in response to tetanus toxoid and pneumococcal polysaccharide serotype 3 were observed in favor of non-pegylated interferon.
Clinical data on the efficacy and safety of administering live attenuated vaccines in patients taking Dimethylfumarate-Pharmak are lacking. Live attenuated vaccines may carry an increased risk of clinical infection and therefore should only be administered to patients receiving treatment with Dimethylfumarate-Pharmak when, in exceptional cases, the potential benefit outweighs the risk of not vaccinating.
During treatment with Dimethylfumarate-Pharmak, concomitant use of other medicinal products containing fumaric acid (topical or systemic) should be avoided.
In humans, dimethylfumarate is extensively metabolized by esterases prior to entering systemic circulation; further metabolism occurs via the tricarboxylic acid cycle without involvement of the cytochrome P450 (CYP) system. Potential risks of interaction with other medicinal products were not identified in in vitro CYP inhibition and induction studies, P-glycoprotein studies, or interaction studies between dimethylfumarate and monomethylfumarate (the primary metabolite of dimethylfumarate bound to blood proteins).
Medicinal products commonly used in patients with multiple sclerosis—interferon beta-1a administered intramuscularly and glatiramer acetate—were clinically tested for potential interaction with dimethylfumarate and did not alter the pharmacokinetic profile of dimethylfumarate.
Data from studies in healthy volunteers suggest that flushing associated with dimethylfumarate intake is likely mediated by prostaglandins. In two studies involving healthy volunteers, administration of 325 mg (or equivalent dose) of enteric-coated aspirin 30 minutes before dimethylfumarate intake over 4 days and 4 weeks, respectively, did not alter the pharmacokinetic profile of dimethylfumarate. In patients with relapsing-remitting multiple sclerosis, potential risks associated with the use of aspirin should be considered before initiating concomitant therapy with dimethylfumarate. Long-term (>4 weeks) continuous use of aspirin has not been studied.
Concomitant treatment with nephrotoxic agents (such as aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, or lithium) may increase the likelihood of renal adverse reactions (e.g., proteinuria, see section "Adverse reactions") in patients taking dimethylfumarate.
Moderate alcohol consumption did not alter the effects of dimethylfumarate 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 taking dimethylfumarate, as alcohol may increase the frequency of gastrointestinal adverse effects.
In vitro CYP induction studies did not reveal any interaction between dimethylfumarate and oral contraceptives. In an in vivo study, concomitant administration of dimethylfumarate and combined oral contraceptives (containing norgestimate and ethinylestradiol) was not associated with clinically significant changes in exposure to oral contraceptives. Interaction studies with oral contraceptives containing other progestogens have not been conducted; however, an effect of dimethylfumarate on their exposure is not expected.
Paediatric population
Interaction studies have been conducted only in adult patients.
Special precautions for use.
Blood analysis/Laboratory tests
Within clinical trials, changes in laboratory parameters of renal function have been observed in patients treated with dimethyl fumarate. The clinical significance of these changes is unknown. Assessment of renal function (e.g., creatinine level, blood urea nitrogen, and urinalysis) is recommended before starting treatment, at 3 and 6 months after initiation of therapy, and every 6–12 months thereafter, as well as whenever clinically indicated.
Drug-induced liver injury, including elevations in liver enzymes (≥ 3 times the upper limit of normal (ULN)) and increased total bilirubin (≥ 2 ULN), may occur with dimethyl fumarate treatment. This may occur immediately, after several weeks, or later. Adverse effects were observed to resolve after discontinuation of treatment.
Assessment of serum aminotransferases (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin is recommended before starting treatment and during therapy, as clinically indicated.
Lymphopenia may develop in patients receiving dimethyl fumarate. A complete blood count, including lymphocyte count, should be determined before initiating dimethyl fumarate treatment.
If lymphocyte counts are below normal, a thorough evaluation of potential causes should be performed prior to initiating dimethyl fumarate therapy. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts; therefore, caution should be exercised when treating such patients. Dimethyl fumarate should not be prescribed to patients with severe lymphopenia (lymphocyte count < 0.5 x 10⁹/L).
After starting treatment, a complete blood count, including lymphocyte count, should be monitored every 3 months.
Due to the increased risk of progressive multifocal leukoencephalopathy (PML), patients with lymphopenia should be under enhanced surveillance as follows:
- dimethyl fumarate treatment should be discontinued in patients with marked prolonged lymphopenia (lymphocyte count < 0.5 x 10⁹/L) lasting more than 6 months due to increased risk;
- benefit-risk assessment should be performed in patients with persistent moderate reduction in lymphocyte count (≥ 0.5 x 10⁹/L to < 0.8 x 10⁹/L) lasting more than 6 months;
- in patients with lymphocyte counts below the lower limit of normal (LLN) as defined by local laboratory reference levels, regular monitoring of absolute lymphocyte count is recommended. Additional factors that may increase individual risk of PML should be considered (see section on PML below).
Lymphocyte counts should be monitored until recovery. During recovery and in the absence of alternative treatment options, the decision on whether to resume dimethyl fumarate therapy after a treatment interruption should be based on clinical assessment of the patient’s condition.
Magnetic resonance imaging (MRI)
Before initiating treatment with Dimethyl fumarate-Pharmak, an MRI should be performed (typically within 3 months) for baseline comparison. The need for further MRI examinations should be considered according to national and local guidelines. MRI scans may be considered part of enhanced monitoring in patients considered to be at increased risk of developing 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 been reported in patients treated with dimethyl fumarate. PML is an opportunistic infection caused by the John Cunningham virus (JCV) that may result in death or severe disability.
Cases of PML have occurred during treatment with dimethyl fumarate and other fumarate-containing medicinal products in the presence of lymphopenia (lymphocyte count below LLN). Prolonged moderate or severe lymphopenia increases the risk of 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 presence of lymphopenia include:
- duration of dimethyl fumarate treatment. Cases of PML have been observed approximately 1–5 years after initiation of treatment, although the exact relationship with treatment duration is unknown;
- significant reduction in CD4+ and particularly CD8+ T-lymphocytes, which are important for immune defense (see section "Adverse reactions");
- prior immunosuppressive or immunomodulatory therapy (see below).
Physicians should evaluate patients to determine whether symptoms indicate neurological dysfunction and, if so, whether these symptoms are typical of multiple sclerosis or possibly indicative of PML development.
At the first signs suggestive of PML, dimethyl fumarate treatment should be discontinued and appropriate diagnostic investigations initiated, including testing for JCV polyomavirus DNA in cerebrospinal fluid (CSF) by quantitative polymerase chain reaction (PCR). Symptoms of PML may mimic those of a multiple sclerosis relapse. Specific symptoms associated with PML are variable, may develop over days or weeks, and include progressive weakness or slowed movement of limbs, visual disturbances, and changes in mental function, 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 inform family members or caregivers about the treatment, as they may observe symptoms the patient is unaware of.
PML can only occur in the presence of JCV infection. When testing for JCV infection, it should be considered that the impact of lymphopenia on the accuracy of JCV antibody detection in patients treated with dimethyl fumarate has not been studied. It should also be noted that a negative JCV antibody test result (with normal lymphocyte count) does not exclude the possibility of subsequent JCV infection.
If a patient develops PML, dimethyl fumarate treatment should be permanently discontinued.
Prior treatment with immunosuppressive or immunomodulatory therapy
No studies have evaluated the efficacy and safety of switching to dimethyl fumarate from other medicinal products. Prior immunosuppressive therapy may contribute to the development of PML in patients treated with dimethyl fumarate.
Cases of PML have been reported 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 during dimethyl fumarate treatment occurred in patients who had received prior immunomodulatory therapy.
When switching patients from another disease-modifying therapy to dimethyl fumarate, the half-life and mechanism of action of the previous therapy should be considered to avoid additive immune effects while minimizing the risk of multiple sclerosis relapse. Complete blood counts are recommended before starting and during dimethyl fumarate treatment (see section "Blood analysis/Laboratory tests" above).
Severe renal and hepatic impairment
Dimethyl fumarate has not been studied in patients with severe renal or hepatic impairment; therefore, caution should be exercised when using the medicinal product in such patients.
Gastrointestinal disorders during active flare-up
Dimethyl fumarate has not been studied in patients with gastrointestinal disorders during active flare-up; therefore, the medicinal product should be used cautiously in this patient group.
Flushing
In clinical trials, flushing occurred in 34% of patients receiving dimethyl fumarate. In most cases, flushing was mild or moderately severe. Data from studies in healthy volunteers suggest that flushing associated with dimethyl fumarate is likely mediated by prostaglandins. A short course of 75 mg enteric-coated aspirin tablets may be beneficial for patients experiencing intolerable flushing. In two studies involving healthy volunteers, a reduction in the frequency and severity of flushing was observed over the treatment period.
In clinical trials, severe flushing symptoms, likely related to hypersensitivity or anaphylactoid reactions, were observed in 3 out of 2560 patients treated with dimethyl fumarate. These events were not life-threatening but led to hospitalization. Physicians and patients should be informed about the potential for severe flushing symptoms.
Anaphylactic reactions
Cases of anaphylaxis/anaphylactoid reactions have been reported during post-marketing surveillance of dimethyl fumarate treatment. Possible symptoms include dyspnea, hypoxia, hypotension, angioedema, rash, or urticaria. The mechanism of anaphylaxis caused by dimethyl fumarate is unknown. These reactions typically occur after the first dose but may also occur at any time during treatment and can be severe 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 or placebo, respectively. However, due to the immunomodulatory properties of dimethyl fumarate, if a patient develops a serious infection, treatment with dimethyl fumarate should be considered for temporary discontinuation, and the benefit-risk balance should be reassessed before resuming therapy. Patients receiving Dimethyl fumarate-Pharmak should be instructed to report symptoms of infection. Patients with serious infections should not initiate dimethyl fumarate therapy until the infection(s) have resolved.
No increase in the frequency of serious infections was observed in patients with lymphocyte counts < 0.8 x 10⁹/L or < 0.5 x 10⁹/L. However, when continuing treatment 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 observed during dimethyl fumarate treatment. Most cases were non-serious; however, serious cases have been reported, including disseminated herpes zoster, herpes zoster with ocular involvement, otalgia due to herpesvirus infection of the seventh cranial nerve and geniculate ganglion, neurological herpesvirus infections, herpesviral meningoencephalitis, and herpesviral meningoencephalomyelitis. 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 resolution.
Initiation of treatment
Treatment with Dimethyl fumarate-Pharmak should be initiated gradually to reduce the occurrence of gastrointestinal adverse effects.
Fanconi syndrome
Cases of Fanconi syndrome have been reported with dimethyl fumarate used 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 concomitant hypophosphatemia). As the condition progresses, symptoms such as polyuria, polydipsia, and proximal muscle weakness may appear. In rare cases, hypophosphatemic osteomalacia may occur, characterized by non-localized bone pain, elevated serum alkaline phosphatase levels, and stress fractures. Importantly, Fanconi syndrome may occur without elevated creatinine levels or reduced glomerular filtration rate. In cases of unexplained symptoms, Fanconi syndrome should be considered and appropriate investigations performed.
Paediatric population
The safety profile in paediatric patients is qualitatively similar to that in adults; therefore, the warnings and precautions also apply to paediatric patients. For quantitative differences in the safety profile, see section "Adverse reactions".
The long-term safety of dimethyl fumarate in paediatric patients has not yet been established.
Use during pregnancy or breastfeeding.
Pregnancy
There is a moderate amount of data (from 300 to 1000 pregnancy cases) based on pregnancy registry data and post-marketing spontaneous reports. The dimethyl fumarate pregnancy registry documented 289 prospectively collected pregnancy outcomes in patients with multiple sclerosis who used dimethyl fumarate. The mean duration of dimethyl fumarate exposure was 4.6 gestational weeks, with limited exposure beyond the sixth gestational week (44 pregnancy outcomes). Exposure to dimethyl fumarate at these early stages of pregnancy does not indicate the presence of congenital malformations or fetal/neonatal toxicity compared to the general population. The risk associated with longer-term exposure to dimethyl fumarate or exposure at later stages of pregnancy is unknown.
Reproductive toxicity has been observed in animal studies. Dimethyl fumarate-Pharmak is not recommended for use in pregnant women or in women of childbearing potential who are not using appropriate contraception. The medicinal product may be prescribed during pregnancy only if absolutely necessary, when the potential benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
There are no data on whether dimethyl fumarate or its metabolites are excreted in human breast milk. Risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue dimethyl fumarate-Pharmak 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 is associated with an increased risk of reduced fertility.
Ability to affect reaction speed when driving or operating machinery.
Dimethyl fumarate-Pharmak has no effect or a negligible effect on the ability to drive or operate machinery. No studies have been conducted on the ability to drive or operate machinery; furthermore, no potential impact of dimethyl fumarate on this ability was observed in clinical trials.
Administration and Dosage
Treatment should be initiated under the supervision of a physician experienced in the management of multiple sclerosis.
Dosage
The initial dose 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 missed dose may be taken only if at least 4 hours have passed since the last dose. Otherwise, the patient should wait until the next scheduled dose.
A temporary reduction in dose to 120 mg twice daily may help reduce the frequency of flushing and gastrointestinal adverse reactions. The recommended maintenance dose of 240 mg twice daily should be restored within 1 month.
Dimethyl fumarate-Farmak should be taken with food. For patients experiencing flushing or gastrointestinal adverse reactions, taking Dimethyl fumarate-Farmak with food may improve tolerability.
Special Patient Populations
Elderly patients
A limited number of patients aged 55 years and older participated in clinical trials of dimethyl fumarate. The number of patients aged 65 years and older was insufficient to determine whether their response differs from younger patients. Based on the mechanism of action of the active substance, there are no theoretical grounds for dose adjustment in elderly patients.
Renal and hepatic impairment
Dimethyl fumarate has not been studied in patients with renal or hepatic impairment. According to clinical pharmacological data, dose adjustment is not required. However, caution should be exercised when treating patients with severe renal or hepatic impairment.
Pediatric population
The dosage is the same for adults and children aged 13 years and older.
Available data are described in the sections "Pharmacodynamics", "Pharmacokinetics", "Special precautions", and "Adverse reactions". Data in children aged 10 to 12 years are limited. The safety and efficacy of dimethyl fumarate in children under 10 years of age have not been established.
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 gastric acid-resistant coating of the microtablets prevents intestinal irritation.
Children
The medicinal product is indicated for children aged 13 years and older. Available data are described in the sections "Pharmacodynamics", "Pharmacokin游戏副本, "Special precautions", and "Adverse reactions". Data in children aged 10 to 12 years are limited. The safety and efficacy of dimethyl fumarate in children under 10 years of age have not been established.
Overdose
Symptoms. Cases of dimethyl fumarate overdose have been reported. The symptoms described in these cases were consistent with the known adverse reaction profile of dimethyl fumarate.
Treatment. There are no known therapeutic interventions to enhance elimination of dimethyl fumarate, and no specific antidotes are known. In the event of overdose, symptomatic and supportive treatment should be initiated as clinically indicated.
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 adverse reactions (diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal adverse reactions occurred more frequently at the beginning of therapy (mainly within the first month), and these symptoms may recur intermittently throughout the treatment period. The most common adverse reactions leading to discontinuation of treatment (incidence > 1%) in patients receiving dimethyl fumarate were flushing (3%) and gastrointestinal adverse reactions (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients received dimethyl fumarate and were observed for up to 12 years, with an overall exposure equivalent to 11,318 patient-years. Approximately 1169 patients received dimethyl fumarate treatment for at least 5 years, and 426 patients for at least 10 years. The experience from uncontrolled clinical trials corresponds to that from placebo-controlled clinical trials.
Summary of adverse reactions is presented in the table below
Adverse reactions observed during clinical studies, safety studies of drug use in the post-marketing period, and spontaneous adverse reaction reports are listed in the table below.
Adverse reactions are classified by system/organ class according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology database. The frequency categories of adverse reactions listed below are defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (frequency cannot be estimated from the available data).
| MedDRA System Organ Class |
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 |
|
| 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 disorders |
common |
|
| Hepatobiliary and biliary tract disorders |
elevation of AST levels |
common |
| elevation of ALT levels |
common |
|
| drug-induced liver injury1 |
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 reactions |
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 sensations (7% vs 2%) was observed in patients receiving dimethyl fumarate compared to those receiving placebo. Flushing sensations are typically described as a rush of blood or warmth, but may also include other symptoms (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 in patients experiencing flushing, episodes may continue intermittently throughout the treatment course.
In most patients, flushing episodes were of mild or moderate severity. Overall, 3% of patients receiving dimethyl fumarate discontinued treatment due to flushing. The incidence of severe flushing episodes characterized by generalized erythema, rash, and/or pruritus was observed in less than 1% of patients receiving dimethyl fumarate.
Gastrointestinal disorders.
The frequency of gastrointestinal events (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 events typically begin at the start of dimethyl fumarate treatment (mainly within the first month), and in patients experiencing gastrointestinal adverse reactions, these may continue intermittently throughout the treatment course. 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 incidence of serious gastrointestinal adverse events, including gastroenteritis and gastritis, was observed in 1% of patients receiving dimethyl fumarate.
Liver function.
According to placebo-controlled studies, in most patients with elevated liver transaminase levels, values were less than 3 times the upper limit of normal (ULN). An increased frequency of elevated liver transaminase levels 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 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 concomitant elevations in liver transaminases to 3 or more times ULN and total bilirubin to 2 or more times ULN were observed. During post-marketing use of dimethyl fumarate, increased liver transaminase levels and drug-induced liver injury (transaminase elevations 3 times ULN and concomitant increase in total bilirubin 2 times ULN) have been reported, which resolved after discontinuation of treatment.
Lymphopenia.
In placebo-controlled studies, the majority (>98%) of patients had normal lymphocyte counts before starting treatment. 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 patients receiving placebo and in 6% of patients receiving dimethyl fumarate. Lymphocyte counts <0.2×10⁹/L were observed in one patient receiving dimethyl fumarate but not in patients receiving placebo.
In clinical studies (both controlled and uncontrolled), lymphopenia (defined in these studies as <0.91×10⁹/L) was observed in 41% of patients receiving dimethyl fumarate treatment. Mild lymphopenia (values from ≥0.8×10⁹/L to <0.91×10⁹/L) was observed in 28% of patients; moderate lymphopenia (values from ≥0.5×10⁹/L to <0.8×10⁹/L), persisting for at least 6 months, was observed in 11% of patients; severe lymphopenia (values <0.5×10⁹/L), persisting for at least 6 months, was observed in 2% of patients. The majority of patients with severe lymphopenia remained below 0.5×10⁹/L during continued therapy.
Additionally, an uncontrolled prospective post-marketing study showed that at week 48 of dimethyl fumarate treatment (n=185), CD4+ T-cell counts were moderately (values ≥0.2×10⁹/L to <0.4×10⁹/L) or markedly (<0.2×10⁹/L) reduced in 37% and 6% of patients, respectively, while CD8+ T-cells were more frequently reduced in 59% of patients with values <0.2×10⁹/L and in 25% of patients with values <0.1×10⁹/L. In controlled and uncontrolled clinical studies, patients who discontinued dimethyl fumarate treatment with lymphocyte counts below the lower limit of normal were monitored until lymphocyte counts returned to normal.
Infections, including PML and opportunistic infections.
Cases of John Cunningham virus (JCV) infection, which causes progressive multifocal leukoencephalopathy (PML), have been reported during treatment with dimethyl fumarate (see section «Special precautions for use»). PML may result in death or severe disability. In one of the clinical trials, a patient receiving dimethyl fumarate developed PML in the context of prolonged severe lymphopenia (lymphocyte count predominantly <0.5×10⁹/L for 3.5 years), which resulted in death. In post-marketing settings, PML has also occurred in patients with moderate and mild lymphopenia (from >0.5×10⁹/L to <ULN, as defined by laboratory standards).
In several PML cases with T-lymphocyte subset analysis performed at the time of PML diagnosis, CD8+ T-cell counts were reduced to <0.1×10⁹/L, while reductions in CD4+ T-cell counts varied (ranging from <0.05 to 0.5×10⁹/L) and correlated more with overall severity (from <0.5×10⁹/L to <ULN). Thus, in these patients, an elevated CD4+/CD8+ ratio was observed.
Prolonged moderate or severe lymphopenia is associated with an increased risk of PML during dimethyl fumarate treatment; however, PML has also occurred in patients with mild lymphopenia. Furthermore, most post-marketing PML cases occurred in patients aged 50 years and older.
Cases of herpes zoster infection have been reported during treatment with dimethyl fumarate. In a long-term extension study in which 1736 patients with multiple sclerosis received dimethyl fumarate, approximately 5% experienced one or more episodes of herpes zoster, most of which were mild or moderate in severity. In most subjects, including those with severe herpes zoster infection, lymphocyte counts were above the lower limit of normal. In most patients with lymphocyte counts below ULN, lymphopenia was assessed as moderate or severe. In post-marketing settings, most herpes zoster infection cases were not serious and were resolved. Data on absolute lymphocyte count (ALC) in patients with herpes zoster infection in the post-marketing setting are limited. However, according to reports, most patients experienced 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 for use»).
Laboratory abnormalities.
In placebo-controlled studies, urinary ketone levels (1+ or higher) were higher in patients receiving dimethyl fumarate (45%) compared to those receiving placebo (10%). No adverse clinical consequences were observed in clinical studies. Levels of 1,25-dihydroxyvitamin D decreased in patients receiving dimethyl fumarate (compared to placebo, mean 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 study with active control involving children aged 10 to 17 years with relapsing-remitting multiple sclerosis (120 mg twice daily for 7 days, followed by 240 mg twice daily for the duration of treatment; study population, n=78), the safety profile in children was similar to that previously observed in adult patients.
The pediatric clinical trial design differed from placebo-controlled clinical trials in adults. Therefore, it cannot be excluded that the trial design influenced the quantitative differences in adverse reactions between pediatric and adult populations.
The following adverse reactions were observed more frequently (≥10%) in pediatric patients compared to adult patients:
- Headache occurred in 28% of patients receiving dimethyl fumarate compared to 36% of patients receiving interferon beta-1a;
- Gastrointestinal disorders occurred in 74% of patients receiving dimethyl fumarate compared to 31% of patients receiving interferon beta-1a. The most common events with dimethyl fumarate were abdominal pain and vomiting;
- Respiratory, thoracic, and mediastinal disorders occurred in 32% of patients receiving dimethyl fumarate compared to 11% of patients receiving interferon beta-1a. The most common events with dimethyl fumarate were sore throat and severe cough;
- Dysmenorrhea occurred in 17% of patients receiving dimethyl fumarate compared to 7% of patients receiving interferon beta-1a.
In a small 24-week open-label uncontrolled study involving pediatric patients aged 13–17 years with relapsing-remitting multiple sclerosis (120 mg twice daily for 7 days, followed by 240 mg twice daily for the duration of treatment; safety population, n=22), followed by a 96-week extension study (240 mg twice daily; safety population, n=20), the safety profile was similar to that observed in adult patients.
Data on children aged 10 to 12 years are limited. The safety and efficacy of dimethyl fumarate in children under 10 years of age have not been established.
Reporting suspected adverse reactions.
Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk ratio 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 the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions. Store at temperatures not exceeding 30°C, in the original packaging, in a place protected from light. Keep out of reach of children.
Packaging.
Enteric-coated hard capsules, 120 mg: 7 capsules in a blister; 3 blisters per pack.
Enteric-coated hard capsules, 240 mg: 7 capsules in a blister; 8 blisters per pack.
Prescription status. Prescription only.
Manufacturer.
JSC "Farmak", Ukraine (secondary packaging, labeling, quality control, batch release of bulk product manufactured by Sanovel Ilac Sanayi ve Ticaret A.S., Turkey (manufacturing, packaging, quality control, and batch release)).
Manufacturer's address and place of business.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.