Fluterio^® (Capsules) Instructions for Use

Marketing Authorization Holder

PSK Pharma, LLC (Russia)

ATC Code

N07XX09 (Dimethyl fumarate)

Active Substance

Dimethyl fumarate (Grouping name)

Dosage Forms

	Fluterio®	Enteric-coated capsules 120 mg: 14 pcs.
		Enteric-coated capsules 240 mg: 56 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated capsules hard gelatin size No. 0, opaque, with a cap and body of blue-green color; capsule contents – white or almost white microtablets.

Excipients: microcrystalline cellulose (PH-112) – 29.6 mg, croscarmellose sodium – 7 mg, silicified microcrystalline cellulose – 10 mg, colloidal anhydrous silicon dioxide – 2.8 mg, talc – 2.8 mg, magnesium stearate – 2.8 mg, methacrylic acid and methyl methacrylate copolymer [1:1] – 5.875 mg, methacrylic acid copolymer – 27.1 mg, triethyl citrate – 3.303 mg, polysorbate 80 – 0.645 mg, sodium lauryl sulfate – 0.197 mg, simethicone emulsion 30% – 0.08 mg.

Capsule body: gelatin – q.s. to 100%, purified water – 14-15%, methylparaben – 0.8%, propylparaben – 0.2%, iron oxide yellow (E172) – 0.18%, brilliant blue (E133) – 0.027%.
Capsule cap: iron oxide yellow (E172) – 0.18%, brilliant blue (E133) – 0.027%, titanium dioxide (E171) – 1.755%.

14 pcs. – jars (1) – cardboard packs^x.
14 pcs. – blisters (1) – cardboard packs^x.

^x a first-opening control label may be applied.

Enteric-coated capsules hard gelatin size No. 0, opaque, with a cap and body of blue-green color; capsule contents – white or almost white microtablets.

Excipients: microcrystalline cellulose (PH-112) – 59.2 mg, croscarmellose sodium – 14 mg, silicified microcrystalline cellulose – 20 mg, colloidal anhydrous silicon dioxide – 5.6 mg, talc – 5.6 mg, magnesium stearate – 5.6 mg, methacrylic acid and methyl methacrylate copolymer [1:1] – 11.749 mg, methacrylic acid copolymer – 54.2 mg, triethyl citrate – 6.606 mg, polysorbate 80 – 1.29 mg, sodium lauryl sulfate – 0.395 mg, simethicone emulsion 30% – 0.16 mg.

Capsule body: gelatin – q.s. to 100%, purified water – 14-15%, methylparaben – 0.8%, propylparaben – 0.2%, iron oxide yellow (E172) – 0.18%, brilliant blue (E133) – 0.027%.
Capsule cap: iron oxide yellow (E172) – 0.18%, brilliant blue (E133) – 0.027%, titanium dioxide (E171) – 1.755%.

56 pcs. – jars (1) – cardboard packs^x.
14 pcs. – blisters (4) – cardboard packs^x.

^x a first-opening control label may be applied.

Clinical-Pharmacological Group

Immunomodulator. A drug used for multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressants; other immunosuppressants

Pharmacological Action

An immunomodulator, it is a derivative of fumaric acid. It has anti-inflammatory and immunomodulatory effects.

The mechanism of the 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 transcription of nuclear factor erythroid 2-related factor 2 (Nrf2). It has been established that Dimethyl fumarate activates Nrf2-dependent antioxidant genes (for example, NAD(P)H dehydrogenase, quinone oxidoreductase type I; [NQO1]).

It has also been shown that Dimethyl fumarate and its main metabolite, monomethyl fumarate, significantly reduce immune cell activity and the 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 (TH1, TH17) and increasing the production of anti-inflammatory cytokines (TH2). The therapeutic activity of dimethyl fumarate has been confirmed in models of inflammation and neuroinflammatory injury. During the first year, the use of 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.

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

In clinical studies, in a subgroup of patients with high disease activity, stable clinical efficacy of dimethyl fumarate was demonstrated in reducing the number of disease relapses, while the effect on the time to 3-month confirmed disability progression was not clearly established.

Pharmacokinetics

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, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate.

T_max of monomethyl fumarate is from 2 to 2.5 hours. 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 27-40%.

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 in the blood 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.

Exhalation of CO₂ is the main route of elimination of dimethyl fumarate; approximately 60% of the administered dose is excreted via respiration. Renal and intestinal excretion are secondary routes of elimination, accounting for 15.5% and 0.9% of the administered dose, respectively.

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.

Indications

Treatment of adult patients with relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

For oral administration.

Initiate treatment under the supervision of a physician experienced in treating multiple sclerosis.

Swallow the capsules whole with liquid. Do not crush, chew, or open the capsules.

Take with food to reduce the incidence of flushing and gastrointestinal adverse reactions.

The initial dose is 120 mg twice daily.

After 7 days, increase the dose to the maintenance dose of 240 mg twice daily.

If intolerable flushing or gastrointestinal events occur, temporary dose reduction to 120 mg twice daily is permitted for up to 4 weeks. Subsequently, re-escalate to the 240 mg twice daily maintenance dose.

Administer the drug consistently, approximately every 12 hours.

Do not interrupt therapy without consulting your physician.

Before initiation, obtain a complete blood count, including lymphocyte count, no older than 6 months.

Re-evaluate the complete blood count after 6 months of treatment, and then every 6 to 12 months thereafter based on clinical assessment.

Monitor liver and renal function tests before treatment, at 3 and 6 months after initiation, and then every 6 to 12 months as clinically indicated.

In case of a severe infection, consider temporary treatment interruption and reassess the benefit-risk ratio.

If the lymphocyte count falls below 0.5×10^9/L and remains low for more than 6 months, consider treatment interruption.

For patients with severe renal impairment (CrCl <30 mL/min) or severe hepatic impairment (Child-Pugh class C), use with caution due to limited clinical data.

Adverse Reactions

Hematopoietic system: leukopenia, lymphopenia.

Cardiovascular system: feeling of heat accompanied by rapid heartbeat.

Digestive system: nausea, vomiting, dyspepsia, pain in the upper abdomen, increased AST, ALT activity, gastritis, gastroenteritis, diarrhea, gastrointestinal disorder.

Skin and subcutaneous tissues: itching, rash, erythema.

Urinary system: proteinuria, ketonuria.

Other: hypersensitivity, flushing, feeling of heat, burning sensation.

Contraindications

Childhood and adolescence under 18 years of age; hypersensitivity to dimethyl fumarate.

Use in Pregnancy and Lactation

Data on the use of dimethyl fumarate in pregnant women are limited. Experimental studies in animals have shown toxic effects of the drug on the reproductive system. Dimethyl fumarate is not recommended during pregnancy and in women of reproductive potential not using reliable methods of contraception. Dimethyl fumarate can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is unknown whether Dimethyl fumarate or its metabolites are excreted in breast milk, so the risk to newborns and infants cannot be excluded. The decision to discontinue breastfeeding or discontinue dimethyl fumarate therapy should be made after careful assessment of the ratio of the expected benefit to the mother and the potential risk to the child.

Results of preclinical studies did not reveal an increased risk of reduced fertility with the use of dimethyl fumarate.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

With caution: initially low total blood lymphocyte count (<0.5×10⁹/L); severe renal impairment (CrCl <30 mL/min/1.73 m²), due to lack of clinical data; severe hepatic impairment (Child-Pugh class C), due to lack of clinical data; gastrointestinal diseases in the acute stage; concomitant use with antineoplastic drugs and immunosuppressants.

Before starting treatment, the results of a complete blood count of the patient (including lymphocyte count, no older than 6 months) should be assessed. Re-evaluation of the blood test (including lymphocyte count) is recommended after 6 months, and then blood tests should be performed regularly every 6-12 months based on clinical indications.

It is recommended to monitor renal function (e.g., based on blood urea nitrogen and creatinine tests, urinalysis) and liver function (e.g., determination of ALT and AST activity) before treatment and 3 and 6 months after the start of treatment, and then every 6-12 months depending on clinical indications.

In clinical studies, 34% of patients receiving Dimethyl fumarate reported flushing. In most cases, the intensity of flushing was assessed as mild or moderate.

Drug Interactions

Antineoplastic drugs or immunosuppressants – caution should be exercised when used concomitantly.

IV corticosteroids – short-term use was not accompanied by a clinically significant increase in the frequency of infections.

Live vaccines – the risk of infectious diseases may be increased. Should not be used in patients receiving Dimethyl fumarate, except when the potential benefit of vaccination outweighs the risk.

Other fumaric acid derivatives (for topical and systemic use) – concomitant use should be avoided.

In vitro studies did not reveal a potential risk of inhibition and induction of cytochrome P450 system isoenzymes, as well as when assessing the effect on P-glycoprotein and studying the binding of dimethyl fumarate and monomethyl fumarate (the main metabolite of dimethyl fumarate) to plasma proteins.

Interferon beta-1a (for IM administration) and glatiramer acetate – do not affect the pharmacokinetic profile of dimethyl fumarate.

Acetylsalicylic acid – long-term use is not recommended; potential risks of using acetylsalicylic acid should be considered before making a decision on co-administration with dimethyl fumarate.

Drugs with nephrotoxic effects (such as aminoglycosides, diuretics, NSAIDs, or lithium preparations) – the risk of adverse reactions from the kidneys and urinary tract (e.g., proteinuria) may be increased.

Ethanol – consumption of moderate amounts of alcohol does not change the exposure of dimethyl fumarate and is not accompanied by an increase in the frequency of adverse reactions. Consumption of large amounts of undiluted strong alcoholic beverages (more than 30% vol.) may lead to an increase in the dissolution rate of dimethyl fumarate and, as a result, an increase in the frequency of gastrointestinal adverse reactions.

Oral contraceptives – interaction is unlikely, but the possibility of using non-hormonal contraceptive methods should be considered.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.