Universal reference book for medicines
Product name: TEKFIDERA (TECFIDERA)

Active substance: dimethylfumarate

Type: Immunomodulator.
The drug used for multiple sclerosis
Composition, form of production and packaging
Intestine-soluble hard gelatine capsules, opaque, size No. 0, with a light green lid and white body, marked with black ink "BG-12 120 mg" on the capsule body; the contents of the capsule are white or almost white microtablets.
1 caps.

dimethyl fumarate 120 mg

[PRING] cellulose microcrystalline - 131.6 mg, croscarmellose sodium 15 mg, talc 19.8 mg, silicon colloidal dioxide 2.6 mg, magnesium stearate 5 mg, triethyl citrate 7.6 mg, methacrylic acid methyl methacrylate copolymer (1: 1) 5.48 mg, dispersion of 30% 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.

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

14 pcs.
- blisters (1) - cardboard envelopes (1) - cardboard packs.
Intestine-soluble hard gelatine capsules, opaque, size No. 0, with a light green lid and body, marked black ink "BG-12 240 mg" on the capsule body;
the contents of the capsule are white or almost white microtablets.
1 caps.

dimethyl fumarate 240 mg

[PRING] microcrystalline cellulose - 106.7 mg, croscarmellose sodium - 18.5 mg, silicon dioxide colloid - 2.2 mg, magnesium stearate - 1.8 mg, triethyl citrate - 9.5 mg, methacrylic acid-methyl methacrylate copolymer (1: 1) - 6.78 mg, dispersion 30% 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.

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

14 pcs.
- blisters (2) - cardboard envelopes (2) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

The mechanism of therapeutic action of dimethyl fumarate in multiple sclerosis is not fully understood.
In preclinical studies, it was shown that the pharmacodiamycetic effect of dimethyl fumarate is mainly due to the activation of the transcription of nuclear factor 2. similar to the erythroid derivative 2 (Nrf2). It has been established that dimethyl fumarate activates Nrf2-dependent antioxidant genes of patients (for example, NAD (P) H-dehydrogenase, quinone 1; [NQO1]).
Influence on the immune system

Dimethyl fumarate has an anti-inflammatory and immunomodulatory effect.
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 response. In patients with psoriasis, dimethyl fumarate influences the phenotype of lymphocytes by reducing the formation of pro-inflammatory cytokines (T n 1, T n 17), and increasing the production of anti-inflammatory cytokines (T n 2). The therapeutic activity of dimethyl fumarate is confirmed in the modeling of inflammation and neuroinflammatory trauma. During the first year, the use of dimethyl fumarate may be accompanied by a decrease in the total number of lymphocytes in the blood, an average of 30% of the initial value, followed by its stabilization.
Influence 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 QT interval c .

Clinical efficacy

The efficacy and safety of the Tecfider drug was confirmed in two randomized, double-blind, placebo-controlled, two-year trials (Study 1, DEFINE, and Study 2, CONFIRM), involving 1,234 patients and 1417 patients with relapsing remitting multiple sclerosis (RRSD), respectively.
Patients with progressive forms of the disease were not included in these studies.
The main averaged characteristics of patients participating in Study 1 were as follows: age 39 years;
duration of the disease - 7.0 years; the sum of scores on the extended scale of disability assessment (RSHOI) is 2.0. In addition, in 16% of patients the sum of scores on the scale of the RSHOI was> 3.5; In 28% of patients, there were 2 relapses in the previous year, and 42% of patients received another common treatment for multiple sclerosis. In 36% of patients in the subgroup with additional evaluation of the results of magnetic resonance imaging (MRI), at least one lesion accumulating gadolinium (Gd + ) was noted. On the average, the number of Gd + -chains was 1.4.
As a "primary" endpoint in Study 1, the proportion of patients with relapse after 2 years of therapy was selected.
"Secondary" endpoints included: the number of new or newly increased T2-hypertensive foci, the number of Gd + choles, the annual relapse rate, and the time to the confirmed persistent (within 12 weeks) progression of disability. In Study 1, the Tecfider demonstrated a clinically significant and statistically significant effect on all "primary" and "secondary" endpoints. The proportion of patients who experienced a relapse of the disease with the use of the drug Tekfidera and placebo was 0.27 and 0.461, respectively (49% risk reduction, p <0.0001).The annual relapse rate in patients in the group of the drug Tekfildera and placebo was, respectively, 0.172 and 0.364 (relative decrease by 53%, p <0.0001). The proportion of patients with confirmed progressive disability was determined, respectively, as 0.164 and 0.271 (risk reduction by 38%, p = 0.005). The number of new or newly increased T2-foci in 2 years of treatment was 3.2 in patients on the background of the use of the drug Tekfider, and 16.5 in the placebo group (85% reduction in risk, p <0.0001), and the number of Gd + 0.1 and 1.8 (relative risk reduction by 90%, p <0.0001).
The design of Study 2 differed from the design of Study 1 in that the physician / investigator evaluating the effectiveness of the drug did not know what method was used for treatment, and also the presence of a third group of patients who received the Glatiramer acetate (GA) -based comparison drug.
The averaged baseline characteristics of the patients in Study 2 were as follows: age 37 years, duration of the disease 6.0 years, sum of scores on the RSHOI scale 2.5. In addition, 17% of patients had a score of> 3.5 on the RSHO scale, 32% had 2 relapses in the previous year, and 30% received another standard for multiple sclerosis. The "primary" endpoint in Study 2 was the annual relapse rate for 2 years. As the "secondary" endpoints, the number of new or newly increased T2-hypertensive foci, the number of T1-hypoinfensive foci, the relative number of relapses and the time to the confirmed persistent (during 12 weeks) progression of disability were chosen.
The feeder showed a clinically significant and statistically significant effect on the "primary" and most "secondary" endpoints in Study 2. The annual relapse rate was 0.224 in the group of patients treated with Tekfidera, 0.401 in the placebo group (44% risk reduction, p < 0.0001) and 0.286 in the group of patients receiving HA.
The shares of patients with recurrent disease were 0.291 in the Tekfieder group, 0.410 in the placebo group (relative risk reduction by 34%, p <0.0001), and 0.321 in the GA group. The proportions of patients with confirmed progressive disability were defined as 0.128 in the group of the drug Tekfildera, 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 increased T2-hyperintensive lesions in 2 years of treatment was 5.7 in the group treated with the drug Tekfildera. 19.9 in the placebo group (relative decrease by 71%, p <0.0001) and 9.6 in the group receiving GA. and the number of Gd + -handles, respectively, 0.5, 2.0 (relative risk reduction of 74%, p <0.0001) and 0.7.
Clinical efficacy in patients with high disease activity

In a subgroup of patients with high disease activity, stable clinical efficacy of the drug Tekfidera was demonstrated with respect to reducing the number of relapses of the disease, while the effect for a period of time before the onset of a three-month steady progression of disability is not clearly established.

PHARMACOKINETICS

The pharmacokinetics of dimethyl fumarate have been studied in patients with multiple sclerosis and healthy volunteers.
Dimethyl fumarate after ingestion undergoes rapid presystemic hydrolysis under the action of esterases and turns into a basic metabolite, monomethyl fumarate, which also has pharmacological activity. Due to the fact that dimethyl fumarate is not detected in the blood plasma after taking the drug Tekfider inside, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate.
Suction

T max of monomethyl fumarate is from 2 to 2.5 hours.
enteric capsules of the Tecfieder preparation contain micro-tablets that are protected by an enteric-soluble membrane, absorption only occurs after evacuation from the stomach (usually less than 1 hour after taking the drug at a dose of 240 mg 2 times / day during meals in patients with multiple sclerosis median C max is 1.72 mg / l, and the total exposure, AUC is 8.02 ppm / mg. In general, C max and AUC increase, approximately, in proportion to the dose received in the range of doses studied (from 120 to 360 mg). sclerosis of two doses of the drug 240 mg every 4 h under 3-a single ingestion per day accompanied by minimal cumulation monomethyl blood and does not affect the safety profile (increase in median C max of 12% compared to administration of the drug 2 times / day (1.72 mg / l and 1.93 mg / l, respectively, for two- and three-time administration).
The use of the drug during meals does not affect the concentration of dimethyl fumarate in the blood.
Nevertheless, taking the drug during meals can improve the tolerability of treatment, taking into account the possibility of developing such undesirable phenomena as "hot flashes" of blood or abnormalities on the part of the digestive tract (see section "Side effect").
Distribution

The apparent V d of monomethyl fumarate after oral administration at a dose of 240 mg varies from 60 liters to 90 liters.
The binding of monomethyl fumarate to human plasma proteins is in the range of 27-40%.
Metabolism

In humans, the metabolism of dimethyl fumarate is largely influenced by esterases of the gastrointestinal tract, blood and body tissues;
less than 0.1% dimethyl fumarate is excreted unchanged in the urine. Then, the dimethyl fumarate metabolism continues with the participation of the tricarboxylic acid cycle without the involvement of cytochrome P450 isoenzymes. With a single dose of 240 mg of isotope-labeled dimethyl fumarate, glucose was determined in human plasma as the main metabolite. Other circulating metabolites in the blood are fumaric acid, citric acid and monomethyl fumarate. The subsequent metabolism of fumaric acid occurs with the participation of a cycle of tricarboxylic acids, and the release of CO 2 with respiration is the main way of excretion.
Excretion

Exhalation of CO 2 is the main way to remove dimethyl fumarate;
with breathing about 60% of the dose of the drug is taken out. Excretion of the drug by the kidneys and intestines are secondary elimination pathways, and constitute 15.5% and 0.9% of the administered dose, respectively.
T 1/2 monomethyl fumarate is short (about 1 hour), and after 24 hours in the blood of most patients monomethyl fumarate is not detected.
With repeated administration of dimethyl fumarate in therapeutic doses, no cumulation of the starting drug or monomethyl fumarate is observed.
Linearity

The concentration of dimethyl fumarate increases approximately in proportion to the dose in the range from 120 mg to 360 mg.
accepted as a one-time, and repeatedly.
Pharmacokinetics in special groups of patients

According to the ANOVA results, the body weight of patients is the main covariant 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 trials.
The sex and age of patients with nc have a clinically significant effect on the pharmacokinetics of dimethyl fumarate.
Patients aged 65 years and older did not undergo pharmacokinetics studies.
Children

The pharmacokinetics of the drug in patients under 18 years of age has not been studied.

In patients with renal insufficiency

Because.
that kidneys are a secondary way of deducing dimethyl fumarate (less than 16% of the accepted dose of the drug), an assessment of the pharmacokinetics parameters in patients with renal insufficiency ns was performed.
In patients with hepatic insufficiency

Because.
that dimethyl fumarate and monomethyl fumarate are metabolized with the participation of liver enzymes, but without the involvement of the cytochrome P450 system. Evaluation of pharmacokinetics parameters in patients with hepatic impairment was not performed.
Results of preclinical safety assessment

Adverse reactions described in the sections below were not observed 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 (the Ames test, a test of chromosomal aberrations in mammalian cells) for dimethyl fumarate and monomethyl fumarate were negative.
The result of a micronuclear test in vivo in rats for dimethyl fumarate was negative.
Carcinogenicity

Studies of the carcinogenicity of dimethyl fumarate in rats and mice lasted up to 2 years.
Mice received dimethyl fumarate in doses up to 400 mg / kg / day, rats up to 150 mg / kg / day. In mice, the incidence of renal tubular carcinoma increased with a dose of 75 mt / day / day, providing exposure (AUC). equivalent therapeutic. In rats, the incidence of kidney tubular carcinoma increased with a dose of 100 mg / kg / day, which is approximately 3 times higher than the recommended therapeutic dose. The applicability of the data for the person is unknown.
The incidence of squamous papilloma and carcinoma of the anterior part of the stomach increased in mice under equivalent exposure, and in rats less than therapeutic (based on AUC).

Toxicology

Preclinical studies on rodents, rabbits and monkeys were conducted with the introduction of a suspension of dimethyl fumarate (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) orally through a probe.
Long-term study on dogs was performed with oral administration of dimethyl fumarate capsules.
After repeated oral administration of dimethyl fumarate, changes in the kidneys were noted in mice, rats, dogs and monkeys.
In all animal species, regeneration of the epithelium of the renal tubules was detected, suggesting the presence of damage. With lifelong administration of the drug (biennial study), renal tubular hyperplasia was observed in rats. In dogs and monkeys, cortical atrophy was noted, point necrosis and interstitial fibrosis was observed in monkeys that received dimethyl fumarate inside daily for 12 months, at a dose that was 6 times higher than the recommended one, calculated on the basis of AUC. The significance of observational data for man is unknown.
In rats and dogs, degeneration of the epithelium of the testicle tubules was noted.
These changes were detected with the use of 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.
In the anterior gastric area of ​​mice and rats, hyperplasia and hyperkeratosis of the flat epithelium, inflammation, and, for a duration of more than 3 months, squamous cell carcinoma and papilloma, were detected.
The structure of the stomach of rodents 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 therapeutic) in male rats before and during mating did not affect fertility.
Oral administration of dimethyl fumarate in female rats at doses up to 250 μ / kg / day before and during mating, continuing up to 7 days of gestation, led to a decrease in the number of astral cyclops in 14 days, as well as an increase in the number of animals with elongated diestrus in the group receiving the highest of the studied doses (11 times higher than the therapeutic dose). Nevertheless, these changes did not affect fertility and the number of complete embryos.
Dimethyl fumarate penetrates the placental barrier into the blood of embryos in rats and rabbits, the ratio of fetal and female blood concentrations is 0.48-0.64 and 0.1, respectively.
There were no tumors in rats and rabbits when using dimethyl fumarate in any dose. Oral administration dimethyl pregnant rats during the period of organogenesis at dosages up to 250 mg / kg / day led to the appearance of side effects in females (dose 4 times higher than the therapeutic) and to reduce the weight of the fetus and a delay of ossification metatarsals and phalanges of the hind limbs (dose 11 times higher therapeutic). Weight loss and ossification delay fruit were regarded as secondary manifestation of toxic effects on the body of the female (decrease in body weight and food intake).
Oral administration at doses of dimethyl fumarate to 150 mg / kg / day to pregnant rabbits during the period of organogenesis has had no effect on development embriofetalnoe. All female body reduced at doses above 7 times the therapeutic, the number of abortions increased at doses 16 times higher therapeutic.
Oral administration at doses of dimethyl fumarate and 250 mg / kg / day to rats during pregnancy and lactation resulting in lower generation F1 progeny of body weight. Slow puberty male F1 generation was observed at doses 11 times higher therapeutic. Changes F1 progeny generation fertility was observed. Reduced offspring body weight was considered as a secondary effect against the toxic effects of the drug on the body of the female.
INDICATIONS

- Treatment of adult patients with relapsing remitting multiple sclerosis (important information about patient populations for whom the established effectiveness of the drug, is described in the section "Pharmacodynamics").
DOSING MODE

For ingestion.
Use of the drug should be started under the supervision of a physician experienced in the treatment of this disease.
Capsules or their contents should not be crushed, divide, dissolve, suck, chew, because enteric coat microtablets inside the capsules, prevents irritation to the gastrointestinal mucosa.
The starting dose is 120 mg, 2 times / day. After 7 days, the dose should be increased to 240 mg of 2 times / day.
In the event of adverse reactions of gastrointestinal episodes or "hot flushes" of blood dose of the drug can momentarily reduced to 120 mg of 2 times / day. Within 1 month it is recommended to resume reception Tekfidera drug at a dose of 240 mg of 2 times / day.
Tekfidera drug should be taken with food, it can help to reduce the intensity of the "tides" of blood and reactions from the gastrointestinal tract.
Features of the application in selected patient populations
Elderly patients
In clinical studies, the drug Tekfidera participated limited number of patients aged 55 years and older. Also, a sufficient number of patients included in the study at the age of 65 years and older in order to judge the differences in tolerability between elderly and younger patients. Considering the action mechanism of the active substance from the theoretical point of view, there is sufficient reason to change the dose in the treatment of elderly patients.
Children and adolescents
Safety and effectiveness of Tekfidera drug in children and adolescents aged between 10 and 18 years of age have not been established due to lack of data. No data on the treatment of drug Tekfidera multiple sclerosis in children under 10 years.
The use in patients with impaired renal function and / or liver
specific studies Tekfidera drug in patients with renal and hepatic insufficiency was conducted. According to clinical and pharmacological studies change the dose in these patients is not required. Treatment of patients with severe renal and hepatic impairment should be performed with caution.
SIDE EFFECT

Patients receiving treatment with Tekfidera most frequently (in ≥10% of patients) have been reported such adverse drug reactions (ADRs). as "hot flashes" and the NAL blood from the gastrointestinal tract (including diarrhea, nausea, abdominal pain, pain in the upper abdomen). "Tides" of blood and ADRs of the gastrointestinal tract often develop at the beginning of therapy (mostly within the first month). In patients who develop these symptoms, "tides" of blood and gastrointestinal effects can occur periodically throughout the treatment period. The most frequent cause cancellation Tekfidera drug (at> 1% of patients) were blood "inflow" (3%) and NLR from the gastrointestinal tract (4%).
ADRs are presented in accordance with the defeat of organs and organ systems (MedDRA) and WHO classification by frequency of occurrence: very often - 1/10 (> 10%);? often - from? 1/100 to <1/10 (between 1% and <10%?); infrequently - from 1/1000 to <1/100 (0.1% to <1%?)? rarely - from 1/10 000 to <1/1000 (from 0.01% to <0.1%?)? very rarely - <1/10 000 (<0.01%); frequency not known - can not be estimated from the available data.
Infectious and parasitic diseases: often - gastroenteritis.
From the blood and lymphatic system: often - leukopenia, lymphopenia
From the immune system: infrequently - hypersensitivity.

From the nervous system: often - a burning sensation.
On the part of the vessels: very often - "tides" of blood; often - a sensation of heat, accompanied by palpitations.
On the part of the digestive tract: often - diarrhea, nausea, pain in the upper abdomen, pain in the abdomen; often - vomiting, dyspepsia, gastritis, gastrointestinal disorder.
Skin and subcutaneous tissue disorders: often - itching, rash, erythema.
On the part of the kidney and urinary tract: often - proteinuria.
General disorders and the site of injection: often - a sensation of heat.
Laboratory and instrumental data: very often - ketonuria; often - albuminuria, increased activity of ACT, ALT, leukopenia.
General Information
"Tides" blood
"Tides" patients as described sensations blood flow to the skin or a sensation of heat, but can also include other symptoms (e.g., sensation of heat, redness, stinging, burning). In a placebo-controlled studies, there was an increase in the incidence of episodes of "Tide" blood (34% vs. 4%) and heat sensation (7% in comparison with 2%), respectively, in patients receiving the drug Tekfidera, compared with patients placebo. In most cases, the intensity of the "hot flashes" noted by patients as mild to moderate. Cases of severe "tides", which were shown widespread erythema, skin rash and / or itching of the skin, were observed in less than 1% of patients,
NLR from the gastrointestinal tract
in patients receiving drug Tekfidera, compared with patients receiving placebo NLR from the gastrointestinal tract frequency was higher (e.g., diarrhea [14% compared to 10%], nausea [12 \% compared to 9% ], pain in the upper abdomen [10% compared to 6%]. abdominal pain [9% compared to 4%], vomiting [8% compared with 5%] and dyspepsia [5%, compared with 3% ]). In most cases, the intensity of the symptoms of the gastrointestinal tract was observed by patients as mild to moderate. Heavy HLR from the gastrointestinal tract. including, gastritis, gastroenteritis were observed in 1% of patients taking the drug Tekfidera.
The activity of "liver" transaminases
During the placebo-controlled studies have been cases increasing the activity of "liver" transaminases. In most patients, the activity of "liver" transaminases did not exceed the upper limit of normal (ULN) data rates of more than 3 times. Increased activity "liver" enzymes in patients treated with the drug Tekfidera, compared with patients receiving placebo were observed mainly during the first 6 months of therapy. Increased ALT activity and ACT 3 times or more from the ULN marked respectively 5% and 2% of patients receiving placebo and 6% and 2% of patients receiving drug Tekfidera. Cases simultaneously increasing the activity of "liver" enzymes in 3 or more times and total bilirubin in 2 and more times by BGN not observed. Increased activity "liver "transaminases caused the discontinuation of less than 1% of patients in the group of patients treated with the drug Tekfidera and placebo.
NLR in the kidneys and urinary tract
Proteinuria was observed more frequently in patients treated with the drug Tekfidera (9%) compared to placebo (7%). The overall frequency HLP from the kidneys and the urinary tract was not different in patients treated with the drug or placebo Tekfidera. Cases of severe renal insufficiency have been reported. The proportion of patients with proteinuria ( "1+" and above) was comparable to treatment with the drug Tekfidera (43%) and placebo (40%). As a rule, the severity of proteinuria do not fall. Compared to placebo, patients treated with the drug Tekfidera. Glomerular filtration rate (GFR) increased, including in patients who have proteinuria was? 1+ during 2 consecutive trials.
ADRs in the blood and lymphatic system
The majority of patients (> 98%) did not reveal the total number of lymphocytes in the blood abnormalities before applying Tekfidera drug within placebo-controlled studies. After the start of drug treatment decreased total lymphocyte count in the first year and their subsequent stabilization. On average, the total number of lymphocytes was decreased by about 30% of the initial value. In this case, the median and the average number of lymphocytes remain in the normal range. ? Total lymphocyte count <0.5 10 9 / L were observed in less than 1% of patients treated with placebo and 6% - receiving Tekfidera drug. Lymphocyte count <0.2 x 10 9/ l was observed in 1 patient, who took medication Tekfidera, but not observed in the placebo group. In clinical studies, both controlled and uncontrolled, at 2% of the patients decreased number of lymphocytes to <0.5 × 10 9 / l for a period lasting at least 6 months. The majority of these patients reduction in the number of lymphocytes remained at the same level with continued therapy. The patients taking the drug or placebo Tekfidera, the frequency was not different infectious diseases, and was respectively 60% and 58%, including and heavy 2% and 2%. Ne observed more frequent development of infectious diseases, including serious, patient e lymphocyte counts <0.8 x 10 9 / L or <0.5 × 10 9/ l. Cases of progressive multifocal leukoencephalopathy in the background of severe and prolonged lymphopenia. In the first 2 months of therapy patients experienced transient eosinophilia.
Other changes in laboratory parameters
during the placebo-controlled studies in patients who received the drug Tekfidera, ketonuria (1+ or greater) were determined more frequently (45%) than in the placebo group (10%). The clinical relevance of this observation has not been determined.
The concentration of 1,25-dihydroxyvitamin D in the blood was reduced in patients taking the drug Tekfidera or placebo, respectively, on average 25% and 15% of the initial value after 2 years of treatment, and the concentration of parathyroid hormone (PTH) increase, respectively, on average 29% and 15%. The average values of both indicators remained within normal limits.
CONTRAINDICATIONS

- increased sensitivity to the active ingredient or any subsidiary component of the drug;
- Children up to age 18 years (in the absence of clinical data).
Carefully

For patients:
- with initially low total number of blood lymphocytes (<0.5 10? 9 / l);
- with severe renal impairment (creatinine clearance <30 mL / min / 1.73 m 2 ) or liver (class C Child-Pugh) (no clinical findings);
- gastrointestinal disease during pregnancy and breastfeeding (because of limited data, see "Application of pregnancy and during lactation.");
- while the use of antineoplastic and immunosuppressive drugs.
PREGNANCY AND LACTATION

Pregnancy

Data on the use of dimethyl fumarate are limited in pregnant women. In animal studies it has been shown toxic effects of the drug on the reproductive system. Do not use the drug Tekfidera during pregnancy and in women of reproductive age who are not using reliable methods of contraception. Tekfidera drug may be administered during pregnancy only if absolutely necessary, the potential benefit to the mother outweighs the potential risk to the fetus.
Breast-feeding
It is not known whether penetrates dimethyl fumarate or its metabolites in human breast milk, therefore it is impossible to eliminate risk to newborns and infants.Breastfeeding decision on termination or cancellation of therapy with Tekfidera should be made after careful assessment of the benefit ratio for the mother and the risk to the child.
Fertility
Data on the effect of the drug on human fertility Tekfidera absent. Preclinical studies showed no increased risk of impaired fertility during treatment with dimethyl fumarate.
APPLICATION FOR FUNCTIONS OF THE LIVER

Precautions apply to patients with severe renal impairment (creatinine clearance <30 mL / min / 1.73 m 2 ).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Be wary of medication to patients with severe hepatic impairment (class C Child-Pugh).
APPLICATION FOR CHILDREN

Do not use this medication for children and adolescents under the age of 18 years (in the absence of clinical data).
APPLICATION IN ELDERLY PATIENTS

No dose adjustment is required.
SPECIAL INSTRUCTIONS

Laboratory parameters
Application Tekfidera drug may be associated with a decrease in the total number of lymphocytes in the blood. Preparation Tekfidera not studied in patients who initially have had a reduced number of lymphocytes, so caution should be exercised when using the drug in these patients. Prior to treatment should be evaluated of full-scale clinical analysis of the patient's blood (including lymphocyte count number, not older than 6 months). Reevaluating blood analysis (including counting the number of lymphocytes) is recommended to 6 months, and then regular blood tests every 6-12 months with the clinical indication.
In clinical studies 2% of patients decreased lymphocyte count to a level <0.5 × 10 9/ liter for periods of at least 6 months. The majority of these patients have a low lymphocyte count remained and continued therapy. Consideration should be given a break in taking the drug Tekfidera in patients with decreased lymphocyte count <0.5 x 10 9/ l remains stable for 6 months. Counting the number of lymphocytes should be carried out regularly to normalize the index. The changes of individual functional indicators of liver and kidney were observed in clinical studies in patients taking the drug Tekfidera. The clinical significance of these changes is not known. It is recommended to monitor renal function (e.g., by results of BUN and blood creatinine studies, general urinalysis), and liver (e.g., determination of ALT activity and ACT) before treatment and after 3 and 6 months from the start of treatment, and then - every 6-12 months depending on the clinical indication.
Severe dysfunction of kidney and liver
Because. Tekfidera that the drug is not studied in patients with severe liver and kidney functions, to use it in these patients with caution.
Gastrointestinal disease during acute expressed
Due to the fact that the drug is not Tekfidera studied in patients with severe an exacerbation
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