Tekafum

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TECAFUM (TECAFUM)

Composition:

Active substance: dimethyl fumarate;

1 capsule contains 120 mg or 240 mg of dimethyl fumarate;

Excipients: microcrystalline cellulose, povidone, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), triacetin, talc, copolymer of methacrylic acid and ethyl acrylate (1:1), titanium dioxide (E 171), triethyl citrate;

Shell of hard gelatin capsule: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), diamond blue FCF-FD&C Blue 1 (E 133);

Composition of black printing ink: shellac (E 904), propylene glycol (E 1520), concentrated ammonia solution (E 527), ammonium hydroxide (E 525), black iron oxide (E 172).

Pharmaceutical form. Hard gastro-resistant capsules.

Main physicochemical properties:

120 mg: size 0 capsules with a green opaque cap and a white opaque body, printed in black ink with "DMF 120" on the body, containing ten mini-tablets of white to almost white color.

240 mg: size 00 capsules with a green opaque cap and body, printed in black ink with "DMF 240" on the body, containing twenty mini-tablets of white to almost white color.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Other immunosuppressants. Dimethyl fumarate.

ATC code L04AX07.

Pharmacological Properties

Mode of Action

The mechanism of the therapeutic effect of dimethyl fumarate in multiple sclerosis has not been fully elucidated. Preclinical studies have shown that the pharmacodynamic activity of dimethyl fumarate is primarily mediated through activation of the nuclear factor (erythroid-derived 2) (Nrf2) transcription pathway. Dimethyl fumarate has been demonstrated to activate Nrf2-dependent antioxidant genes in patients (e.g., NAD(P)H dehydrogenase, quinone 1 [NQO1]).

Pharmacodynamics

Effects on the Immune System

In preclinical and clinical studies, dimethyl fumarate has 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 phenotypes 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 Phase III studies in patients with multiple sclerosis, treatment with dimethyl fumarate was associated with a reduction in mean lymphocyte count (on average approximately 30% from baseline values during the first year, followed by stabilization). In these studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below the lower limit of normal (LLN) of 0.9×10⁹/L showed recovery of lymphocyte counts to LLN.

Pharmacokinetics

Following 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.

The pharmacokinetics of dimethyl fumarate have been studied in patients with multiple sclerosis and in healthy volunteers.

Absorption

The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the gastro-resistant hard capsules of dimethyl fumarate contain mini-tablets coated with an enteric coating, absorption occurs only after evacuation from the stomach (typically within less than 1 hour). After administration of the 240 mg dose twice daily with food, the mean maximum 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 hours×mg/L. Overall, Cmax and AUC increased approximately dose-proportionally 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, for twice- and three-times-daily dosing)).

Administration with food does not affect the plasma concentration of dimethyl fumarate. 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. The binding of monomethyl fumarate to human plasma proteins 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 via the TCA cycle, with CO2 release as the primary elimination pathway.

Elimination

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 it is generally not detectable in blood 24 hours after administration. No accumulation of dimethyl fumarate or monomethyl fumarate occurs with repeated administration at the therapeutic dose.

Linearity

The concentration of dimethyl fumarate increases approximately dose-proportionally in the range of 120 to 360 mg, both after single and multiple doses.

Pharmacokinetics in Special Patient Populations

Based on the results of an analysis of variance (ANOVA), body weight is the main covariate influencing exposure (Cmax and AUC) in patients with relapsing-remitting multiple sclerosis (RRMS), 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.

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.

Paediatric Population

The pharmacokinetic profile of dimethyl fumarate following administration 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 a total daily AUC of 7.24 hours×mg/L).

Clinical characteristics.

Indications.

The medicinal product Tecafum 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 multiple sclerosis relapses during clinical trials of 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 71 patients with relapsing-remitting multiple sclerosis), comparable immune responses (defined as ≥ 2-fold increase from pre-vaccination titer) to tetanus toxoid (T-cell-dependent antigen) and conjugated polysaccharide vaccine against meningococcus C (neoantigen) were observed in patients receiving 240 mg dimethyl fumarate twice daily for at least 6 months (n = 38) or non-pegylated interferon for at least 3 months (n = 33), whereas immune responses to different serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell-independent antigen) varied between both 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.

Other fumaric acid derivatives

During treatment with dimethyl fumarate, 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) 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 studies on binding of dimethyl fumarate and monomethyl fumarate to plasma proteins were also unremarkable.

Effect of other substances on dimethyl fumarate

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 dimethyl fumarate-associated flushing is likely mediated by prostaglandins. In two studies in healthy volunteers, administration of 325 mg (or equivalent) of non-enteric-coated acetylsalicylic acid 30 minutes before dimethyl fumarate intake for 4 days and 4 weeks did not alter the pharmacokinetic profile of dimethyl fumarate. The potential risk 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 with nephrotoxic medicinal products (such as aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, lithium) increases the likelihood of renal adverse reactions (e.g., proteinuria – see section "Adverse reactions") in patients taking dimethyl fumarate (see section "Special precautions for use. Blood tests/laboratory tests").

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 Tecafum, as alcohol may increase the frequency of gastrointestinal adverse reactions.

Effect of dimethyl fumarate on other substances

In vitro CYP induction studies did not demonstrate interactions between dimethyl fumarate and oral contraceptives. In an in vivo study, concomitant administration of dimethyl fumarate with combined oral contraceptives (norgestimate and ethinylestradiol) did not cause any significant changes in exposure to oral contraceptives. No interaction studies have been conducted with oral contraceptives containing other progestogens; however, no impact of dimethyl fumarate on their exposure is expected.

Children. Interaction studies have been conducted only in adults.

Special precautions for use.

Blood tests/laboratory tests

Renal function

In clinical trials, changes in renal laboratory parameters have been observed in patients receiving dimethyl fumarate therapy (see section "Adverse reactions"). The clinical significance of these changes is unknown. Assessment of renal function (e.g., creatinine, blood urea nitrogen, and urinalysis) is recommended before starting treatment, at 3 and 6 months after initiation, every 6–12 months thereafter, and 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 (ULN)) and increased total bilirubin levels (≥ 2 × ULN). Hepatic dysfunction may occur immediately after starting treatment, within several weeks, or later. Resolution of adverse events has been observed after discontinuation of dimethyl fumar ate. Serum aminotransferases (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels should be assessed before starting dimethyl fumarate treatment and during treatment as clinically indicated.

• Lymphocytes*

A complete blood count, including lymphocyte count, should be performed before initiating dimethyl fumarate therapy. If lymphocyte counts are found to be below normal, a thorough evaluation of potential causes should be conducted prior to starting treatment. The effect of dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts; therefore, caution is advised when treating such patients. Dimethyl fumarate treatment should not be initiated in patients with severe lymphopenia (lymphocyte count < 0.5×10⁹/L). A complete blood count, including lymphocyte count, should be performed every 3 months after starting therapy.

Increased vigilance is recommended for patients with lymphopenia due to an increased risk of progressive multifocal leukoencephalopathy (PML):

• Patients with prolonged severe lymphopenia (lymphocyte count < 0.5×10⁹/L) persisting for more than 6 months should discontinue dimethyl fumarate;
• In patients with persistent moderate reduction in absolute lymphocyte count (≥ 0.5×10⁹/L and < 0.8×10⁹/L) lasting more than 6 months, the benefit-risk ratio of dimethyl fumarate treatment should be re-evaluated;
• In patients with lymphocyte counts below the lower limit of normal (LLN) as defined by local laboratory standards, regular monitoring of absolute lymphocyte count is recommended.

Additional factors that may increase the individual risk of PML should be considered (see subsection on PML below). Lymphocyte counts should be monitored until recovery. After recovery and in the absence of alternative treatment options, the decision to restart dimethyl fumarate after discontinuation should be based on clinical assessment.

Magnetic resonance imaging (MRI)

Before initiating TecaFum, an MRI (typically within 3 months) should be performed, which may serve as a baseline. The need for further MRI scans should be considered according to national and local guidelines. MRI may be considered as part of enhanced monitoring in patients at increased risk of progressive multifocal leukoencephalopathy. In case of clinical suspicion of PML, an MRI should be performed urgently for diagnostic purposes.

Progressive multifocal leukoencephalopathy (PML)

Cases of PML have been reported in patients receiving dimethyl fumarate therapy (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 occurred with dimethyl fumarate and other fumarate-containing medicinal products in the context of lymphopenia (lymphocyte count below LLN). Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate; however, this risk cannot be excluded in patients with mild lymphopenia.

Additional factors that may contribute to increased risk of PML in the context of lymphopenia include:

• Duration of dimethyl fumarate therapy (PML cases occurred approximately 1–5 years after treatment initiation, although the exact relationship with treatment duration is unknown);
• Significant reduction in CD4+ and particularly CD8+ T-lymphocytes, which are important for immunological defense (see section "Adverse reactions");
• Prior immunosuppressive or immunomodulatory therapy (see below).

Physicians should monitor their patients for symptoms suggestive of neurological dysfunction and determine whether these symptoms are typical of multiple sclerosis or possibly indicative of PML.

At the first sign or symptom suggestive of PML, administration of 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). Symptoms of PML may resemble a multiple sclerosis relapse. Typical symptoms associated with PML are variable, progress over days or weeks, and may 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 attentive to 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 test for JCV antibodies (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 been conducted to evaluate the efficacy and safety of switching patients from other disease-modifying therapies to dimethyl fumarate. Prior immunosuppressive therapy may contribute to the development of PML in patients receiving dimethyl fumarate. Cases of PML have been reported in patients previously treated with natalizumab, for which PML is a known 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 therapy.

When switching patients from another disease-modifying therapy to dimethyl fumarate, the half-life and mechanism of action of the other agent should be considered to avoid additive immune effects while minimizing the risk of MS reactivation. Before starting dimethyl fumarate and regularly during treatment, a complete blood count is recommended (see subsection "Blood tests/laboratory tests" above).

Severe renal and hepatic impairment

Dimethyl fumarate has not been studied in patients with severe renal or severe hepatic impairment; therefore, caution should be exercised when administering to such patients (see section "Dosage and administration").

Severe active gastrointestinal disease

Dimethyl fumarate has not been studied in patients with severe active gastrointestinal disease; therefore, caution is advised in such patients.

Flushing

During clinical trials, flushing was observed in 34% of patients receiving dimethyl fumarate. In most cases, the intensity of flushing was rated as mild or moderately severe. Data from studies in healthy volunteers suggest that dimethyl fumarate-associated flushing is likely mediated by prostaglandins. A short course of 75 mg aspirin (non-enteric coated) may be beneficial for patients experiencing flushing. In two studies in 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 resulting from possible hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but led to hospitalization. Physicians prescribing the drug and patients should consider this possible cause in the event of severe flushing reactions (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 after dimethyl fumarate use in post-marketing surveillance. Symptoms may include dyspnea, hypoxia, arterial hypotension, angioedema, rash, or urticaria. The mechanism of dimethyl fumarate-induced anaphylaxis is unknown. Reactions typically occur after the first dose but may also 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. Treatment should not be resumed.

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 (see section "Pharmacological properties"), if a patient develops a serious infection, consideration should be given to temporarily discontinuing dimethyl fumarate therapy and re-evaluating the benefit-risk ratio before reinitiating treatment. Patients receiving dimethyl fumarate should inform their physician of symptoms of infection. Patients with serious infections should not initiate dimethyl fumarate treatment until the infection is 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. If therapy is continued in the presence of moderate or severe prolonged lymphopenia, the risk of opportunistic infections, including PML, cannot be excluded.

Herpes zoster

Cases of herpes zoster have been reported during dimethyl fumarate use. Most cases were non-serious; however, serious cases have been reported, including disseminated herpes zoster, herpes zoster with ocular involvement, herpes zoster with ear involvement, herpes zoster with nervous system involvement, herpes zoster with meningoencephalitis, and herpes zoster with meningo-myelitis. These complications may occur at any time during treatment. Patients receiving dimethyl fumarate should be monitored for signs and symptoms of herpes zoster, particularly in the presence of lymphocytopenia. If herpes zoster occurs, appropriate treatment should be initiated. Consideration should be given to discontinuing dimethyl fumarate in patients with serious infections until resolved (see section "Adverse reactions").

Initiation of treatment

Treatment with TecaFum 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 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.

Use during pregnancy or breastfeeding.

Pregnancy

A moderate amount of data is available from pregnant women (300 to 1000 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 collected in the pregnancy registry indicate that the average duration of dimethyl fumarate exposure was 4.6 gestational weeks, with limited exposure beyond the sixth week of pregnancy (outcomes in 44 pregnancies). Exposure to dimethyl fumarate at these early stages of pregnancy does not indicate developmental abnormalities or fetal/neonatal toxicity compared to the general population. The risk of prolonged exposure to dimethyl fumarate or exposure at later stages of pregnancy is unknown.

Animal studies have shown reproductive toxicity. TecaFum is not recommended during pregnancy. The drug may be administered during pregnancy only if clearly needed, when the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

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 TecaFum 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 impaired fertility.

Ability to affect reaction speed when driving or operating machinery.

TecaFum has no or negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Treatment with the medicinal product should be initiated under the supervision of a physician experienced in the treatment of multiple sclerosis.

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.

If a patient misses a dose, a double dose should not be taken. The missed dose may be taken only if the interval between doses is at least 4 hours. Otherwise, the patient should wait until the next scheduled dose.

A temporary reduction of the 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. The medicinal product Tecafum should be taken with food. For patients who may experience flushing or gastrointestinal adverse reactions, taking dimethyl fumarate with food may improve tolerability.

Special patient groups

Elderly patients

A limited number of patients aged 55 years and older participated in clinical studies with dimethyl fumarate. Also, an insufficient number of patients aged 65 years and older were included in the studies to draw conclusions about differences in 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

Dimethyl fumarate 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.

Administration

For oral use.

The capsule should be swallowed whole. The capsule or its contents should not be crushed, divided, dissolved, sucked, or chewed, as the enteric coating of the microtablets prevents gastrointestinal irritation.

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 dimethyl fumarate in children under 10 years of age have not been established. No data are available.

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 known antidotes. In case of overdose, symptomatic and supportive treatment should be initiated as clinically indicated.

Adverse reactions.

Summary of safety profile

The most common adverse reactions are flushing (35%) and gastrointestinal disorders (diarrhea (14%), nausea (12%), abdominal pain (10%), upper abdominal pain (10%)). Flushing and gastrointestinal disorders usually occur at the beginning of treatment (mostly within the first month); in patients experiencing flushing and gastrointestinal disorders, these events may recur periodically during dimethyl fumarate treatment. The most common adverse reactions leading to discontinuation of treatment are flushing (3%) and gastrointestinal disorders (4%).

In phases 2 and 3 placebo-controlled and uncontrolled clinical trials, a total of 2513 patients received dimethyl fumarate for up to 12 years, with a total exposure equivalent to 11,318 patient-years. Overall, 1169 patients received dimethyl fumarate for at least 5 years, and 426 patients for 10 years. The experience from uncontrolled clinical trials is consistent with that from placebo-controlled clinical trials.

List of adverse reactions

Adverse reactions, for which information was collected from clinical trials, post-marketing safety studies, and spontaneous reports, are presented in the table below.

Adverse reactions are listed by system organ class and frequency of occurrence. Frequencies are 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 (cannot be estimated from available data).

Description of individual adverse reactions

Flushing

In placebo-controlled studies, an increased incidence of flushing (34% compared to 4%) and sensation of warmth (7% compared to 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, but may also include other phenomena (e.g., feeling of heat, redness, itching, and burning sensation). Flushing usually begins at the start of dimethyl fumarate treatment (mainly within the first month) and may occur intermittently during therapy. In most patients, flushing episodes were of mild to moderate severity. Overall, 3% of patients treated with 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 treated with dimethyl fumarate.

Gastrointestinal disorders

The incidence 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 treated with dimethyl fumarate compared to placebo. Gastrointestinal adverse reactions typically began 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 mild to moderate. Four percent (4%) of patients treated with dimethyl fumarate discontinued treatment due to gastrointestinal adverse reactions. The incidence of serious gastrointestinal adverse reactions, including gastroenteritis and gastritis, was observed in 1% of patients treated with 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). Increased frequency of elevated liver transaminases in patients treated with dimethyl fumarate compared to placebo was observed mainly during the first 6 months of treatment. Elevations in ALT and AST of ≥3 times the ULN were reported in 5% and 2% of placebo-treated patients, and in 6% and 2% of dimethyl fumarate-treated patients, respectively. Discontinuation of treatment due to elevated liver transaminases was <1% and was similar in patients receiving dimethyl fumarate and those receiving placebo.

No cases of transaminase elevations ≥3 × ULN with concomitant elevation of total bilirubin ≥2 × ULN were observed in placebo-controlled studies.

Elevations in liver enzymes and cases of drug-induced liver injury (transaminase elevations ≥3 × ULN with concomitant elevation of total bilirubin ≥2 × ULN) have been reported during post-marketing use of dimethyl fumarate. These events resolved upon 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 dimethyl fumarate-treated patients. Lymphocyte counts <0.2×10⁹/L were observed in one patient receiving dimethyl fumarate but not in placebo-treated patients.

In clinical studies (both controlled and uncontrolled), 41% of patients receiving dimethyl fumarate experienced lymphopenia (defined in these studies as lymphocyte count <0.91×10⁹/L). Mild lymphopenia (lymphocyte count ≥0.8×10⁹/L and <0.91×10⁹/L) was observed in 28% of patients; moderate lymphopenia (lymphocyte count ≥0.5×10⁹/L and <0.8×10⁹/L), persisting for at least six months, was observed in 11% of patients; severe lymphopenia (lymphocyte count <0.5×10⁹/L), persisting for at least six months, was observed in 2% of patients. In the group with severe lymphopenia, lymphocyte counts mostly remained <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 counts 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 reduced in 59% of patients to a count <0.2×10⁹/L and in 25% of patients to a count <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 normal levels.

Progressive multifocal leukoencephalopathy

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 in the context of prolonged severe lymphopenia (lymphocyte count predominantly <0.5×10⁹/L for 3.5 years), resulting in a fatal outcome. In post-marketing settings, PML has also occurred in patients with moderate and mild lymphopenia (from >0.5×10⁹/L to <LLN, as defined by laboratory standards).

In several PML cases where T-cell subsets were assessed at 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 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, open-label extension study in which 1736 patients with MS received dimethyl fumarate, herpes zoster occurred in approximately 5% of patients, with 42% of cases being mild, 55% moderate, and 3% severe. The onset of the first dose of dimethyl fumarate ranged from approximately 3 months to 10 years. Adverse reactions were reversible in four patients.

In most patients, including those who experienced serious herpes zoster infection, lymphocyte counts were above the lower limit of normal. In most patients with lymphocyte counts below the LLN, lymphopenia was classified as moderate or severe. In post-marketing settings, most herpes zoster infections were non-serious and resolved with treatment. Limited data are available on absolute lymphocyte counts (ALC) in patients with herpes zoster infection during the post-marketing period. However, reports indicate that most patients experienced moderate (from ≥0.5×10⁹/L to <0.8×10⁹/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 during clinical studies. Levels of 1,25-dihydroxyvitamin D decreased in patients receiving dimethyl fumarate compared to placebo (median 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, active-controlled study, children with multiple sclerosis (n=7 aged 10 to less than 13 years and n=71 aged 13 to less than 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 pediatric clinical trial design 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 in the following percentages among pediatric patients:

• Headache occurred in 28% of patients receiving dimethyl fumarate versus 36% of patients receiving interferon beta-1a.
• Gastrointestinal disorders were reported in 74% of patients receiving dimethyl fumarate versus 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 versus 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 versus 7% of patients receiving interferon beta-1a.

In a small 24-week open-label, uncontrolled study involving children with multiple sclerosis aged 13 to 17 years (120 mg twice daily for 7 days, then 240 mg twice daily for the remainder of the treatment period; 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 suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special temperature storage requirements. Store in the original packaging to protect from light. Keep out of reach and sight of children.

Packaging.

120 mg dosage: 7 capsules per blister; 2 blisters per cardboard pack.

240 mg dosage: 7 capsules per blister; 8 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Kevara GROUP EOOD

Manufacturer's location and address of business operations.

5th Floor, Tsaritsa Yoanna 9, Office 23, Sofia, 1618, Bulgaria.