Dissemil (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

L04AA31 (Teriflunomide)

Active Substance

Teriflunomide (Rec.INN registered by WHO)

Dosage Form

Dissemil

Film-coated tablets, 14 mg: 10, 28, 30, 50, 84, or 140 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, round, biconvex; the core on the cross-section is white to almost white.

Excipients: hypromellose E5 – 2.1 mg, sodium carboxymethyl starch – 7.5 mg, lactose monohydrate 200M – 85.9 mg, magnesium stearate – 0.5 mg, microcrystalline cellulose 101 – 40 mg.

Film coating composition: hypromellose E5 – 3.6 mg, calcium carbonate – 0.9 mg, macrogol 6000 – 0.2 mg, talc – 0.3 mg.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (10) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

It is an immunomodulatory drug with anti-inflammatory properties, which selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is necessary for de novo pyrimidine synthesis.

Thus, Teriflunomide blocks the proliferation of stimulated lymphocytes, which require de novo pyrimidine synthesis.

The exact mechanism of action of teriflunomide in multiple sclerosis is not fully understood but may be due to a reduction in the number of circulating lymphocytes.

Pharmacokinetics

The mean T_max in plasma is from 1 to 4 hours after multiple oral administrations of teriflunomide with high bioavailability (approximately 100%).

The binding of teriflunomide to plasma proteins is high – more than 99%, likely with albumin.

The main part is distributed in the plasma.

It undergoes reabsorption in the intestine.

Teriflunomide is moderately metabolized and is the only component determined in the plasma.

T_1/2 after multiple doses is 19 days.

After a single IV administration, the total clearance of teriflunomide from the body is 30.5 ml/h.

The elimination of teriflunomide from the bloodstream can be accelerated by prescribing cholestyramine or activated charcoal, probably by interrupting the process of reabsorption in the intestine.

Indications

Treatment of adult patients with relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

Take one 14 mg tablet orally once daily, with or without food.

Swallow the tablet whole with water; do not crush or chew.

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

Before starting therapy, confirm the diagnosis of relapsing-remitting multiple sclerosis.

Obtain baseline measurements including blood pressure, ALT levels, and a complete blood count with differential and platelet count.

Monitor blood pressure and ALT levels regularly during treatment.

Perform a complete blood count if new symptoms, such as signs of infection, develop.

Delay initiation in patients with serious active infections until resolved.

Consider the need for an accelerated elimination procedure with cholestyramine or activated charcoal to rapidly reduce plasma teriflunomide concentrations if necessary.

Do not administer live attenuated vaccines during therapy.

Exercise caution when switching from natalizumab or fingolimod therapy; observe recommended washout periods to avoid additive immune effects.

Discontinue treatment and initiate accelerated elimination if severe hypersensitivity, serious skin reactions, or peripheral neuropathy occurs.

If pregnancy is planned, discontinue therapy and undergo accelerated elimination until plasma concentrations are confirmed to be below 0.02 mg/L.

Adverse Reactions

Infections common – influenza, upper respiratory tract infections, genitourinary tract infections, bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral herpes, dental infections, laryngitis, tinea pedis; unknown – severe infections, including sepsis.

Blood and lymphatic system disorders common – neutropenia, anemia, decreased white blood cell count; uncommon – mild thrombocytopenia (platelets <100×10⁹/L).

Immune system disorders common – mild mixed allergic reactions; unknown – hypersensitivity reactions (immediate or delayed), including anaphylactic shock and angioedema.

Psychiatric disorders common – anxiety.

Nervous system disorders very common – headache; common – paresthesia, lumbosacral radiculitis, carpal tunnel syndrome; uncommon – hyperesthesia, neuralgia, peripheral neuropathy.

Cardiovascular disorders common – palpitations, arterial hypertension.

Respiratory system disorders very rare – interstitial lung diseases.

Digestive system disorders: very common – diarrhea, nausea, increased ALT activity; common – upper abdominal pain, vomiting, toothache, increased GGT, AST activity; unknown – pancreatitis, stomatitis.

Skin and subcutaneous tissue disorders very common – alopecia; common – rash, acne; unknown – severe skin reactions.

Musculoskeletal and connective tissue disorders common – musculoskeletal pain, myalgia, arthralgia, increased blood CPK level.

Renal and urinary disorders common – pollakiuria.

Reproductive system and breast disorders common – menorrhagia.

General disorders and administration site conditions common – pain, weight loss; unknown – post-traumatic pain.

Contraindications

Severe hepatic insufficiency (Child-Pugh class C), severe immunodeficiency (including AIDS), severe bone marrow hematopoiesis disorders, including clinically significant anemia, leukopenia, neutropenia or thrombocytopenia, severe renal failure requiring hemodialysis, severe active infections, severe hypoproteinemia; children and adolescents under 18 years of age; hypersensitivity to teriflunomide; pregnancy; women of childbearing potential not using reliable methods of contraception, and with plasma teriflunomide concentration above 0.02 mg/L; lactation (breastfeeding).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Reproductive toxicity has been shown in animal studies.

The risk of embryofetal toxicity in men as a result of teriflunomide therapy is considered low.

Use in Hepatic Impairment

Contraindicated in patients with severe hepatic insufficiency.

Pediatric Use

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

Geriatric Use

The drug is contraindicated for use in elderly patients.

Special Precautions

Treatment should be carried out under the supervision of a physician experienced in the treatment of patients with multiple sclerosis.

The following tests should be performed before starting treatment: blood pressure measurement, ALT activity determination, complete blood count, including leukocyte formula and platelet count in the blood.

During treatment with teriflunomide, the following parameters should be regularly monitored: blood pressure, ALT activity.

If new symptoms and signs (e.g., infections) appear during treatment, a complete blood count, including leukocyte formula, and platelet count in the blood should be performed.

Teriflunomide is slowly eliminated from the plasma: plasma concentrations reach values below 0.02 mg/L on average in 8 months, although due to individual variations in the drug elimination process, it may last up to 2 years.

Drug elimination can be accelerated by an accelerated elimination procedure.

The accelerated elimination procedure can be used at any time after discontinuation of teriflunomide.

Increased liver enzyme activity has been observed in patients taking Teriflunomide.

These adverse reactions occurred mainly in the first 6 months of treatment.

Patients with a history of liver disease are at risk of worsening liver function while taking teriflunomide.

In this group of patients, symptoms of liver damage should be carefully monitored.

Teriflunomide should be prescribed with caution to patients who abuse alcohol.

Since Teriflunomide is characterized by a high degree of binding to plasma proteins, mainly albumin, the concentration of unbound teriflunomide in plasma may increase in patients with hypoproteinemia, for example, in nephrotic syndrome.

Teriflunomide should not be prescribed to patients with severe hypoproteinemia.

In case of increased blood pressure, appropriate antihypertensive therapy should be administered before and during treatment with teriflunomide.

The initiation of teriflunomide treatment should be delayed in patients with serious active infections until complete recovery.

Given the immunomodulatory effect of teriflunomide, if a patient develops a serious infection, it is necessary to consider the need to suspend treatment with the drug, and before resuming therapy, assess the potential benefits and risks.

Due to the long T_1/2, the need for accelerated elimination using cholestyramine or activated charcoal should be considered.

Patients with a positive tuberculosis test on screening should receive appropriate treatment before starting teriflunomide.

During therapy, interstitial lung diseases can develop acutely.

Pulmonary symptoms, such as persistent cough and shortness of breath, may be a reason to discontinue therapy and conduct further examination.

In patients with pre-existing anemia, leukopenia and/or thrombocytopenia, as well as in patients with impaired bone marrow function or at risk of bone marrow suppression, the risk of hematological disorders during teriflunomide therapy is increased.

If these adverse reactions develop, the possibility of using an accelerated elimination procedure to reduce the plasma concentration of teriflunomide should be considered.

In cases of severe hematological reactions, including pancytopenia, administration of teriflunomide and any other myelosuppressive drug should be discontinued.

The advisability of performing an accelerated elimination procedure should be considered.

If ulcerative stomatitis occurs, teriflunomide should be discontinued.

If serious generalized skin reactions (Stevens-Johnson syndrome or toxic epidermal necrolysis – Lyell’s syndrome) are suspected when skin and/or mucous membrane reactions develop, administration of teriflunomide and any other drugs potentially causing such reactions must be discontinued, and an accelerated elimination procedure should be initiated immediately.

In such cases, patients should not be re-prescribed Teriflunomide.

If peripheral neuropathy is diagnosed in a patient taking Teriflunomide, the possibility of discontinuing teriflunomide and performing an accelerated elimination procedure should be considered.

The use of live attenuated vaccines may be associated with a risk of infection and should therefore be avoided.

Since leflunomide is the parent compound for teriflunomide, concomitant administration of teriflunomide with leflunomide is not recommended.

Switching to or from teriflunomide Based on clinical data related to the simultaneous administration of teriflunomide with interferon beta or with glatiramer acetate, it can be said that there is no need for a waiting period when starting teriflunomide therapy after interferon beta or glatiramer acetate, or when starting interferon beta or glatiramer acetate therapy after teriflunomide.

Due to the long T_1/2 of natalizumab, simultaneous exposure and, consequently, simultaneous impact on the immune system may occur if teriflunomide therapy is started within 2-3 months after discontinuation of natalizumab.

Therefore, precautions should be taken when switching from natalizumab therapy to Teriflunomide.

Given the T_1/2 of fingolimod, a 6-week therapy-free interval is required for the elimination of circulating substances from the body.

From 1 to 2 months are required for the lymphocyte count to return to normal after discontinuation of fingolimod.

This may lead to a combined impact on the immune system.

Therefore, precautions should be taken when switching from fingolimod therapy to Teriflunomide.

In multiple sclerosis, the median T_1/2 was approximately 19 days after repeated doses of 14 mg.

If a decision is made to stop teriflunomide treatment during an interval of 5 T_1/2 (approximately 3.5 months, although it may be longer in some patients), starting another therapy will lead to simultaneous exposure with teriflunomide.

This may lead to an additive effect on the immune system, which requires mandatory adherence to precautions.

Effect on ability to drive vehicles and operate machinery

If adverse reactions from the nervous system occur, for example, dizziness, you should refrain from driving vehicles and engaging in other potentially hazardous activities.

Drug Interactions

Concomitant long-term use (600 mg once daily for 22 days) of rifampicin (an inducer of isoenzyme CYP2B6, 2C8, 2C9, 2C19, 3A), as well as an inducer of transporter proteins, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), and teriflunomide led to a decrease in teriflunomide exposure by approximately 40%.

Rifampicin and other known inducers of CYP and transporter proteins, such as carbamazepine, phenobarbital, phenytoin and St. John’s wort should be prescribed with caution during teriflunomide therapy.

Concomitant administration of teriflunomide and cholestyramine or activated charcoal is not recommended, as this leads to a rapid and significant decrease in the plasma concentration of teriflunomide, except in cases where accelerated elimination is necessary.

The mechanism of accelerated elimination is likely the interruption of hepatointestinal cycles and/or gastrointestinal dialysis of teriflunomide.

An increase in the mean C_max and AUC for repaglinide (1.7- and 2.4-fold, respectively) was noted after administration of multiple doses of teriflunomide, suggesting that Teriflunomide acts as an inhibitor of the CYP2C8 isoenzyme in vivo.

Therefore, when teriflunomide is prescribed, drugs metabolized by the CYP2C8 isoenzyme, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, should be used with caution.

After administration of multiple doses of teriflunomide, an increase in the mean C_max and AUC_0-24 for ethinyl estradiol (1.58- and 1.54-fold, respectively), and C_max and AUC_0-24 of levonorgestrel (1.33- and 1.41-fold, respectively) was noted.

Although this interaction of teriflunomide should not have an adverse effect on the effectiveness of oral contraceptives, the type and dose of oral contraceptives used in combination with teriflunomide should be taken into account.

Repeated doses of teriflunomide reduced the mean C_max and AUC of caffeine (a substrate of the CYP1A2 isoenzyme) by 18% and 55%, respectively, suggesting that Teriflunomide weakly induces the CYP1A2 isoenzyme in vivo.

Therefore, drugs metabolized by the CYP1A2 isoenzyme (such as duloxetine, alosetron, theophylline and tizanidine) during treatment with teriflunomide should be used with caution, as this may lead to a decrease in the effectiveness of these products.

Repeated doses of teriflunomide did not affect the pharmacokinetics of S-warfarin, indicating that Teriflunomide is not an inhibitor or inducer of the CYP2C9 isoenzyme.

However, a 25% decrease in the maximum INR value was noted with the simultaneous administration of teriflunomide and warfarin, compared with the administration of warfarin alone.

Therefore, with the simultaneous administration of warfarin and teriflunomide, careful follow-up and ongoing monitoring of INR is recommended.

An increase in C_max and AUC concentrations (1.43- and 1.54-fold, respectively) of cefaclor is observed after repeated doses of teriflunomide, indicating that Teriflunomide is an inhibitor of organic anion transporters 3 (OAT3) in vivo.

Therefore, caution should be exercised if Teriflunomide is prescribed together with OAT3 substrates, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate and zidovudine.

The effect of teriflunomide on BCRP and/or organic anions transporting polypeptide substrates B1 and B3 (OATP1B1/B3): an increase in C_max and AUC values (2.64- and 2.51-fold, respectively) of rosuvastatin was observed after administration of repeated doses of teriflunomide.

However, no clear effect of this increase in rosuvastatin plasma exposure on HMG-CoA reductase activity was observed.

For rosuvastatin, a 50% dose reduction is recommended for co-administration with teriflunomide.

Other BCRP substrates (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family, especially HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) simultaneously with teriflunomide should be prescribed with caution.

Patients should be carefully monitored for signs and symptoms of excessive drug exposure and the dose should be reduced if necessary.

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.