Dimethylfumarate-mili-120

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIMETHYLFUMARATE-MILI-120 DIMETHYLFUMARATE-MILI-240 (Dimethylfumarate-Mili-120 Dimethylfumarate-Mili-240)

Composition:

Active substance: dimethyl fumarate;

One modified-release capsule contains 120 mg or 240 mg of dimethyl fumarate;

Excipients:

Core of mini-tablets: microcrystalline cellulose (Avicel PH 102), sodium croscarmellose (Ac-Di-Sol), colloidal silicon dioxide (Cab-O-Sil M-5P), magnesium stearate (Hyqual);

Coating of mini-tablets (12% w/w dispersion): methacrylic acid and methyl methacrylate copolymer (Eudragit L100), triethyl citrate, talc, isopropyl alcohol, purified water;

Enteric coating of mini-tablets (15% w/w dispersion): methacrylic acid and methyl methacrylate copolymer (Eudragit L30 D-55), triethyl citrate, talc, purified water;

Composition of hard gelatin capsule (size “0”): gelatin, purified water, titanium dioxide (E 171), yellow iron oxide (E 172), diamond blue FCF (E 133), sodium lauryl sulfate;

Composition of printing ink (TekPrint™ SW-9008 Black Ink): shellac, anhydrous alcohol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide, purified water.

Pharmaceutical form. Modified-release capsules.

Main physicochemical properties:

120 mg: modified-release capsules with an opaque white body printed with “8” in black ink and an opaque green cap printed with “SML”. The capsule contents are white coated mini-tablets.

240 mg: modified-release capsules with an opaque green body printed with “9” in black ink and an opaque green cap printed with “SML”. The capsule contents are white coated mini-tablets.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents.

ATC code: L04AX07.

Pharmacological properties.

Pharmacodynamics.

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

Effects on the immune system

In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory effects. Dimethyl fumarate and its primary metabolite, monomethyl fumarate, have been shown to significantly reduce immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli. In clinical studies in patients with psoriasis, dimethyl fumarate influenced lymphocyte phenotype by suppressing pro-inflammatory cytokine profiles (TH1, TH17) and shifting towards an anti-inflammatory profile (TH2). Dimethyl fumarate 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 when lymphocyte counts were below the lower limit of normal (LLN) of 910 cells/mm³ were monitored for lymphocyte count recovery.

Pharmacokinetics.

The pharmacokinetics of dimethyl fumarate have been studied in patients with multiple sclerosis and in healthy volunteers. After oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted into its primary metabolite, monomethyl fumarate, which also 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.

Absorption

The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the enteric-coated hard capsules contain mini-tablets protected by an enteric coating, absorption occurs only after evacuation from the stomach (usually within less than 1 hour). After administration of the 240 mg dose twice daily with food, the mean peak concentration (Cmax) in patients with multiple sclerosis was 1.72 mg/L, and the total area under the curve (AUC) was 8.02 h×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 regimens).

Administration with food does not affect the blood concentration of dimethyl fumarate. Dimethyl fumarate should be administered with food to improve tolerability of adverse reactions (flushing or gastrointestinal disturbances) (see section "Dosage and administration").

Distribution

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

Biotransformation

In humans, dimethyl fumarate is extensively metabolized, with less than 0.1% of the dose excreted unchanged in urine. It is initially metabolized by esterases in the gastrointestinal tract, blood, and tissues before reaching systemic circulation. Further metabolism occurs via the tricarboxylic acid (TCA) cycle without involvement of the cytochrome P450 (CYP) system. In one study using a 240 mg dose of 14C-dimethyl fumarate, glucose was identified as the primary metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. Further metabolism of fumaric acid proceeds through the TCA cycle, with CO2 release as the primary elimination pathway.

Excretion

Exhalation of CO2 is the primary route of elimination of dimethyl fumarate, accounting for 60% of the dose. Renal and fecal excretion are secondary elimination pathways, accounting for 15.5% and 0.9% of the dose, respectively.

The elimination half-life (T½) of monomethyl fumarate is short (approximately 1 hour), and the drug is not detectable in blood in most patients after 24 hours. No accumulation of unchanged dimethyl fumarate or monomethyl fumarate occurs with repeated administration of dimethyl fumarate in the therapeutic regimen.

Linearity

Dimethyl fumarate concentrations increase approximately dose-proportionally within the range of 120 to 360 mg, both after single and multiple doses.

Pharmacokinetics in special patient populations

According to analysis of variance (ANOVA), body weight is the main covariate influencing exposure (Cmax and AUC) in patients with relapsing-remitting multiple sclerosis, but it does not affect safety and efficacy outcomes as assessed in clinical studies.

Age and sex had no clinically significant effect on the pharmacokinetics of dimethyl fumarate. Pharmacokinetics in patients aged 65 years and older have not been studied.

Children

The pharmacokinetic profile of dimethyl fumarate following administration of 240 mg twice daily was evaluated in a small, open-label, uncontrolled study in patients aged 13 to 17 years with relapsing-remitting multiple sclerosis (n = 21). The pharmacokinetics of dimethyl fumarate in adolescent patients were similar to those in adults (Cmax: 2.00 ± 1.29 mg/L; AUC0–12h: 3.62 ± 1.16 h×mg/L, corresponding to total daily AUC of 7.24 h×mg/L).

Renal impairment

Since renal excretion is a secondary elimination pathway for dimethyl fumarate and accounts for less than 16% of the administered dose, pharmacokinetic evaluation in patients with renal impairment has not been performed.

Hepatic impairment

Since dimethyl fumarate and monomethyl fumarate are metabolized by esterases without involvement of the CYP450 system, pharmacokinetic evaluation in individuals with hepatic impairment has not been performed.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Contraindications.

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

Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

Interaction with other medicinal products and other types of interactions.

Studies on the use of dimethyl fumarate in combination with antineoplastic or immunosuppressive agents have not been conducted; therefore, caution should be exercised when administering them concomitantly. Concomitant short-term intravenous administration of corticosteroids for the prevention of relapses in multiple sclerosis during clinical trials of dimethyl fumarate was not associated with a clinically significant increase in the frequency of infections.

Administration of inactivated vaccines according to national vaccination schedules may be considered during therapy with dimethyl fumarate. In a clinical study (involving a total of 71 patients with relapsing multiple sclerosis), comparable immune responses (defined as at least a 2-fold increase from pre-vaccination titer) to tetanus toxoid (a T-cell-dependent antigen) and conjugated polysaccharide vaccine against meningococcus C (a neoantigen) were observed in patients receiving 240 mg of dimethyl fumarate twice daily for at least 6 months (n = 38) or non-pegylated interferon for at least 3 months (n = 33). However, immune responses to different serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (a T-cell-independent antigen) varied between treatment groups. A positive immune response, defined as a 4-fold increase in antibody titer to three vaccines, was achieved in fewer patients in both treatment groups. Small quantitative differences in response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were observed in favor of non-pegylated interferon.

There are no clinical data on the safety and efficacy of administering live attenuated vaccines to patients taking dimethyl fumarate. Live vaccines may increase the risk of infectious diseases and therefore should not be administered to patients receiving dimethyl fumarate, except when the potential benefit of vaccination outweighs the risk of administration.

During treatment with the drug, 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, and studies evaluating P-glycoprotein effects and plasma protein binding of dimethyl fumarate and monomethyl fumarate (the main metabolite of dimethyl fumarate) revealed no significant interactions.

Clinical studies have established that medicinal products used for the treatment of multiple sclerosis (intramuscular interferon beta-1a and glatiramer acetate) do not interact with dimethyl fumarate and do not alter its pharmacokinetic profile.

Data from studies involving healthy volunteers suggest that flushing associated with dimethyl fumarate is mediated by prostaglandins. In two studies involving healthy volunteers, administration of acetylsalicylic acid at a dose of 325 mg (or equivalent) in a non-enteric-coated formulation 30 minutes before dimethyl fumarate for more than 4 days and more than 4 weeks, respectively, did not alter the pharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acid therapy should be considered before prescribing concomitant use with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis. Long-term (> 4 weeks) continuous use of acetylsalicylic acid has not been studied (see section "Special precautions for use" and "Adverse reactions").

Concomitant therapy of dimethyl fumarate with nephrotoxic medicinal products (such as aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, or lithium) may increase the potential for adverse reactions affecting the kidneys and urinary system (e.g., proteinuria, see section "Adverse reactions"). (See subsection "Blood / laboratory tests" in section "Special precautions for use".)

Moderate alcohol consumption did not affect dimethyl fumarate exposure and was not associated with an increased incidence of adverse reactions. Consumption of large amounts of strong alcoholic beverages (more than 30% alcohol by volume) should be avoided within one hour after administration of the medicinal product, as alcohol may increase the frequency of gastrointestinal adverse reactions.

In vitro studies on possible induction of cytochrome P450 enzymes did not reveal interactions between dimethyl fumarate and oral contraceptives. In an in vivo study, co-administration of dimethyl fumarate with combined oral contraceptives (norgestimate and ethinylestradiol) showed no significant changes in exposure to the oral contraceptive. Studies on interactions with oral contraceptives containing other progestogens have not been conducted; however, an effect of dimethyl fumarate on exposure is not expected.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Blood / laboratory tests

Changes in individual kidney function parameters were observed in clinical trials in patients receiving dimethyl fumarate (see section "Adverse reactions"). The clinical significance of these changes is unknown. Assessment of kidney function (creatinine, blood urea nitrogen levels, and urinalysis) is recommended before starting treatment, at 3 and 6 months of treatment, and every 6–12 months thereafter, as clinically indicated.

Dimethyl fumarate may cause liver injury, including increased levels of liver enzymes (≥ 3 × ULN [upper limit of normal]) and increased total bilirubin levels (≥ 2 × ULN). Liver function abnormalities may occur immediately after starting the drug, after several weeks, or later. Adverse reactions resolved after discontinuation of dimethyl fumarate treatment. Monitoring of serum aminotransferase levels (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and total bilirubin levels is recommended before starting dimethyl fumarate treatment and during treatment, as clinically indicated.

Patients receiving dimethyl fumarate may develop severe, prolonged lymphopenia (see section "Adverse reactions"). A complete blood count, including lymphocyte count, should be performed before initiating treatment with dimethyl fumarate.

The effect of dimethyl fumarate has not been studied in patients who had low lymphocyte counts at the start of treatment; therefore, caution should be exercised when treating such patients. The medicinal product should not be administered to patients with severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L).

After starting therapy, a complete blood count, including lymphocyte count, should be performed every 3 months.

Patients with lymphopenia should be closely monitored due to an increased risk of progressive multifocal leukoencephalopathy (PML), and the following recommendations should be followed:

• The medicinal product should be discontinued in patients with prolonged severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L) lasting more than 6 months.
• In patients with persistent moderate reduction in absolute lymphocyte count (≥0.5 × 10⁹/L and < 0.8 × 10⁹/L) for more than six months, the benefit-risk ratio of dimethyl fumarate treatment should be re-evaluated.

Patients with lymphocyte counts below the lower limit of normal (LLN), as defined by local laboratory reference values, should undergo regular monitoring of absolute lymphocyte count. Factors that may further increase the individual risk of PML should be considered (see subsection "Progressive multifocal leukoencephalopathy (PML)" below).

Lymphocyte counts should be monitored until normalization. After lymphocyte count normalization and in the absence of alternative treatment options, the decision on whether to resume dimethyl fumarate after treatment discontinuation should be based on clinical assessment.

Magnetic resonance imaging (MRI)

An MRI scan (typically within 3 months) should be performed before starting the medicinal product and may be used for comparison purposes. The need for further MRI scans should be considered in accordance with national and local guidelines. MRI may be considered as part of enhanced monitoring for patients at increased risk of developing progressive multifocal leukoencephalopathy (PML). In case of clinical suspicion of PML, an MRI should be performed immediately for diagnostic purposes.

Progressive multifocal leukoencephalopathy (PML)

Cases of PML have occurred with the use of dimethyl fumarate (see section "Adverse reactions"). PML is an opportunistic infection caused by the John Cunningham virus (JCV) that may lead to severe disability or death.

Cases of PML have been observed with the use of dimethyl fumarate and other fumarate-containing medicinal products in patients with prolonged lymphopenia (lymphocyte count below LLN). Prolonged moderate to severe lymphopenia increases the risk of PML with dimethyl fumarate; however, this risk cannot be excluded in patients with mild lymphopenia.

Additional risk factors for PML in the context of lymphopenia include:

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

Physicians should examine their patients to determine whether symptoms indicate neurological dysfunction and, if so, whether symptoms are typical of MS or possibly suggestive of PML.

Upon first signs or symptoms suggestive of PML, the medicinal product should be discontinued and appropriate diagnostic investigations initiated, including quantitative polymerase chain reaction (PCR) testing for JCV DNA in cerebrospinal fluid (CSF). Symptoms of PML may resemble those of a multiple sclerosis relapse. Typical symptoms of PML are variable, progress over several days or weeks, and include progressive weakness on one side of the body or limb clumsiness, blurred vision, changes in thinking, memory and orientation, leading to confusion and personality changes.

Physicians should be particularly vigilant for symptoms suggestive of PML that the patient may not notice. Patients should also be advised to inform their partner or caregiver about their treatment, as they may observe symptoms the patient is unaware of.

PML can only occur in the presence of JCV infection. It should be noted that the impact of lymphopenia on the accuracy of the serum JCV antibody test in patients receiving dimethyl fumarate has not been studied. A negative JCV antibody test (with normal lymphocyte count) does not exclude the possibility of subsequent JCV infection.

If a patient develops PML, dimethyl fumarate must be permanently discontinued.

Prior treatment with immunosuppressive or immunomodulatory agents

No studies have evaluated the efficacy and safety of switching from other medicinal products to dimethyl fumarate. Prior immunosuppressive therapy may influence the risk of PML in patients receiving dimethyl fumarate.

Cases of PML have occurred in patients previously treated with natalizumab, in whom PML is a known risk. Physicians should be aware that cases of PML occurring after recent discontinuation of natalizumab may occur without lymphopenia.

Furthermore, most confirmed cases of PML with dimethyl fumarate occurred in patients who had prior immunomodulatory treatment.

When switching disease-modifying therapies to dimethyl fumarate, the half-life and mechanism of action of other agents should be considered to avoid additive immune effects while minimizing the risk of multiple sclerosis reactivation. A complete blood count is recommended before starting dimethyl fumarate therapy and regularly during treatment (see subsection "Blood / laboratory tests" above).

Severe renal and hepatic impairment

The effect of dimethyl fumarate has not been studied in patients with severe renal or hepatic impairment; therefore, the medicinal product should be used with caution in this patient group (see section "Posology and method of administration").

Active gastrointestinal disorders

The effect of dimethyl fumarate has not been studied in patients with active gastrointestinal disorders; therefore, the medicinal product should be used with caution in this patient group.

Flushing

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

During clinical trials, three out of 2,560 patients receiving dimethyl fumarate experienced serious flushing symptoms, possibly due to hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but required hospitalization. Physicians and patients should be informed about the potential for severe flushing symptoms (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Adverse reactions").

Anaphylactic reactions

Cases of anaphylaxis/anaphylactoid reactions have been reported during post-marketing surveillance of dimethyl fumarate treatment. Symptoms may include dyspnea, hypoxia, hypotension, angioedema, rash, or urticaria. The mechanism of dimethyl fumarate-induced anaphylaxis is unknown. Reactions usually occur after the first dose but may also occur at any time during treatment and can be serious and life-threatening. Patients should discontinue dimethyl fumarate and seek immediate medical attention if they experience signs or symptoms of anaphylaxis. Treatment should not be resumed (see section "Adverse reactions").

Infections

In phase III placebo-controlled trials, the incidence of infections (60% vs. 58%) and serious infections (2% vs. 2%) was similar in patients receiving dimethyl fumarate and placebo, respectively. If a patient develops a serious infection, treatment with the medicinal product should be discontinued. The benefit-risk ratio should be evaluated when considering resumption of therapy.

Patients receiving dimethyl fumarate should inform their physician about symptoms of infection. Patients with serious infections should not initiate dimethyl fumarate treatment until the infection has resolved.

No increase in the frequency of serious infections was observed in patients with lymphocyte counts < 0.8 × 10⁹/L or < 0.5 × 10⁹/L (see section "Adverse reactions").

If therapy continues in the presence of prolonged moderate or severe lymphopenia, the risk of opportunistic infections, including PML, cannot be excluded (see subsection "Progressive multifocal leukoencephalopathy (PML)" above).

Herpes zoster infections

Cases of herpes zoster infections have been reported during dimethyl fumarate treatment. Most cases were non-serious; however, serious cases have been reported, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster oticus, neurological herpesvirus infections, herpesviral meningitis, and meningomyelitis. These adverse reactions may occur at any time during treatment. Signs and symptoms of herpes zoster should be monitored, especially in patients with lymphocytopenia receiving dimethyl fumarate. If herpes zoster occurs, appropriate treatment should be initiated. Discontinuation of the medicinal product should be considered in patients with serious infections until recovery (see section "Adverse reactions").

Initiation of treatment

Treatment with dimethyl fumarate should be initiated gradually to reduce the risk of flushing and gastrointestinal adverse reactions (see section "Posology and method of administration").

Fanconi syndrome

Cases of Fanconi syndrome have been reported with dimethyl fumarate use in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome and discontinuation of dimethyl fumarate treatment are important to prevent renal dysfunction and osteomalacia, as the syndrome is usually reversible. Key signs include proteinuria, glucosuria (with normal blood glucose levels), hyperaminoaciduria, and phosphaturia (possibly with hypophosphatemia). Progression may include symptoms such as polyuria, polydipsia, and proximal muscle weakness. In rare cases, hypophosphatemic osteomalacia may occur, characterized by non-localized bone pain, elevated serum alkaline phosphatase, and stress fractures. Importantly, Fanconi syndrome may occur without elevated creatinine or reduced glomerular filtration rate. In the presence of unexplained symptoms, Fanconi syndrome should be considered and appropriate investigations performed.

Pediatric population

Safety and efficacy in the pediatric population have not been established.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of dimethyl fumarate in pregnant women. Reproductive toxicity was observed in animal studies. Dimethyl fumarate is not recommended for use in pregnant women or in women of childbearing potential who are not using appropriate contraception (see section "Interaction with other medicinal products and other forms of interaction"). The medicinal product may be prescribed during pregnancy only if absolutely necessary, when the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk; therefore, a risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue dimethyl fumarate therapy should be made after careful consideration of the benefit to the mother and the risk to the infant.

Fertility

There are no data on the effect of dimethyl fumarate on human fertility. Preclinical data do not indicate that dimethyl fumarate increases the risk of reduced fertility.

Ability to drive and use machines.

Dimethyl fumarate has no effect or a negligible effect on the ability to drive or operate machinery. Although no specific studies on driving or operating machinery have been conducted, clinical trials have not revealed any potential impact of dimethyl fumarate on this ability.

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.

Method of Administration

For oral use.

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

Dosage

The initial dose of the medicinal product is 120 mg twice daily. After 7 days, the dose should be increased to the recommended maintenance dose of 240 mg twice daily (see section "Special Instructions").

If a patient misses a dose, a double dose should not be taken. A 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.

Dimethyl fumarate should be taken with food (see section "Pharmacological Properties"). For patients who experience flushing or gastrointestinal adverse reactions, taking dimethyl fumarate with food may improve tolerability (see sections "Special Instructions", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Adverse Reactions").

Special Populations

Elderly patients

A limited number of patients aged 55 years and older participated in clinical studies of dimethyl fumarate, and an insufficient number of patients aged 65 years and older were included to draw conclusions about differences in tolerability between elderly and younger patients (see section "Pharmacological Properties"). Based on the mechanism of action of the active substance, there are no theoretical grounds to justify dose adjustment in elderly patients.

Renal and hepatic impairment

The effect of dimethyl fumarate has not been studied in patients with renal or hepatic impairment. Based on data from clinical pharmacological studies, dose adjustment in these patient populations is not required (see section "Pharmacological Properties"). Treatment of patients with severe renal or hepatic impairment should be conducted with caution (see section "Special Instructions").

Children

Safety and efficacy in the pediatric population have not been established.

Overdose

Cases of dimethyl fumarate overdose have been reported. Symptoms described in these cases were consistent with the known adverse reaction profile of dimethyl fumarate. There are no known therapeutic measures to enhance elimination of dimethyl fumarate, and no antidotes are known. In case of overdose, symptomatic and supportive treatment should be initiated according to clinical indications.

Adverse Reactions

Short description of the safety profile

In patients treated with dimethyl fumarate, the most commonly observed adverse reactions (occurring in >10% of patients) were flushing and gastrointestinal disorders (diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal adverse reactions occurred more frequently at the beginning of therapy (mainly during the first month). These symptoms may recur intermittently throughout the entire treatment period. The most common adverse reactions leading to discontinuation of treatment (frequency >1%) in patients receiving dimethyl fumarate were flushing (3%) and gastrointestinal adverse reactions (4%).

Adverse reactions observed during clinical trials, post-marketing safety studies, and spontaneous reports are presented in the table below.

The frequency of adverse reactions is categorized as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (available data do not permit estimation of frequency).

MedDRA System Organ Classes [Medical Dictionary for Regulatory Activities]	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 disorder	common
	acute pancreatitis	frequency unknown
Hepatobiliary disorders	increased AST levels	common
	increased ALT levels	common
	drug-induced liver injury	frequency unknown
Skin and subcutaneous tissue disorders	pruritus	common
	rash	common
	erythema	common
	alopecia	common
Renal and urinary disorders	proteinuria	common
General disorders and administration site conditions	sensation of heat	common
Investigations	ketonuria	very common
	albuminuria	common
	decreased white blood cell count	common

Description of individual adverse reactions

Flushing

In placebo-controlled studies, an increased incidence of flushing episodes (34% vs. 4%) and sensation of warmth (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 early in treatment with dimethyl fumarate (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. Severe flushing episodes, characterized by generalized erythema, rash, and/or pruritus, were observed in less than 1% of patients treated with dimethyl fumarate (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").

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 treated with dimethyl fumarate compared to placebo. Gastrointestinal disturbances usually occur early in treatment with dimethyl fumarate (mainly within the first month) and may recur intermittently during therapy. In most cases, the intensity of gastrointestinal symptoms was mild or moderate. 4% of patients treated with dimethyl fumarate discontinued treatment due to gastrointestinal adverse events. Serious gastrointestinal adverse events, including gastroenteritis and gastritis, were observed in 1% of patients treated with dimethyl fumarate (see section "Dosage and administration").

Liver function

According to placebo-controlled studies, in most patients, elevations in liver transaminase levels did not exceed three times the upper limit of normal. An increased frequency of liver transaminase elevations in patients treated with dimethyl fumarate compared to placebo was observed mainly during the first 6 months of treatment. Elevations in ALT and AST activity to 3 times or more above the upper limit of normal were observed in 5% and 2% of placebo-treated patients, and in 6% and 2% of dimethyl fumarate-treated patients, respectively. Treatment with dimethyl fumarate was discontinued due to elevated liver transaminases in less than 1% of cases.

No cases of concomitant elevation of liver transaminases to 3 times or more above the upper limit of normal and total bilirubin to 2 times or more above the upper limit of normal were observed.

During the post-marketing period, elevations in liver transaminases and drug-induced liver injury (elevation of transaminases to 3 times and concurrent increase in total bilirubin to 2 times the upper limit of normal) were reported with dimethyl fumarate use, which resolved after discontinuation of treatment.

Lymphopenia

In placebo-controlled studies, the majority of patients (>98%) had normal lymphocyte counts before starting treatment. After administration of dimethyl fumarate, a decrease in mean lymphocyte count was observed during the first year, followed by a plateau. On average, lymphocyte count decreased by approximately 30% from baseline. Mean and median lymphocyte counts remained within the normal range. Lymphocyte count < 0.5 × 10⁹/L was observed in less than 1% of placebo-treated patients and in 6% of dimethyl fumarate-treated patients. Lymphocyte count < 0.2 × 10⁹/L was observed in one patient receiving dimethyl fumarate but not in any placebo-treated patients.

In clinical studies (both controlled and uncontrolled), 41% of patients receiving dimethyl fumarate experienced lymphopenia (defined in these studies as < 0.91 × 10⁹/L). Mild lymphopenia (count ≥ 0.8 × 10⁹/L to < 0.91 × 10⁹/L) occurred in 28% of patients; moderate lymphopenia (count ≥ 0.5 × 10⁹/L to < 0.8 × 10⁹/L), persisting for at least six months, occurred in 11% of patients; severe lymphopenia (count < 0.5 × 10⁹/L), persisting for at least six months, occurred in 2% of patients. In most patients with severe lymphopenia, lymphocyte counts remained below 0.5 × 10⁹/L during continued therapy.

Additionally, in an uncontrolled prospective post-marketing study at week 48 of dimethyl fumarate treatment (n = 185), reductions in CD4+ T-cells were moderate (count ≥ 0.2 × 10⁹/L to < 0.4 × 10⁹/L) or marked (< 0.2 × 10⁹/L) in 37% and 6% of patients, respectively, while CD8+ T-cell counts decreased to < 0.2 × 10⁹/L in 59% of patients and to < 0.1 × 10⁹/L in 25% of patients.

Infections, including PML and opportunistic infections

Cases of John Cunningham virus (JCV) infection leading to progressive multifocal leukoencephalopathy (PML) have been reported during treatment with dimethyl fumarate (see section "Special precautions for use"). PML can be fatal or result in 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 (ranging from < 0.5 × 10⁹/L to below the lower limit of normal [LLN], as defined by the local laboratory).

In several PML cases with T-cell subset analysis at diagnosis, CD8+ T-cell counts were reduced to < 0.1 × 10⁹/L, while reductions in CD4+ T-cell counts were variable (ranging from 0.05 to 0.5 × 10⁹/L) and more closely correlated with the overall severity of lymphopenia (from < 0.5 × 10⁹/L to below LLN). Thus, the CD4+/CD8+ ratio in these patients was increased.

Prolonged moderate or severe lymphopenia is associated with an increased risk of PML with dimethyl fumarate use; however, PML has also occurred in patients with mild lymphopenia. Furthermore, most post-marketing PML cases occurred in patients over 50 years of age.

Cases of herpes zoster infection have been reported with dimethyl fumarate use. In a long-term study of 1736 patients with multiple sclerosis receiving dimethyl fumarate, approximately 5% experienced one or more episodes of herpes zoster, most of which were moderate or severe. In most patients, including those with serious herpes zoster infections, lymphocyte counts were above the lower limit of normal. Grade 2 and 3 lymphopenia was predominant in patients with concurrent lymphocytopenia. In post-marketing observations, most cases of herpes zoster were non-serious and responsive to treatment. Post-marketing data on absolute lymphocyte count (ALC) in patients with herpes zoster are limited; however, most patients had Grade 2 (from < 0.8 × 10⁹/L to 0.5 × 10⁹/L) or Grade 3 (from < 0.5 × 10⁹/L to 0.2 × 10⁹/L) lymphopenia (see section "Special precautions for use").

Laboratory abnormalities

In placebo-controlled studies, urinary ketone levels (1+ or higher) were higher in patients treated with dimethyl fumarate (45%) compared to placebo (10%). No adverse clinical consequences of this finding were observed.

Levels of 1,25-dihydroxyvitamin D decreased in patients treated with dimethyl fumarate compared to placebo (median percentage decrease from baseline at 2 years was 25% vs. 15%, respectively), while parathyroid hormone levels increased in dimethyl fumarate-treated patients 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

Safety and efficacy in the pediatric population have not been established.

In a small open-label, uncontrolled 24-week study in pediatric patients with multiple sclerosis aged 13 to 17 years (120 mg twice daily for 7 days, then 240 mg twice daily until end of treatment; safety 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.

Reporting of adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and 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.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging.

14 capsules in a bottle, 1 bottle in a cardboard box (for 120 mg dosage).

60 capsules in a bottle, 1 bottle in a cardboard box (for 240 mg dosage).

Prescription status. Prescription only.

Manufacturer.

Shilpa Medicare Limited.

Manufacturer's address and location of operations.

Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India.