Difurate^® (Capsules) Instructions for Use

Marketing Authorization Holder

Pharma-Sintez, JSC (Russia)

Manufactured By

Novamedica Innotech, LLC (Russia)

ATC Code

L04AX07 (Dimethyl fumarate)

Active Substance

Dimethyl fumarate (Grouping name)

Dosage Forms

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

Dosage Form, Packaging, and Composition

Enteric-coated capsules opaque, hard gelatin, size No. 0, cylindrical in shape, with a white body and a dark green cap; the contents are white or almost white microtablets.

Excipients: microcrystalline cellulose PH102, croscarmellose sodium, talc, colloidal silicon dioxide, magnesium stearate.

Microtablet insulating coating triethyl citrate, Eudragit L100 (methacrylic acid-methyl methacrylate copolymer (1:1), sodium lauryl sulfate).
Microtablet enteric coating triethyl citrate, Eudragit L30 D-55 (methacrylic acid-ethyl acrylate copolymer (1:1), sodium lauryl sulfate, polysorbate 80), talc (micronized), simethicone.
Capsule body titanium dioxide, gelatin.
Capsule cap titanium dioxide, indigo carmine (indigotine FD&C Blue2), yellow iron oxide, gelatin.

14 pcs. – contour cell packaging (1) – cardboard packs.

Enteric-coated capsules opaque, hard gelatin, size No. 0, cylindrical in shape, with a blue body and a blue cap; the contents are white or almost white microtablets.

Excipients: microcrystalline cellulose PH102, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Microtablet insulating coating triethyl citrate, Eudragit L100 (methacrylic acid-methyl methacrylate copolymer (1:1), sodium lauryl sulfate).
Microtablet enteric coating triethyl citrate, Eudragit L30 D-55 (methacrylic acid-ethyl acrylate copolymer (1:1), sodium lauryl sulfate, polysorbate 80), talc (micronized), simethicone.
Capsule body titanium dioxide, indigo carmine (indigo carmine FD&C Blue2), gelatin.
Capsule cap titanium dioxide, indigo carmine (indigotine FD&C Blue2), gelatin.

14 pcs. – contour cell packaging (4) – cardboard packs.

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 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.

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 three-month sustained 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.

The 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 largely occurs 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. Excretion of the drug by the kidneys and intestines are secondary routes of elimination, accounting 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.

Indications

Treatment of adult patients with relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

Take Difurate^® orally.

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

Swallow the capsules whole with a full glass of water. Do not crush, chew, or open the capsules.

Take the capsules with food to reduce the incidence and severity of gastrointestinal adverse reactions, such as flushing and abdominal pain.

The initial dosage is one 120 mg capsule, taken twice daily.

After 7 days of treatment, increase the dosage to the maintenance dose of one 240 mg capsule, taken twice daily.

If you miss a dose, take it as soon as you remember. If it is almost time for the next dose, skip the missed dose and continue with the regular schedule. Do not take a double dose to make up for a forgotten one.

Before starting treatment, obtain a complete blood count, including lymphocyte count. Monitor blood counts every 6 months, or more frequently if clinically indicated.

Assess liver and renal function tests before treatment initiation, and again after 3 and 6 months. Continue monitoring every 6 to 12 months based on clinical evaluation.

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 activity of AST, ALT, 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 a toxic effect of the drug on the reproductive system. It is not recommended to use Dimethyl fumarate during pregnancy and in women of reproductive age 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 anticancer drugs and immunosuppressants.

Before starting treatment, the results of the patient’s complete blood count (including lymphocyte count, no older than 6 months) should be assessed. A repeat blood test (including lymphocyte count) is recommended after 6 months, and then blood tests should be performed regularly every 6-12 months, taking into account 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

Anticancer 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 derivatives of fumaric acid (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 of 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 intramuscular administration) and glatiramer acetate – do not affect the pharmacokinetic profile of dimethyl fumarate.

Acetylsalicylic acid – long-term use is not recommended, the potential risks of using acetylsalicylic acid should be considered before deciding 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% by volume) 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 25°C (77°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.