Tecfidera (Capsules) Instructions for Use

Marketing Authorization Holder

Biogen Idec, Ltd. (United Kingdom)

Manufactured By

Vifor, SA (Switzerland)

ATC Code

N07XX09 (Dimethyl fumarate)

Active Substance

Dimethyl fumarate (Grouping name)

Dosage Forms

	Tecfidera	Enteric-coated capsules 120 mg: 14 pcs.
		Enteric-coated capsules 240 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated capsules hard gelatin, opaque, size No. 0, with a light green cap and a white body, marked with black ink “BG-12 120 mg” on the capsule body; the capsule contents are white or almost white microtablets.

Excipients: microcrystalline cellulose – 131.6 mg, croscarmellose sodium – 15 mg, talc – 19.8 mg, colloidal silicon dioxide – 2.6 mg, magnesium stearate – 5 mg, triethyl citrate – 7.6 mg, methacrylic acid-methyl methacrylate copolymer (1:1) – 5.48 mg, 30% dispersion of methacrylic acid and ethyl acrylate copolymer [1:1] – 32.01 mg, simethicone – 0.2 mg, sodium lauryl sulfate – 0.25 mg, polysorbate 80 – 0.76 mg, talc (micronized) – 13.7 mg.

Capsule shell composition body: gelatin – 56.45 mg, titanium dioxide – 1.15 mg; cap – gelatin – 37.41 mg, titanium dioxide (E171) – 0.92 mg, iron oxide yellow dye (E172) – 0.06 mg, brilliant blue FCF dye (E133) – 0.01 mg.
Composition of black ink (capsule marking) shellac 24-27% (w/w), potassium hydroxide – 0.05-0.1% (w/w), iron oxide black dye (E172) – 24-28% (w/w).

14 pcs. – blisters (1) – cardboard envelopes (1) – cardboard packs.

Enteric-coated capsules hard gelatin, opaque, size No. 0, with light green cap and body, marked with black ink “BG-12 240 mg” on the capsule body; the capsule contents are white or almost white microtablets.

Excipients: microcrystalline cellulose – 106.7 mg, croscarmellose sodium – 18.5 mg, colloidal silicon dioxide – 2.2 mg, magnesium stearate – 1.8 mg, triethyl citrate – 9.5 mg, methacrylic acid-methyl methacrylate copolymer (1:1) – 6.78 mg, 30% dispersion of methacrylic acid and ethyl acrylate copolymer [1:1] – 39.87 mg, simethicone – 0.2 mg, sodium lauryl sulfate – 0.3 mg, polysorbate 80 – 0.95 mg, talc (micronized) – 17.1 mg.

Capsule shell composition body: gelatin – 56.11 mg, titanium dioxide (E172) – 1.38 mg, iron oxide yellow dye (E172) – 0.09 mg, brilliant blue FCF dye (E133) – 0.01 mg; cap – gelatin – 37.41 mg, titanium dioxide (E171) – 0.92 mg, iron oxide yellow dye (E172) – 0.06 mg, brilliant blue FCF dye (E133) – 0.01 mg.
Composition of black ink (capsule marking) shellac – 24-27% (w/w), potassium hydroxide – 0.05-0.1% (w/w), iron oxide black dye (E172) – 24-28% (w/w).

14 pcs. – blisters (2) – cardboard envelopes (2) – cardboard packs.

Clinical-Pharmacological Group

Immunomodulator. A drug used for multiple sclerosis

Pharmacotherapeutic Group

Other drugs for the treatment of nervous system diseases

Pharmacological Action

The mechanism of therapeutic action of dimethyl fumarate in multiple sclerosis is not fully understood. Preclinical studies have shown that the pharmacodynamic action of dimethyl fumarate is mainly due to the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription pathway.

It has been established that Dimethyl fumarate activates Nrf2-dependent antioxidant genes in patients (for example, NAD(P)H dehydrogenase, quinone 1; [NQO1]).

Effect on the immune system

Dimethyl fumarate has anti-inflammatory and immunomodulatory effects. It has also been shown that Dimethyl fumarate and its main metabolite, monomethyl fumarate, significantly reduce immune cell activity and subsequent release of pro-inflammatory cytokines in response to an induced inflammatory reaction.

In patients with psoriasis, Dimethyl fumarate affects the lymphocyte phenotype by reducing the formation of pro-inflammatory cytokines (T_h1, T_h17) and increasing the production of anti-inflammatory cytokines (T_h2).

The therapeutic activity of dimethyl fumarate has been confirmed in models of inflammation and neuroinflammatory injury.

During the first year of use, dimethyl fumarate may be accompanied by a decrease in the total lymphocyte count in the blood, on average by 30% from the baseline value, with subsequent stabilization.

Effect on the cardiovascular system

A single dose of dimethyl fumarate at a dose of 240 mg or 360 mg does not change the duration of the QTc interval.

Clinical efficacy

The efficacy and safety of Tecfidera were confirmed in two randomized, double-blind, placebo-controlled, two-year studies (Study 1, DEFINE, and Study 2, CONFIRM) involving 1234 patients and 1417 patients with relapsing-remitting multiple sclerosis (RRMS), respectively.

Patients with progressive forms of the disease were not included in these studies.

The main average characteristics of the patients who participated in Study 1 were as follows: age – 39 years; disease duration – 7.0 years; score on the Expanded Disability Status Scale (EDSS) – 2.0.

In addition, 16% of patients had an EDSS score >3.5; 28% of patients had ≥2 relapses in the previous year, and 42% of patients had received other conventional multiple sclerosis therapy.

In 36% of patients in the subgroup with additional magnetic resonance imaging (MRI) outcome assessment, at least one gadolinium-enhancing (Gd⁺) lesion was noted.

On average, the number of Gd⁺ lesions was 1.4.

The “primary” endpoint in Study 1 was the proportion of patients with disease relapse after 2 years of therapy.

The “secondary” endpoints included: the number of new or newly enlarged T2-hyperintense lesions, the number of Gd⁺ lesions, the annualized relapse rate, and the time to confirmed sustained (over 12 weeks) disability progression.

In Study 1, Tecfidera demonstrated a clinically pronounced and statistically significant effect on all “primary” and “secondary” endpoints.

The proportion of patients who experienced a disease relapse while taking Tecfidera and placebo was 0.27 and 0.461, respectively (49% risk reduction, p < 0.0001).

The annualized relapse rate in patients in the Tecfidera group and the placebo group was 0.172 and 0.364, respectively (relative reduction of 53%, p<0.0001).

The proportion of patients with confirmed disability progression was determined as 0.164 and 0.271, respectively (38% risk reduction, p=0.005).

The number of new or newly enlarged T2 lesions over 2 years of treatment was 3.2 in patients taking Tecfidera, and 16.5 in the placebo group (85% risk reduction, p<0.0001), and the number of Gd⁺ lesions was 0.1 and 1.8, respectively (90% relative risk reduction, p<0.0001).

The design of Study 2 differed from the design of Study 1 in that the physician/investigator assessing the effectiveness of the treatment was unaware of the treatment method, and there was a third group of patients receiving the comparator drug based on glatiramer acetate (GA).

The average baseline characteristics of patients in Study 2 were as follows: age 37 years, disease duration 6.0 years, EDSS score 2.5.

In addition, 17% of patients had an EDSS score >3.5, 32% of patients had ≥2 relapses in the previous year, and 30% of patients had received other conventional multiple sclerosis therapy.

The “primary” endpoint in Study 2 was the annualized relapse rate over 2 years.

The “secondary” endpoints were the number of new or newly enlarged T2-hyperintense lesions, the number of T1-hypointense lesions, the relative number of relapses, and the time to confirmed sustained (over 12 weeks) disability progression.

Tecfidera demonstrated a clinically pronounced and statistically significant effect on the “primary” and most “secondary” endpoints in Study 2.

The annualized relapse rate was 0.224 in the group of patients receiving Tecfidera, 0.401 in the placebo group (44% risk reduction, p<0.0001) and 0.286 in the group of patients receiving GA.

The proportions of patients with disease relapse were 0.291 in the Tecfidera group, 0.410 in the placebo group (relative risk reduction of 34%, p<0.0001) and 0.321 in the GA group.

The proportions of patients with confirmed disability progression were determined as 0.128 in the Tecfidera group, 0.169 in the placebo group (relative risk reduction of 21%, p=0.25) and 0.156 in the GA group.

The number of new or newly enlarged T2-hyperintense lesions over 2 years of treatment was 5.7 in the group receiving Tecfidera, 19.9 in the group receiving placebo (relative reduction of 71%, p<0.0001) and 9.6 in the group receiving GA, and the number of Gd⁺ lesions, respectively, 0.5, 2.0 (relative risk reduction 74%, p<0.0001) and 0.7.

Clinical efficacy in patients with high disease activity

In the subgroup of patients with high disease activity, a stable clinical efficacy of Tecfidera in reducing the number of disease relapses was demonstrated, while the effect on the time to three-month sustained disability progression was not clearly established.

Pharmacokinetics

The pharmacokinetics of dimethyl fumarate were studied in patients with multiple sclerosis and healthy volunteers. Dimethyl fumarate after oral administration undergoes rapid presystemic hydrolysis by esterases and is converted into the main metabolite, monomethyl fumarate, which also has pharmacological activity.

Since Dimethyl fumarate is not detected in plasma after oral administration of Tecfidera, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate.

Absorption

The T_max of monomethyl fumarate is from 2 to 2.5 hours.

Since the enteric-coated capsules of Tecfidera contain microtablets that are protected by an enteric coating, absorption occurs only after gastric emptying (usually less than 1 hour).

After administration of the drug at a dose of 240 mg twice daily with food in patients with multiple sclerosis, the median C_max is 1.72 mg/L, and the total exposure, AUC, is 8.02 h×mg/L.

In general, C_max and AUC increase approximately proportionally to the administered dose in the range of studied doses (from 120 to 360 mg).

Administration of two doses of the drug 240 mg with a 4-hour interval as part of three-times-daily administration to patients with multiple sclerosis is accompanied by minimal accumulation of monomethyl fumarate in the blood and does not affect the safety profile of the drug (the median C_max increase is 12% compared to twice-daily administration (1.72 mg/L and 1.93 mg/L, respectively, for twice and three times daily administration).

Taking the drug with food does not affect the blood concentration of dimethyl fumarate.

However, taking the drug with food may improve treatment tolerance given the possibility of developing adverse events such as flushing or gastrointestinal disorders (see section “Adverse Reactions”).

Distribution

The apparent V_d of monomethyl fumarate after oral administration of a 240 mg dose ranges from 60 L to 90 L. The binding of monomethyl fumarate to human plasma proteins is in the range of 27-40%.

Metabolism

In humans, the metabolism of dimethyl fumarate occurs largely under the influence of esterases of the gastrointestinal tract, blood, and body tissues; less than 0.1% of dimethyl fumarate is excreted unchanged in the urine.

Then, the metabolism of dimethyl fumarate continues with the participation of the tricarboxylic acid cycle without the involvement of cytochrome P450 isoenzymes.

After a single dose of 240 mg of isotopically labeled dimethyl fumarate, glucose was identified in human plasma as the main metabolite.

Other circulating metabolites are fumaric acid, citric acid, and monomethyl fumarate.

Subsequent metabolism of fumaric acid occurs with the participation of the tricarboxylic acid cycle, and the excretion of CO₂ in the breath is the main route of elimination.

Excretion

Exhalation of CO₂ is the main route of excretion of dimethyl fumarate; approximately 60% of the administered dose of the drug is excreted through breathing.

Excretion of the drug by the kidneys and intestines are secondary routes of elimination, and account for 15.5% and 0.9% of the administered dose of the drug, respectively.

The T_1/2 of monomethyl fumarate is short (approximately 1 hour), and after 24 hours, monomethyl fumarate is not detected in the blood of most patients.

With repeated administration of dimethyl fumarate at therapeutic doses, no accumulation of the parent drug or monomethyl fumarate is observed.

Linearity

The concentration of dimethyl fumarate increases approximately proportionally to the dose in the range from 120 mg to 360 mg, taken either as a single dose or repeatedly.

Pharmacokinetics in special patient groups

According to the results of the analysis of variance (ANOVA), patient body weight is the main covariate of exposure (C_max and AUC) in patients with relapsing-remitting multiple sclerosis.

However, it does not affect the efficacy and safety parameters assessed in clinical studies.

Patient gender and age do not have a clinically significant effect on the pharmacokinetic parameters of dimethyl fumarate.

No pharmacokinetic studies of the drug have been conducted in patients aged 65 years and older.

In children

No pharmacokinetic studies of the drug have been conducted in patients under 18 years of age.

In patients with renal impairment

Since the kidneys are a secondary route of excretion of dimethyl fumarate (less than 16% of the administered dose of the drug), an assessment of pharmacokinetic parameters in patients with renal impairment has not been conducted.

In patients with hepatic impairment

Since Dimethyl fumarate and monomethyl fumarate are metabolized with the participation of liver enzymes, but without the involvement of the cytochrome P450 system, an assessment of pharmacokinetic parameters in patients with hepatic impairment has not been conducted.

Results of preclinical safety assessment

Adverse reactions described in the sections below were not noted in clinical studies but were recorded in animal studies at exposure levels comparable to clinical exposure.

Mutagenicity

The results of a standard series of in vitro and in vivo tests (Ames test, mammalian cell chromosomal aberration test) for dimethyl fumarate and monomethyl fumarate were negative.

The result of the in vivo micronucleus test in rats for dimethyl fumarate was negative.

Carcinogenicity

Carcinogenicity studies of dimethyl fumarate in rats and mice lasted up to 2 years.

Mice received Dimethyl fumarate orally at doses up to 400 mg/kg/day, rats up to 150 mg/kg/day.

In mice, the incidence of renal tubular carcinoma increased at a dose of 75 mg/kg/day, providing exposure (AUC) equivalent to the therapeutic one.

In rats, the incidence of renal tubular carcinoma increased at a dose of 100 mg/kg/day, which is approximately 3 times higher than the recommended therapeutic dose.

The applicability of these data to humans is unknown.

The incidence of squamous cell papilloma and carcinoma of the forestomach increased in mice at exposure equivalent to, and in rats lower than, the therapeutic exposure (based on AUC).

Toxicology

Preclinical studies in rodents, rabbits, and monkeys were conducted with the administration of a dimethyl fumarate suspension (Dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) orally via gavage.

A long-term study in dogs was conducted with the oral administration of dimethyl fumarate capsules.

After repeated oral administration of dimethyl fumarate to mice, rats, dogs, and monkeys, changes in the kidneys were noted.

In all animal species, regeneration of the renal tubular epithelium was detected, suggesting the presence of damage.

With lifelong use of the drug (two-year study), renal tubular hyperplasia was observed in rats.

Cortical atrophy, focal necrosis, and interstitial fibrosis were observed in monkeys receiving Dimethyl fumarate orally daily for 12 months at a dose 6 times the recommended dose, calculated based on AUC.

The significance of these observations for humans is unknown.

Degeneration of the seminiferous tubule epithelium of the testes was noted in rats and dogs.

These changes were detected at doses close to therapeutic in rats, and 6 times higher than therapeutic (based on AUC) in dogs.

The applicability of these results to humans is unknown.

Hyperplasia and hyperkeratosis of the squamous epithelium, inflammation, and with a study duration of more than 3 months, squamous cell papilloma and carcinoma were detected in the forestomach of mice and rats.

The structure of the rodent stomach does not correspond to the structure of the human stomach.

Reproductive toxicity

Oral administration of dimethyl fumarate at doses up to 375 mg/kg/day (at least 2 times higher than the therapeutic dose) to male rats before and during mating did not affect fertility.

Oral administration of dimethyl fumarate to female rats at doses up to 250 mg/kg/day before and during mating, continuing until day 7 of gestation, led to a decrease in the number of estrous cycles over 14 days, as well as an increase in the number of animals with prolonged diestrus in the group receiving the highest of the studied doses (11 times higher than the therapeutic dose).

However, these changes did not affect fertility and the number of viable embryos.

Dimethyl fumarate crosses the placental barrier into the blood of embryos in rats and rabbits, the ratio of concentration in fetal and maternal blood is 0.48-0.64 and 0.1, respectively.

No malformations were detected in rats and rabbits with the use of dimethyl fumarate at any dose.

Oral administration of dimethyl fumarate to pregnant rats during the period of organogenesis at doses up to 250 mg/kg/day led to the appearance of adverse effects in the female (dose 4 times higher than therapeutic), and to a decrease in fetal weight and delayed ossification of the metatarsal bones and phalanges of the hind limbs (dose 11 times higher than therapeutic).

The decrease in fetal weight and delayed ossification were considered as a secondary manifestation of the toxic effect on the female body (decrease in body weight and food consumption).

Oral administration of dimethyl fumarate at doses up to 150 mg/kg/day to pregnant rabbits during the period of organogenesis did not affect embryofetal development.

The body weight of the females decreased at doses 7 times higher than the therapeutic dose, the number of miscarriages increased at doses 16 times higher than the therapeutic dose.

Oral administration of dimethyl fumarate to rats at doses up to 250 mg/kg/day during pregnancy and lactation led to a reduction in body weight of the F1 generation offspring. Delayed sexual maturation in male F1 generation offspring was observed at doses 11 times higher than the therapeutic dose. No changes in the fertility of the F1 generation offspring were noted. The reduction in offspring body weight was considered a secondary effect relative to the drug’s toxic effect on the female organism.

Indications

• Treatment of adult patients with relapsing-remitting multiple sclerosis (important information about patient populations for whom efficacy has been established is provided in the “Pharmacodynamics” section).

ICD codes

Dosage Regimen

For oral administration.

Initiation of treatment with the drug should be under the supervision of a physician experienced in the treatment of this disease.

Capsules or their contents should not be crushed, divided, dissolved, sucked, or chewed, as the enteric coating of the microtablets inside the capsules prevents irritating effects on the gastrointestinal mucosa.

The initial dose is 120 mg twice daily. After 7 days, the dose should be increased to 240 mg twice daily.

If gastrointestinal adverse reactions or episodes of flushing occur, the drug dose can be temporarily reduced to 120 mg twice daily. Within 1 month, it is recommended to resume taking Tecfidera at a dose of 240 mg twice daily.

Tecfidera should be taken with food, which may help reduce the intensity of flushing and gastrointestinal reactions.

Use in Specific Patient Groups

Elderly patients

A limited number of patients aged 55 years and older participated in the clinical trials of Tecfidera. Also, a sufficient number of patients aged 65 years and older were not included in the studies to determine differences in tolerability between elderly and younger patients. Considering the mechanism of action of the active substance, from a theoretical standpoint, there is insufficient basis for dose adjustment when treating elderly patients.

Children and adolescents

The safety and efficacy of Tecfidera in children and adolescents aged 10 to 18 years have not been established due to a lack of data. There are no data on the treatment of multiple sclerosis with Tecfidera in children under 10 years of age.

Use in patients with impaired renal and/or hepatic function

No specific studies of Tecfidera have been conducted in patients with renal or hepatic impairment. According to clinical and pharmacological studies, dose adjustment in this category of patients is not required. Treatment of patients with severe renal and hepatic impairment should be conducted with caution.

Adverse Reactions

In patients treated with Tecfidera, the most frequently (in ≥10% of patients) reported adverse drug reactions (ADRs) were flushing and gastrointestinal ADRs (including diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal ADRs occur more frequently at the start of therapy (mainly within the first month). In patients who develop such symptoms, flushing and gastrointestinal events may occur periodically throughout the entire treatment period. The most common reasons for discontinuation of Tecfidera (in >1% of patients) were flushing (3%) and gastrointestinal ADRs (4%).

ADRs are presented according to the system organ class (MedDRA) and WHO classification of frequency: very common – ≥1/10 (>10%); common – from ≥1/100 to <1/10 (from ≥1% to <10%); uncommon - from ≥1/1000 to <1/100 (from ≥0.1% to <1%); rare - from ≥1/10,000 to <1/1000 (from ≥0.01% to <0.1%); very rare - <1/10,000 (<0.01%); frequency not known - cannot be estimated from the available data.

Infections and infestations Common – gastroenteritis.

Blood and lymphatic system disorders: Common – leukopenia, lymphopenia.

Immune system disorders Uncommon – hypersensitivity.

Nervous system disorders Common – burning sensation.

Vascular disorders Very common – flushing; Common – feeling of heat accompanied by rapid heartbeat.

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

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

Renal and urinary disorders Common – proteinuria.

General disorders and administration site conditions: Common – feeling hot.

Investigations: Very common – ketonuria; Common – albuminuria, increased AST activity, increased ALT activity, leukopenia.

Additional Information

Flushing

Flushing is described by patients as sensations of blood rushing to the skin or sensations of heat, but may include other manifestations (e.g., sensations of warmth, redness, tingling, burning). In placebo-controlled studies, an increased frequency of flushing episodes (34% compared to 4%) and feeling of heat (7% compared to 2%) was observed in patients receiving Tecfidera compared to patients receiving placebo, respectively. In most cases, the intensity of flushing was rated by patients as mild or moderate. Cases of severe flushing, manifested by widespread erythema, skin rash, and/or skin itching, were observed in less than 1% of patients taking Tecfidera.

Gastrointestinal ADRs

In patients receiving Tecfidera compared to patients receiving placebo, the frequency of gastrointestinal ADRs was higher (e.g., diarrhea [14% compared to 10%], nausea [12% compared to 9%], upper abdominal pain [10% compared to 6%], abdominal pain [9% compared to 4%], vomiting [8% compared to 5%], and dyspepsia [5% compared to 3%]). In most cases, the intensity of gastrointestinal symptoms was rated by patients as mild or moderate. Severe gastrointestinal ADRs, including gastroenteritis and gastritis, were observed in 1% of cases in patients taking Tecfidera.

Hepatic transaminase activity

Cases of increased hepatic transaminase activity were observed during placebo-controlled studies. In most patients, hepatic transaminase activity did not exceed the upper limit of normal (ULN) by more than 3 times. Increased hepatic transaminase activity in patients treated with Tecfidera compared to patients receiving placebo was observed mainly during the first 6 months of therapy. Increases in ALT and AST to 3 times or more the ULN were noted in 5% and 2% of patients receiving placebo, and in 6% and 2% of patients receiving Tecfidera, respectively. No cases of concurrent increase in hepatic transaminases to 3 times or more the ULN and total bilirubin to 2 times or more the ULN were observed. Increased hepatic transaminase activity led to therapy discontinuation in less than 1% of patients in both the Tecfidera and placebo groups.

Renal and urinary ADRs

Proteinuria was observed more frequently in patients taking Tecfidera (9%) compared to placebo (7%). The overall frequency of renal and urinary ADRs did not differ between patients receiving Tecfidera or placebo. No cases of severe renal failure were reported. The proportion of patients with proteinuria (“1+” and above) was comparable during treatment with Tecfidera (43%) and placebo (40%). Typically, the severity of proteinuria did not progress. Compared to placebo, in patients receiving Tecfidera, the glomerular filtration rate (GFR) increased, including in patients whose proteinuria was ≥1+ in 2 consecutive tests.

Blood and lymphatic system ADRs

In most patients (>98%), no abnormalities in total lymphocyte count in the blood were detected prior to the use of Tecfidera in placebo-controlled studies. After initiation of treatment, a decrease in total lymphocyte count was observed during the first year, followed by stabilization. On average, the total lymphocyte count decreased by approximately 30% from baseline. However, the median and mean lymphocyte counts remained within the normal range. A total lymphocyte count of <0.5×10⁹/L was observed in less than 1% of patients receiving placebo and in 6% of those receiving Tecfidera. A lymphocyte count of <0.2×10⁹/L was noted in 1 patient taking Tecfidera but was not observed in the placebo group. In clinical trials, both controlled and uncontrolled, 2% of patients had a decrease in lymphocyte count to <0.5×10⁹/L for a period of at least 6 months. In most of these patients, the low lymphocyte count persisted with continued therapy. The advisability of interrupting Tecfidera treatment should be considered in patients with a lymphocyte count <0.5×10⁹/L persisting for 6 months. Lymphocyte count should be monitored regularly until the value normalizes. In patients taking Tecfidera or placebo, the frequency of infectious diseases did not differ and was 60% and 58%, respectively, including severe infections 2% and 2%. No increased frequency of infectious diseases, including serious ones, was observed in patients with lymphocyte counts <0.8×10⁹/L or <0.5×10⁹/L. A case of progressive multifocal leukoencephalopathy was noted against a background of severe and prolonged lymphopenia. During the first 2 months of therapy, patients experienced transient eosinophilia.

Other laboratory parameter changes

In placebo-controlled studies, ketonuria (1+ and above) was detected more frequently (45%) in patients receiving Tecfidera than in the placebo group (10%). The clinical significance of this observation is undetermined.

The blood concentration of 1,25-dihydroxyvitamin D decreased in patients taking Tecfidera or placebo by an average of 25% and 15% from baseline after 2 years of treatment, respectively, and the concentration of parathyroid hormone (PTH) increased by an average of 29% and 15%, respectively. The mean values of both parameters remained within the normal range.

Contraindications

• Hypersensitivity to the active substance or any excipient of the drug;
• Children under 18 years of age (due to lack of clinical data).

With caution

In patients

• With initially low total blood lymphocyte count (<0.5×10⁹/L);
• With severe renal impairment (CrCl <30 mL/min/1.73 m²) or hepatic impairment (Child-Pugh class C) (lack of clinical data);
• With gastrointestinal diseases during pregnancy and breastfeeding (due to limited data);
• With concurrent use of antineoplastic and immunosuppressive drugs.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of dimethyl fumarate in pregnant women are limited. Studies in animals have shown toxic effects of the drug on the reproductive system. The use of Tecfidera during pregnancy and in women of reproductive potential not using reliable contraception is not recommended. Tecfidera should be prescribed during pregnancy only if strictly necessary, when the potential benefit to the mother outweighs the possible risk to the fetus.

Breastfeeding

It is unknown whether dimethyl fumarate or its metabolites pass into human breast milk, so a risk to newborns and infants cannot be excluded. The decision to discontinue breastfeeding or to stop Tecfidera therapy should be made after a thorough assessment of the benefit-risk ratio for the mother and the child.

Fertility

Data on the effect of Tecfidera on human fertility are lacking. Results from preclinical studies did not reveal an increased risk of impaired fertility with the use of dimethyl fumarate.

Use in Hepatic Impairment

Use with caution in patients with severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Use with caution in patients with severe renal impairment (CrCl <30 mL/min/1.73 m²).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age (due to lack of clinical data).

Geriatric Use

Dose adjustment is not required.

Special Precautions

Laboratory parameters

The use of Tecfidera may be accompanied by a decrease in total lymphocyte count in the blood. Tecfidera has not been studied in patients who initially had a reduced lymphocyte count, so caution should be exercised when using the drug in such patients. Before starting treatment, the results of a complete blood count (including lymphocyte count, not older than 6 months) should be assessed. Re-evaluation of the blood count (including lymphocyte count) is recommended after 6 months, and then blood tests should be performed regularly every 6-12 months based on clinical indications.

In clinical trials, 2% of patients had a decrease in lymphocyte count to <0.5×10⁹/L for a period of at least 6 months. In most of these patients, this low lymphocyte count persisted with continued therapy. The advisability of interrupting Tecfidera treatment should be considered in patients with a lymphocyte count <0.5×10⁹/L persisting for 6 months. Lymphocyte count should be monitored regularly until the value normalizes. Changes in certain liver and kidney function parameters were observed in clinical trials in patients taking Tecfidera. The clinical significance of these changes is unknown. It is recommended to monitor renal function (e.g., based on blood urea nitrogen and creatinine, urinalysis) and liver function (e.g., determination of ALT and AST activity) before treatment and 3 and 6 months after starting treatment, and then every 6-12 months depending on clinical indications.

Severe renal and hepatic impairment

Since Tecfidera has not been studied in patients with severe renal and hepatic impairment, it should be used with caution in this category of patients.

Gastrointestinal diseases during severe exacerbation

Since Tecfidera has not been studied in patients with severe exacerbations of gastrointestinal diseases, it should be used with caution in this category of patients.

Flushing

In clinical trials, 34% of patients receiving Tecfidera reported flushing. In most cases, the intensity of flushing was rated as mild or moderate.

According to clinical trial data, in 3 out of 2560 patients using Tecfidera, the symptoms of flushing were characterized as severe. They may have been due to hypersensitivity reactions or anaphylactoid reactions. These reactions were not life-threatening but led to patient hospitalization. Physicians and patients should be aware of the possible cause of severe flushing symptoms in patients.

Infections

The frequency of infectious diseases, including severe ones, was comparable in patients taking Tecfidera and placebo, 60% and 58%, and 2% and 2%, respectively. No increase in the frequency of severe infections was observed in patients with blood lymphocyte counts less than 0.8×10⁹/L or less than 0.5×10⁹/L. In patients receiving Tecfidera, a decrease in total lymphocyte count of approximately 30% from baseline was observed during the first year of treatment, followed by stabilization. The mean lymphocyte count remained within normal limits. A decrease in lymphocyte count to <0.5×10⁹/L was noted in <1% of patients in the placebo group and in 6% of patients in the Tecfidera group.

In clinical trials (controlled and uncontrolled), 2% of patients had a decrease in lymphocyte count to <0.5×10⁹/L for a period of at least 6 months. In most of these patients, the decreased lymphocyte count remained at the same level with continued therapy. The advisability of interrupting Tecfidera treatment should be considered in patients with a lymphocyte count <0.5×10⁹/L persisting for 6 months. Lymphocyte count should be monitored regularly until the value normalizes. If a patient develops a severe infection, the need for an interruption in Tecfidera treatment should be considered. To decide on resuming treatment, the benefit-risk ratio for the patient should be assessed. Patients receiving Tecfidera must inform their doctor about the occurrence of symptoms of any possible infection. Patients with a severe infectious disease should not use Tecfidera until they have recovered.

Effect on ability to drive and operate machinery

The effect on the ability to drive and operate machinery has not been studied.

Overdose

No cases of Tecfidera overdose have been reported.

Drug Interactions

No studies of Tecfidera in combination with antineoplastic or immunosuppressive drugs have been conducted, so caution should be exercised when using these drugs concomitantly. Concomitant short-term intravenous use of corticosteroids for the prevention of multiple sclerosis relapses during the clinical trials of Tecfidera was not associated with a clinically significant increase in the frequency of infections. The use of vaccines during treatment with Tecfidera has not been studied. There is no information on a possible reduction in the efficacy of any vaccines during treatment with Tecfidera. Live vaccines may increase the risk of infectious diseases and should not be administered to patients receiving Tecfidera, except when the potential benefit of vaccination outweighs the risk.

During therapy with Tecfidera, concomitant use of other fumaric acid derivatives (both for topical and systemic use) should be avoided.

Before entering the systemic circulation, Dimethyl fumarate is metabolized in the human body with the participation of esterases. Subsequently, enzymes of the tricarboxylic acid cycle participate in its metabolism without the involvement of cytochrome P450 system isoenzymes. In vitro studies did not reveal a potential risk of inhibition or induction of cytochrome P450 system isoenzymes, nor was any identified when assessing the influence of P-glycoprotein or studying the binding of dimethyl fumarate and monomethyl fumarate (the primary metabolite of dimethyl fumarate) with plasma proteins.

It has been established that interferon beta-1a for intramuscular injection and glatiramer acetate, commonly used for the treatment of multiple sclerosis, did not affect the pharmacokinetic profile of dimethyl fumarate.

Administration of 325 mg of a non-enteric-coated form of acetylsalicylic acid (or an equivalent) for 4 days, 30 minutes before taking Tecfidera, did not affect the pharmacokinetic profile of Tecfidera but led to a reduction in the frequency and severity of flushing in healthy volunteers. However, long-term use of acetylsalicylic acid for the treatment of flushing is not recommended. The potential risks of using acetylsalicylic acid should be considered before deciding on its concomitant use with Tecfidera.

Concomitant use of Tecfidera with medications that have nephrotoxic effects (such as aminoglycosides, diuretics, NSAIDs, or lithium preparations) may increase the risk of adverse drug reactions related to the kidneys and urinary tract (for example, causing proteinuria) (see “Adverse Reactions”).

Consumption of a moderate amount of alcohol does not change the exposure of Tecfidera and is not associated with an increased frequency of adverse drug reactions. In contrast, consumption of large amounts of undiluted strong alcoholic beverages (more than 30% ABV) may lead to an increased rate of dissolution of Tecfidera and, consequently, an increased frequency of gastrointestinal adverse drug reactions.

Results from in vitro studies on the potential induction of cytochrome P450 system isoenzymes found no interaction between Tecfidera and oral contraceptives. In vivo studies investigating interactions with oral contraceptives have not been conducted. Although an interaction between Tecfidera and oral contraceptives is unlikely, the possibility of using non-hormonal contraceptive methods during treatment with Tecfidera should be considered.

Storage Conditions

The drug should be stored in the original packaging, protected from light and out of the reach of children, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life: 120 mg capsules – 4 years; 240 mg capsules – 3 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.