Dimethylfumarate-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dimethylfumarate-Teva (Dimethylfumarate-Teva)

Composition:

Active substance: dimethyl fumarate;

1 gastro-resistant hard capsule contains 120 mg or 240 mg of dimethyl fumarate;

Excipients: capsule contents: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, methacrylic acid copolymer (type A), triethyl citrate, methacrylic copolymer dispersion, talc;

capsule shell: gelatin, titanium dioxide (E 171), diamond blue FCF (E 133), erythrosine (E 127), special red AG (E 129).

Pharmaceutical form. Gastro-resistant hard capsules.

Main physicochemical properties:

Gastro-resistant hard capsules 120 mg: hard gelatin capsules with a white opaque body and light blue opaque cap, marked "A188" on both cap and body, filled with white or almost white tablets;

Gastro-resistant hard capsules 240 mg: hard gelatin capsules with a light blue opaque body and light blue opaque cap, marked "A240" on both cap and body, filled with white or almost white tablets.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. ATC code: L04AX07.

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 effects of dimethyl fumarate appear to be predominantly mediated through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription pathway. Dimethyl fumarate has been shown to activate Nrf2-dependent regulation of antioxidant genes in patients (e.g., NAD(P)H dehydrogenase, quinone 1; [NQO1]).

Effect on the Immune System. Preclinical and clinical studies have demonstrated that dimethyl fumarate has anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and its main metabolite, monomethyl fumarate, significantly reduce immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies involving patients with psoriasis, dimethyl fumarate affected lymphocyte phenotype by suppressing pro-inflammatory cytokine profiles (TH1, TH17) and shifting towards anti-inflammatory production (TH2). Dimethyl fumarate has demonstrated therapeutic activity in multiple models of inflammation and neuroinflammatory damage. In phase 3 studies in patients with multiple sclerosis, after treatment with dimethyl fumarate, the mean lymphocyte count decreased by approximately 30% from baseline during the first year, followed by a plateau. In these studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below the lower limit of normal (LLN, 910 cells/mm³) were monitored for lymphocyte count recovery to LLN.

Clinical Efficacy and Safety. Two 2-year, randomized, double-blind, placebo-controlled studies [Study 1 (DEFINE) with 1234 patients and Study 2 (CONFIRM) with 1417 patients] were conducted in patients with relapsing-remitting multiple sclerosis (RRMS). Patients with progressive forms of multiple sclerosis (MS) were not included in these studies. Efficacy and safety were demonstrated in patients with an Expanded Disability Status Scale (EDSS) score from 0 to 5 inclusive, who had at least one relapse within the year prior to randomization or who had undergone brain magnetic resonance imaging (MRI) within 6 weeks prior to randomization and had at least one gadolinium-enhancing (Gd+) lesion. Study 2 also included a comparison with glatiramer acetate.

Efficacy in Patients with High Disease Activity. In the subgroup of patients with high disease activity, the treatment effect on relapses was consistent, while the effect on time to 3-month confirmed disability progression was not clearly established.

Pharmacokinetics

Following oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted into its main metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is not quantifiable in plasma after oral administration of the drug; therefore, all pharmacokinetic parameters were determined for monomethyl fumarate. Pharmacokinetic data were obtained from patients with multiple sclerosis and healthy volunteers.

Absorption. The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the gastro-resistant hard capsules contain microtablets coated with an enteric coating, absorption does not begin until they leave the stomach (typically less than 1 hour). In patients with multiple sclerosis, after administration of 240 mg twice daily with food, the median maximum concentration (Cmax) was 1.72 mg/L, and total exposure (AUC) was 8.02 h*mg/L. Overall, Cmax and AUC increased approximately proportionally with dose in the studied dose range (120–360 mg). Patients with multiple sclerosis received two 240 mg doses separated by 4 hours as part of a thrice-daily dosing regimen. Minimal accumulation was observed, resulting in a 12% increase in median Cmax compared to twice-daily dosing (1.72 mg/L with twice-daily dosing versus 1.93 mg/L with thrice-daily dosing), without affecting safety.

Food does not have a clinically significant effect on dimethyl fumarate exposure. However, dimethyl fumarate should be taken with food to improve tolerability regarding flushing or gastrointestinal adverse reactions.

Distribution. The apparent volume of distribution after oral administration of 240 mg dimethyl fumarate ranges from 60 L to 90 L. The plasma protein binding of monomethyl fumarate in human plasma is typically between 27% and 40%.

Biological Transformation. 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 entering systemic circulation. Further metabolism occurs via the tricarboxylic acid (TCA) cycle without involvement of the cytochrome P450 (CYP) system. In a study using 240 mg of 14C-dimethyl fumarate, glucose was identified as its main metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. Further metabolism of fumaric acid occurs through the TCA cycle, with exhalation of CO2 being the primary elimination pathway.

Elimination. Exhalation of CO2 is the main elimination pathway of dimethyl fumarate, accounting for 60% of the dose. Renal and fecal excretion are secondary elimination routes, accounting for 15.5% and 0.9% of the dose, respectively. The terminal half-life of monomethyl fumarate is short (approximately 1 hour), and circulating monomethyl fumarate is generally undetectable in most individuals after 24 hours. With repeated administration of dimethyl fumarate at therapeutic doses, no accumulation of the parent drug or monomethyl fumarate occurs.

Linearity. Dimethyl fumarate exposure increases approximately in proportion to dose following single and multiple doses within the studied dose range of 120 mg to 360 mg.

Pharmacokinetics in Special Patient Populations.

Based on results from an analysis of variance (ANOVA), body weight is a major covariate affecting exposure (Cmax and AUC) in patients with RRMS, but it does not impact safety and efficacy outcomes as assessed in clinical studies.

Gender and age 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 of dimethyl fumarate, accounting for less than 16% of the administered dose, pharmacokinetic assessment in individuals 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 assessment in individuals with hepatic impairment was not conducted.

Clinical characteristics.

Indications.

For the treatment of adult patients with relapsing-remitting multiple sclerosis (important information on patient populations in which efficacy of the medicinal product has been established is provided in the section «Pharmacodynamics»).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

Safety precautions.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

No studies have been conducted on the use of dimethyl fumarate in combination with antineoplastic or immunosuppressive agents; therefore, caution should be exercised when co-administering these agents. In clinical studies of multiple sclerosis, concomitant treatment of relapses with short courses of intravenous corticosteroids was not associated with a clinically significant increase in the frequency of infections.

During treatment with dimethyl fumarate, concomitant administration of inactivated vaccines according to the vaccination schedule may be considered. In a clinical study involving 71 patients with RRMS, 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) demonstrated comparable immune responses (defined as at least a 2-fold increase in titre compared to pre-vaccination levels) to tetanus toxoid (T-cell-dependent antigen) and serogroup C meningococcal conjugated polysaccharide vaccine (neo-antigen), whereas immune responses to various serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell-independent antigen) varied in both treatment groups. A positive immune response, defined as at least a 4-fold increase in antibody titre to three vaccines, was achieved in fewer individuals in both treatment groups. Small quantitative differences in response to tetanus toxoid and pneumococcal serotype 3 polysaccharide favored non-pegylated interferon.

There are no clinical data on the efficacy and safety of live attenuated vaccines in patients taking dimethyl fumarate. Live vaccines may carry an increased risk of clinical infection and should not be administered to patients taking dimethyl fumarate, except when the potential risk is considered less than the risk of remaining unvaccinated for the individual.

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. No potential risks of drug interactions were identified in in vitro studies of CYP inhibition and induction, studies on P-glycoprotein, and studies on protein binding of dimethyl fumarate and monomethyl fumarate (the primary metabolite of dimethyl fumarate).

Medicinal products commonly used in patients with multiple sclerosis, such as intramuscular interferon beta-1a and glatiramer acetate, were clinically tested for potential interaction with dimethyl fumarate and did not alter the pharmacokinetic profile of dimethyl fumarate.

Data from studies in healthy volunteers suggest that flushing associated with dimethyl fumarate 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 for 4 days and 4 weeks did not alter the pharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acid therapy should be considered before concomitant use with dimethyl fumarate in patients with RRMS. Long-term (more than 4 weeks) continuous use of acetylsalicylic acid has not been studied (see sections «Special precautions for use» and «Side effects»).

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 «Side effects») in patients taking dimethyl fumarate (see section «Special precautions for use. Blood tests/laboratory tests»).

Moderate alcohol consumption did not alter dimethyl fumarate exposure and was not associated with an increased incidence of adverse reactions. Consumption of large amounts of strong alcoholic beverages (over 30 vol.% alcohol) should be avoided within one hour after taking dimethyl fumarate, as alcohol may lead to an increased frequency of gastrointestinal adverse reactions.

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 a combined oral contraceptive (norgestimate and ethinylestradiol) did not cause any significant changes in exposure to the oral contraceptive. Studies on interaction with oral contraceptives containing other progestogens have not been conducted; however, no impact of dimethyl fumarate on their exposure is expected.

Paediatric population. Interaction studies have only been performed in adults.

Special precautions for use.

Blood tests / laboratory tests

In clinical studies, 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 initiating treatment, at 3 and 6 months of treatment, every 6–12 months thereafter, and as clinically indicated.

Dimethyl fumarate treatment may lead to drug-induced liver injury, including elevations in liver enzymes (≥3 × ULN [upper limit of normal]) and increased total bilirubin levels (≥2 × ULN). This liver injury may occur during treatment, several weeks later, or even later. These adverse reactions have been observed to resolve after discontinuation of treatment. Serum aminotransferases (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and total bilirubin levels should be assessed before starting treatment and during treatment as clinically indicated.

Lymphopenia may develop in patients receiving dimethyl fumarate (see section "Adverse reactions"). A complete blood count, including lymphocyte count, should be performed before initiating dimethyl fumarate therapy. If lymphocyte counts are 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 should be exercised when treating such patients. Dimethyl fumarate treatment should not be initiated in patients with severe lymphopenia (lymphocyte count <0.5×10⁹/L). After starting therapy, a complete blood count, including lymphocyte count, should be performed every 3 months.

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 individual risk of PML should be considered (see subsection on PML below). Lymphocyte counts should be monitored until recovery (see section "Pharmacological properties. Pharmacodynamics"). 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)

A baseline MRI (typically within 3 months) is required before initiating dimethyl fumarate therapy as a reference. The need for further MRI scans should be considered according to current guidelines. MRI may be considered as part of enhanced monitoring in patients at increased risk of PML. In case of clinical suspicion of PML, an MRI should be performed urgently for diagnostic purposes.

Progressive multifocal leukoencephalopathy

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) and may result in death or severe disability. Cases of PML 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, the risk cannot be excluded in patients with mild lymphopenia.

Additional factors increasing the 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 definitive data on the relationship with treatment duration are lacking);
• Significant reduction in CD4+ and particularly CD8+ T-cells, which are important for immune defense (see section "Adverse reactions");
• Prior immunosuppressive or immunomodulatory therapy (see below).

Physicians should monitor their patients for symptoms indicating neurological dysfunction and determine whether these symptoms are typical of MS or possibly suggestive of PML. At the first sign or symptom suggestive of PML, dimethyl fumarate should be discontinued and appropriate diagnostic investigations initiated, including quantitative polymerase chain reaction (PCR) testing for JCV DNA in cerebrospinal fluid. Symptoms of PML may resemble an MS relapse. Typical symptoms associated with PML are diverse, progress over days or weeks, and may include progressive weakness on one side of the body or clumsiness of limbs, 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 partner or caregivers about their treatment, as they may observe symptoms the patient is unaware of. PML can only occur in the presence of JCV infection. It should be noted that the impact of lymphopenia on the accuracy of serum JCV antibody testing has not been studied in patients receiving dimethyl fumarate. It should also be noted that a negative JCV antibody test (with normal lymphocyte count) does not exclude the possibility of subsequent JCV infection. If a patient develops PML, dimethyl fumarate must be discontinued and not restarted.

Prior treatment with immunosuppressive or immunomodulatory medicinal products

No studies have been conducted to evaluate the efficacy and safety of switching patients from other disease-modifying agents to dimethyl fumarate. Prior immunosuppressive therapy may contribute to the development of PML in patients receiving dimethyl fumarate. Cases of PML have been observed in patients previously treated with natalizumab, for which 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 previously received immunomodulatory treatment. When switching patients from another disease-modifying agent 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. A complete blood count is recommended before initiating dimethyl fumarate and regularly during treatment (see subsection "Blood tests / laboratory tests" above).

Severe renal or hepatic impairment

Dimethyl fumarate has not been studied in patients with severe renal or hepatic impairment; therefore, caution should be exercised in 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 should be exercised in such patients.

Flushing

During clinical studies, flushing was observed in 34% of patients receiving dimethyl fumarate. In most patients experiencing flushing, it was mild or moderate in severity. Data from studies in healthy volunteers suggest that dimethyl fumarate-associated flushing is likely mediated by prostaglandins. A short course of 75 mg non-enteric-coated acetylsalicylic acid may be beneficial for patients suffering from intolerable flushing (see section "Interaction with other medicinal products and other forms of interaction"). In two studies in healthy volunteers, the frequency and intensity of flushing decreased over the treatment period.

During clinical studies, three out of 2,560 patients receiving dimethyl fumarate experienced serious flushing symptoms, likely due to hypersensitivity or anaphylactoid reactions. These reactions were not life-threatening but required hospitalization. Physicians prescribing the medicinal product and patients should consider this possible cause in case 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 in the post-marketing period following dimethyl fumarate use. Symptoms may include dyspnea, hypoxia, hypotension, angioedema, rash, and 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; they may be severe 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 placebo-controlled Phase III studies, 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 (see section "Pharmacological properties"), if a patient develops a serious infection, consideration should be given to temporarily discontinuing dimethyl fumarate therapy, and the benefit-risk balance should be re-evaluated before resuming treatment. Patients receiving dimethyl fumarate should inform their physician of any infection symptoms. Patients with serious infections should not initiate dimethyl fumarate treatment until the infection has resolved. No increased incidence of serious infections was observed in patients with lymphocyte counts <0.8×10⁹/L or <0.5×10⁹/L. However, if therapy is continued in the presence of moderate or severe prolonged lymphopenia, the risk of opportunistic infections, including PML (see subsection "Progressive multifocal leukoencephalopathy" above), cannot be excluded.

Herpes zoster

Cases of herpes zoster have been reported with dimethyl fumarate use. Most cases were mild; however, severe 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. Discontinuation of dimethyl fumarate should be considered in patients with serious infections until the infection resolves (see section "Adverse reactions").

Initiation of treatment

Dimethyl fumarate therapy 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 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 accompanied by 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 levels or reduced glomerular filtration rate. In the presence of unexplained symptoms, the possibility of Fanconi syndrome should be considered and appropriate investigations performed.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of dimethyl fumarate in pregnant women are limited or unavailable. Reproductive toxicity has been observed in animal studies. Dimethyl fumarate is not recommended during pregnancy and in women of childbearing potential who are not using appropriate contraception (see section "Interaction with other medicinal products and other forms of interaction"). Dimethyl fumarate may be used during pregnancy only if clearly necessary, when potential benefit outweighs the possible 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. A decision should be made whether to discontinue breastfeeding or to discontinue dimethyl fumarate therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility. There are no data on the effect of dimethyl fumarate on human fertility. Preclinical data do not suggest that dimethyl fumarate may reduce fertility.

Ability to drive and use machines.

Dimethyl fumarate has no or negligible influence on the ability to drive or use machines. No studies have been conducted on the ability to drive or use machines; no potential impact of dimethyl fumarate on this ability was observed in clinical studies.

Method of Administration and Dosage

Treatment with this medicinal product 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 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 occurrence of flushing and gastrointestinal adverse reactions. The recommended maintenance dose of 240 mg twice daily should be restored within 1 month.

Dimethylfumarate-Teva should be taken with food (see section "Pharmacokinetics"). In patients who experience flushing or gastrointestinal adverse reactions, taking dimethylfumarate with food may improve tolerability (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use", "Adverse Reactions").

Special Patient Groups

Elderly patients. A limited number of patients aged 55 years and older participated in clinical studies of dimethylfumarate. An insufficient number of patients aged 65 years and older were enrolled in the studies to allow conclusions regarding differences in use between elderly and younger patients (see section "Pharmacokinetics"). Based on the mechanism of action of the active substance, there are theoretically no grounds for changing the dose in elderly patients.

Renal and hepatic impairment. Dimethylfumarate has not been studied in patients with renal or hepatic impairment. Based on data from clinical pharmacological studies, dose adjustment in these patient groups is not required (see section "Pharmacokinetics"). Treatment of patients with severe renal or hepatic impairment should be undertaken with caution (see section "Special Warnings and Precautions for Use").

Method of Administration

For oral use.

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

Children.

This medicinal product is not recommended for use in children (under 18 years of age).

Overdose.

Cases of dimethylfumarate overdose have been reported. The symptoms described were consistent with the known adverse reaction profile of dimethylfumarate. There are no known therapeutic measures to enhance the elimination of dimethylfumarate, and no antidote exists. In case of overdose, symptomatic and supportive treatment should be initiated based on clinical indications.

Adverse Reactions

In patients treated with dimethyl fumarate, the most common adverse reactions (occurring in ≥10% of patients) were flushing and gastrointestinal adverse reactions (diarrhea, nausea, abdominal pain, and upper abdominal pain). Flushing and gastrointestinal adverse reactions typically occurred at the beginning of treatment (mainly within the first month). In patients who experienced flushing and gastrointestinal adverse reactions, these events may recur intermittently throughout the entire 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 2468 patients received dimethyl fumarate and were observed for up to 4 years, with total drug exposure equivalent to 3588 patient-years. Approximately 1056 patients received dimethyl fumarate treatment for more than 2 years. The experience from uncontrolled clinical studies was consistent with that from placebo-controlled clinical studies.

Adverse reactions reported in clinical trials, post-marketing safety studies, and spontaneous reports are listed below. Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined 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).

Infections and infestations: common – gastroenteritis; frequency not known – progressive multifocal leukoencephalopathy (PML), herpes zoster.

Blood and lymphatic system disorders: common – lymphopenia, leukopenia; uncommon – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity; frequency not known – anaphylaxis, dyspnea, hypoxia, hypotension, angioedema.

Nervous system disorders: common – burning sensation.

Vascular disorders: very common – flushing; common – hot flush.

Respiratory, thoracic and mediastinal disorders: frequency not known – rhinorrhea.

Gastrointestinal disorders: very common – diarrhea, nausea, upper abdominal pain, abdominal pain; common – vomiting, dyspepsia, gastritis, gastrointestinal disorder.

Hepatobiliary disorders: common – increased AST levels, increased ALT levels; frequency not known – drug-induced liver injury.

Skin and subcutaneous tissue disorders: common – pruritus, rash, erythema, alopecia.

Renal and urinary disorders: common – proteinuria.

General disorders and administration site conditions: common – feeling of warmth.

Investigations: very common – ketonuria; common – albuminuria, decreased white blood cell count.

Description of selected adverse reactions

Flushing

In placebo-controlled studies, an increased incidence of flushing (34% vs. 4%) and feeling of warmth (7% vs. 2%) was observed in patients receiving dimethyl fumarate compared to those receiving placebo. Flushing is typically described as a sensation of warmth or flushing, but may also include other symptoms (e.g., warmth, redness, pruritus, and burning sensation). Flushing usually occurs at the beginning of dimethyl fumarate treatment (mainly within the first month) and may recur intermittently throughout the treatment period. Most flushing events were mild to moderate in severity. Overall, 3% of patients receiving dimethyl fumarate discontinued treatment due to flushing. Severe flushing events, characterized by generalized erythema, rash, and/or pruritus, were observed in less than 1% of patients receiving 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%], dyspepsia [5% vs. 3%]) was higher in patients receiving dimethyl fumarate compared to placebo. Gastrointestinal adverse reactions typically occurred at the beginning of treatment (mainly within the first month) and may recur intermittently throughout the treatment period. Most gastrointestinal adverse reactions were mild to moderate in severity. 4% of patients receiving dimethyl fumarate discontinued treatment due to gastrointestinal adverse reactions. Severe gastrointestinal adverse reactions, including gastroenteritis and gastritis, were observed in 1% of patients receiving dimethyl fumarate.

Liver function

In placebo-controlled studies, in most patients with elevated liver transaminases, the increase was <3 × ULN. An increased frequency of elevated liver transaminases was observed in patients receiving dimethyl fumarate compared to placebo, mainly during the first 6 months of treatment. Elevations in ALT and AST levels ≥3 × ULN were observed 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 between patients receiving dimethyl fumarate and those receiving placebo. No cases of transaminase elevations ≥3 × ULN with concomitant total bilirubin elevations ≥2 × ULN were observed in placebo-controlled studies.

Post-marketing reports have included elevations in liver enzymes and cases of drug-induced liver injury (transaminase elevations ≥3 × ULN with concomitant total bilirubin elevations ≥2 × ULN) during post-approval 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 treatment with dimethyl fumarate, 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 and were not observed 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) occurred in 28% of patients; moderate lymphopenia (lymphocyte count ≥0.5×10⁹/L and <0.8×10⁹/L), persisting for at least six months, occurred in 10% of patients; severe lymphopenia (lymphocyte count <0.5×10⁹/L), persisting for at least six months, occurred in 2% of patients. In patients with severe lymphopenia, lymphocyte counts generally remained below 0.5×10⁹/L during continued therapy. Additionally, in an uncontrolled prospective post-marketing study at 48 weeks 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 to <0.2×10⁹/L in 59% of patients and to <0.1×10⁹/L in 25% of patients. In controlled and uncontrolled clinical studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below LLN were monitored for lymphocyte count recovery to normal levels (see section "Pharmacological properties. Pharmacodynamics").

Infections, including PML and opportunistic infections

Cases of infection with the John Cunningham virus (JCV), leading to progressive multifocal leukoencephalopathy (PML), have been reported during treatment with dimethyl fumarate (see section "Special precautions"). PML may result in death or severe disability. In one clinical trial, a patient receiving dimethyl fumarate developed PML following 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 (>0.5×10⁹/L to <LLN, as defined by local laboratory standards).

In several PML cases, when T-cell subsets were analyzed during PML diagnosis, CD8+ T-cell counts were reduced to <0.1×10⁹/L, while CD4+ T-cell reductions 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 <LLN). Thus, an increased CD4+/CD8+ ratio was observed in these patients.

Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate; however, PML has also been reported in patients with mild lymphopenia. Furthermore, most post-marketing PML cases occurred in patients over 50 years of age.

Cases of herpes zoster have been reported during treatment with dimethyl fumarate. In an ongoing long-term extension study, in which 1736 patients with MS received dimethyl fumarate, approximately 5% experienced one or more episodes of herpes zoster, mostly of mild to moderate severity. In most patients, including those with severe herpes zoster infection, lymphocyte counts were above the lower limit of normal. In most patients with lymphocyte counts below LLN, lymphopenia was classified as moderate or severe. In the post-marketing period, most herpes zoster cases were non-severe and resolved with treatment. Post-marketing data indicate that in most patients with herpes zoster, moderate (from <0.8×10⁹/L to 0.5×10⁹/L) or severe lymphopenia (from <0.5×10⁹/L to 0.2×10⁹/L) was observed (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 clinically adverse consequences were observed in clinical studies.

Serum levels of 1,25-dihydroxyvitamin D decreased in patients receiving dimethyl fumarate compared to placebo (mean percent decrease from baseline at 2 years was 25% vs. 15%, respectively), while parathyroid hormone levels increased in patients receiving dimethyl fumarate compared to placebo (mean percent 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.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Shelf life after first opening of the bottle – 90 days.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of reach of children.

Packaging.

Enteric-coated hard capsules, 120 mg: 14 capsules in a bottle; 1 bottle in a carton.

Enteric-coated hard capsules, 240 mg: 60 capsules in a bottle; 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer.

Teva Pharmaceutical Industries Ltd.

Manufacturer's address and location of operations.

18 Hulvei Hurbatz Street, Industrial Zone, Kfar Saba, Israel.