Active ingredients: Dimethyl fumarate (dimethylis fumaras)
Tecfidera 120 mg gastro-resistant hard capsules
Tecfidera 240 mg gastro-resistant hard capsules
Why is Tecfidera used? What is it for?
What is Tecfidera
Tecfidera is a medicine that contains the active substance dimethyl fumarate.
What is Tecfidera
Tecfidera is used to treat relapsing-remitting multiple sclerosis (MS).
Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS), including the brain and spinal cord. Relapsing-remitting MS is characterized by repeated attacks (relapses) of symptoms affecting the nervous system. Symptoms vary from patient to patient, but typically include difficulty walking, a feeling of imbalance, and difficulty with vision. These symptoms may disappear completely when the relapse resolves, but some problems may remain.
How Tecfidera works
Tecfidera appears to work by preventing the body's defense system from damaging the brain and spinal cord. This can also help delay future worsening of multiple sclerosis.
Contraindications When Tecfidera should not be used
Do not take Tecfidera:
- if you are allergic to dimethyl fumarate or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Tecfidera
Tecfidera can affect the number of white blood cells in the blood, kidneys and liver. Before you start taking Tecfidera, your doctor will do a blood test to count the number of your white blood cells and check that your kidneys and liver are working properly. The doctor will carry out tests periodically during the treatment. If your white blood cell count falls during treatment, your doctor may consider stopping the therapy.
Talk to your doctor before taking Tecfidera if you have:
- severe kidney disease
- severe liver disease
- stomach or bowel disease
- a "severe infection (such as pneumonia)
Children and adolescents
Tecfidera should not be used in children and adolescents under the age of 18. The safety and efficacy of Tecfidera are not known in this age group.
Interactions Which drugs or foods may change the effect of Tecfidera
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, especially:
- Medicines that contain fumaric acid esters (fumarates) used to treat psoriasis.
- Medicines that affect the body's immune system, including other medicines used to treat multiple sclerosis, such as fingolimod, natalizumab or mitoxantrone, or some commonly used cancer treatments.
- Medicines that affect the kidneys, including some antibiotics (used to treat infections), diuretics, some types of pain relievers (such as ibuprofen and other similar anti-inflammatory drugs, and medicines bought without a prescription from a doctor) and medicines that contain lithium.
- Vaccinations given while taking Tecfidera may be less effective than normal. Taking Tecfidera with certain types of vaccines (live vaccines) could cause you to become infected and should therefore be avoided.
Tecfidera with food, drink and alcohol
The consumption of high alcoholic beverages (more than 30% alcohol by volume, eg liqueurs) greater than a small amount (more than 50 ml) should be avoided within one "hour of taking Tecfidera, because the" alcohol can interact with this medicine.This could cause inflammation of the stomach (gastritis), particularly in people already prone to gastritis.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Do not use Tecfidera if you are pregnant unless you have discussed this with your doctor
Feeding time
It is not known whether the ingredients in Tecfidera pass into breast milk. Tecfidera must not be used during breastfeeding. Your doctor will help you decide whether you should stop breastfeeding or treatment with Tecfidera. This weighs the benefit of breastfeeding for your baby versus the benefit of therapy for she.
Driving and using machines
The effect of Tecfidera on the ability to drive or use machines is not known. Your doctor will tell you if your disease allows you to drive and use machines safely.
Dose, Method and Time of Administration How to use Tecfidera: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Initial dose
120 mg twice a day.
Take this starting dose for the first 7 days, and then take the regular dose
Regular dose
240 mg twice daily.
Swallow each capsule whole, with some water. You should not split, crush, dissolve, suck or chew the capsule as this may increase some unwanted effects.
Take Tecfidera with food - it may help reduce some more common side effects (listed in section 4).
Overdose What to do if you have taken too much Tecfidera
If you take more Tecfidera than you should
If you have taken too many capsules, contact your doctor immediately.
If you forget to take Tecfidera
If you forget or miss a dose, do not take a double dose to make up for a forgotten dose.
You can take the missed dose if you leave at least 4 hours between doses. Otherwise wait until the next scheduled dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Tecfidera
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
Very low levels of lymphocytes - The number of lymphocytes (a type of white blood cell) may decrease over a long period of time. Maintaining low levels of white blood cells over a long period of time can increase the risk of infections, including the risk of a rare brain infection called progressive multifocal leukoencephalopathy (PML). Symptoms of PML can be similar to those of an MS relapse. Symptoms may include the onset or worsening of weakness on one side of the body (hemiparesis); poor coordination; changes in vision, thinking, or memory; or confusion or personality changes lasting more than a few days.
- If you get any of these symptoms, call your doctor right away.
Allergic reactions - these are not common and may affect up to 1 in 100 people
Redness of the face or body (flushing) is a very common side effect (may affect more than 1 in 10 people). However, if you suffer from redness and have any of these signs:
- swelling of the face, lips, mouth or tongue
- wheezing, difficulty breathing or shortness of breath
Stop taking Tecfidera and call a doctor immediately.
Very common side effects
These may affect more than 1 in 10 people:
- redness of the face or body, feeling hot, hot, burning or itching (flushing)
- loose stools (diarrhea)
- feeling of impending vomiting (nausea)
- stomach pain or stomach cramps
Taking the medicine with food can help reduce the side effects mentioned above.
The presence of substances called ketones, which are naturally produced by the body, is very commonly revealed in urine tests while taking Tecfidera.
Talk to your doctor for information on how to manage these side effects. Your doctor can reduce your dose. Do not reduce the dose unless your doctor tells you to.
Common side effects
These may affect up to 1 in 10 people:
- inflammation of the lining of the intestine (gastroenteritis)
- He retched
- indigestion (dyspepsia)
- inflammation of the stomach lining (gastritis)
- gastrointestinal disease
- burning sensation
- hot flush, feeling of warmth
- itchy (itchy) skin
- rash
- pink or red patches on the skin (erythema)
Common side effects, which may show up in blood or urine tests
- low level of white blood cells (lymphocytopenia, leukopenia) in the blood. The reduction in the number of white blood cells may indicate that your body is less able to fight an "infection. If you have a" serious infection (such as pneumonia), see your doctor immediately.
- protein (albumin) in the urine
- increased levels of liver enzymes (alanine aminotransferase, ALT and aspartate aminotransferase, AST) in the blood
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of that month.
Do not store above 30 ° C.
Store in the original package to protect the medicine from light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Tecfidera contains
The active ingredient is dimethyl fumarate. Tecfidera 120 mg: Each capsule contains 120 mg of dimethyl fumarate.
Tecfidera 240 mg: Each capsule contains 240 mg of dimethyl fumarate.
The other ingredients are microcrystalline cellulose, croscarmellose sodium, talc, colloidal anhydrous silica, magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer (1: 1), methacrylic acid-ethyl acrylate copolymer (1: 1) dispersion 30%, simethicone, sodium lauryl sulfate , polysorbate 80, gelatin, titanium dioxide (E171), Brilliant Blue FCF (E133), yellow iron oxide (E172), shellac, potassium hydroxide and black iron oxide (E172).
Description of what Tecfidera looks like and contents of the pack
Tecfidera 120 mg gastro-resistant hard capsules are green and white and imprinted with 'BG-12 120 mg' and are available in packs containing 14 capsules.
Tecfidera 240 mg hard gastro-resistant capsules are green and imprinted with 'BG-12 240 mg' and are available in packs containing 56 or 168 capsules.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TECFIDERA 120 - 240 MG HARD GASTRORESISTANT CAPSULES.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Tecfidera 120 mg capsule
Each capsule contains 120 mg of dimethyl fumarate.
Tecfidera 240 mg capsule
Each capsule contains 240 mg of dimethyl fumarate
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard gastro-resistant capsule
Tecfidera 120mg capsule
Green and white gastro-resistant hard capsule, imprinted with "BG-12 120 mg".
Tecfidera 240 mg capsule
Green capsule, hard, gastro-resistant, imprinted with "BG-12 240 mg"
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tecfidera is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (see section 5.1 for important information on the populations for which efficacy has been demonstrated).
04.2 Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of the disease.
Dosage
The starting dose is 120 mg twice a day. After 7 days, the dose is increased to the recommended dose of 240 mg twice a day.
Temporary dose reduction to 120 mg twice daily may reduce the onset of flushing and gastrointestinal adverse reactions. Within 1 month, the recommended dose of 240 mg twice daily should be resumed.
Tecfidera must be taken with food (see section 5.2). Taking Tecfidera with food may improve tolerability in those patients who may be prone to redness or gastrointestinal adverse reactions (see sections 4.4, 4.5 and 4.8).
Senior citizens
Clinical studies of Tecfidera included a limited number of patients aged 55 and over and did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients (see section 5.2). Based on the mechanism of action of the active substance there is no theoretical reason why dose adjustments are needed in the elderly.
Renal and hepatic impairment
Tecfidera has not been studied in patients with renal or hepatic impairment. Based on clinical pharmacology studies, no dose adjustments are required (see section 5.2). Caution should be exercised in the treatment of patients with severe renal impairment or severe hepatic impairment (see section 4.4).
Pediatric population
The safety and efficacy of Tecfidera in children and adolescents aged 10 to 18 years have not yet been established. There are no data available. There is no relevant use of Tecfidera in children aged less than 10 years for "Relapsing remitting multiple sclerosis indication.
Method of administration
For oral use.
The capsule or its contents should not be crushed, divided, dissolved, sucked or chewed, as the enteric coating of the micro-tablets prevents irritating effects on the intestine.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Blood tests / laboratory analysis
Laboratory changes in renal and hepatic function have been observed in clinical studies in subjects treated with Tecfidera (see section 4.8).The clinical implications of these changes are unknown. Assessments of renal function (e.g. creatinine, blood urea nitrogen values, and urinalysis) and liver function (e.g. alanine aminotransferase, ALT and aspartate aminotransferase (AST) are recommended before initiation of therapy, after 3 and 6 months of therapy and every 6-12 months thereafter, as clinically indicated.
Patients treated with Tecfidera may develop severe and prolonged lymphopenia (see section 4.8). Tecfidera has not been studied in patients with pre-existing low lymphocyte counts and caution should be used when these patients are treated. Before starting treatment with Tecfidera, an updated complete blood count, including lymphocytes, should be done. If lymphocyte counts are found to be below the normal range, a careful assessment of possible causes should be conducted prior to initiation of Tecfidera therapy.
After initiation of therapy, a complete blood count, including lymphocytes, should be evaluated every 3 months. In patients with lymphocyte counts
Lymphocyte counts should be monitored until they recover. Following recovery and in the absence of alternative treatment options, decisions as to whether or not to restart Tecfidera after discontinuation of treatment should be based on clinical judgment.
Magnetic resonance imaging (MRI)
Before starting treatment with Tecfidera, a baseline MRI (usually within 3 months) should be available for use as a reference. The need for further magnetic resonance imaging (MRI) examinations should be assessed in accordance with national and local recommendations. Magnetic resonance imaging (MRI imaging) may be considered as part of raising alertness in patients considered to be at increased risk for PML. If PML is clinically suspected, an MRI should be performed immediately for diagnostic purposes.
Progressive multifocal leukoencephalopathy (PML)
With Tecfidera and other products containing fumarate, there have been cases of PML in the "setting of severe and prolonged lymphopenia. PML is an" opportunistic infection caused by John Cunningham's virus (JCV), which can be fatal or result in severe disability. . PML can only occur in the presence of a JCV infection. When testing JCV, it should be taken into account that the influence of lymphopenia on the accuracy of the anti-JCV antibody test has not been studied in treated patients. It is also necessary to bear in mind that a negative test for the presence of anti-JCV antibodies (in the presence of normal lymphocyte counts) does not preclude the possibility of JCV infection in the future.
Previous treatment with immunosuppressive or immunomodulatory therapies
No studies have been performed to evaluate the efficacy and safety of Tecfidera in patients switching from other disease-modifying therapies to Tecfidera. The contribution of previous immunosuppressive therapies in the development of PML in patients treated with Tecfidera is unknown. When patients switch from another disease-modifying therapy to Tecfidera, the half-life and mode of action of the other therapy must be taken into account to avoid an additive effect on the immune system and, at the same time, reduce the risk of MS reactivation.
A complete blood count is recommended before starting treatment with Tecfidera and at regular intervals during treatment (see Blood tests / laboratory analysis on).
Generally, Tecfidera therapy can be started immediately after discontinuation of interferon or glatiramer acetate.
Severe renal and hepatic impairment
Tecfidera has not been studied in patients with severe renal impairment or severe hepatic impairment and therefore caution should be used in these patients (see section 4.2).
Severe active gastrointestinal disease
Tecfidera has not been studied in patients with severe active gastrointestinal disease and therefore caution should be used in these patients.
Redness (flushing)
In clinical studies, 34% of patients treated with Tecfidera experienced redness. In most patients with redness, this was mild or moderate in degree.
In clinical studies, 3 out of a total of 2,560 patients treated with Tecfidera experienced severe symptoms of flushing, possibly attributable to hypersensitivity or anaphylactoid reactions. These events were not life-threatening but required hospitalization. Prescribers and patients should be aware of this possibility in the case of severe flushing reactions (see sections 4.2, 4.5 and 4.8).
Infections
In the phase III placebo-controlled studies, the incidence of infections (60% versus 58%) and serious infections (2% versus 2%) was similar in patients treated with Tecfidera or placebo, respectively. It was not observed. an increased incidence of serious infections in patients with stabilizing lymphocyte counts (see section 4.8). The mean lymphocyte count remained within normal limits. Lymphocyte count
If therapy is continued in the presence of severe and prolonged lymphopenia, the risk of opportunistic infections, including lymphopenia, cannot be excluded.progressive multifocal eukoencephalopathy (PML) (see the subsection on PML above for further details).
If a patient develops a severe infection, discontinuation of Tecfidera should be considered and the benefits and risks reassessed before restarting therapy. Patients on Tecfidera should be advised to report symptoms of infections to physician Patients with severe infections should not start Tecfidera until the infection (s) have resolved.
04.5 Interactions with other medicinal products and other forms of interaction
Tecfidera has not been studied in combination with antineoplastic or immunosuppressive therapies and therefore caution should be exercised during concomitant administration. In multiple sclerosis clinical trials, concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase in infection.
Vaccination during Tecfidera treatment has not been evaluated. It is not known whether treatment with Tecfidera will reduce the efficacy of some vaccines. Live vaccines may carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered less important than the risk of failure to vaccinate the individual.
During treatment with Tecfidera, concomitant use of other fumaric acid derivatives (topical or systemic) should be avoided.
In humans, dimethyl fumarate is extensively metabolised by esterases before reaching the systemic circulation and further metabolism occurs through the tricarboxylic acid cycle, without any involvement of the cytochrome P450 (CYP) system. No potential risks of drug interactions were identified from the studies in vitro inhibition and induction of CYP, a study of p-glycoproteins or protein binding studies of dimethyl fumarate and monomethyl fumarate (a primary metabolite of dimethyl fumarate).
Medicines commonly used in patients with multiple sclerosis, such as intramuscularly administered interferon beta-1a and glatiramer acetate, have been clinically tested for potential interactions with dimethyl fumarate and have not changed the pharmacokinetic profile of dimethyl fumarate.
In a study conducted in healthy volunteers, administration of 325 mg (or equivalent) of non-enteric-coated acetylsalicylic acid, 30 minutes prior to Tecfidera, over the course of 4 days of dosing, did not change the pharmacokinetic profile of Tecfidera and reduced the "Onset and severity of flushing. However, long-term use of acetylsalicylic acid is not recommended for the treatment of redness. The potential risks associated with acetylsalicylic acid therapy should be considered prior to concomitant administration. with Tecfidera (see sections 4.2, 4.4 and 4.8).
Concomitant therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, NSAIDs or lithium) may increase potential renal adverse reactions (e.g. proteinuria) in patients treated with Tecfidera (see section 4.8).
Consumption of moderate amounts of alcohol did not change exposure to Tecfidera and was not associated with an increase in adverse reactions. Consumption of large amounts of high alcoholic beverages (more than 30% alcohol by volume) may result in an increase in the dissolution rates of Tecfidera and may, therefore, increase the frequency of gastrointestinal adverse reactions.
Studies in vitro induction of CYP have not shown an interaction between Tecfidera and oral contraceptives. No studies have been performed in vivo on interaction with oral contraceptives. Although no interaction is expected, non-hormonal contraceptive measures with Tecfidera should be considered (see section 4.6).
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and lactation
Pregnancy
No data or limited amount of data are available on the use of dimethyl fumarate in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Tecfidera is not recommended during pregnancy and in women of childbearing potential. not using appropriate contraceptives (see section 4.5) Tecfidera should only be used during pregnancy if clearly needed and if the potential benefit justifies the potential risk to the fetus.
Feeding time
It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Tecfidera therapy. The benefit of breast-feeding for the child and the benefit of therapy for the woman must be considered.
Fertility
There are no data on the effects of Tecfidera on human fertility. Data provided from preclinical studies do not suggest that dimethyl fumarate is associated with an increased risk of decreased fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
The most common adverse reactions (incidence ≥10%) for patients treated with Tecfidera were flushing (flushing) and gastrointestinal events (i.e. diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal events tend to occur early in therapy (especially during the first month) and in patients prone to redness and gastrointestinal events, these events may continue to occur intermittently throughout treatment with Tecfidera. Adverse reactions reported more Commonly leading to discontinuation of therapy (incidence> 1%) in patients treated with Tecfidera were flushing (3%) and gastrointestinal events (4%).
In placebo-controlled and uncontrolled clinical trials, a total of 2,468 patients received Tecfidera and followed for up to 4 years with an overall exposure equivalent to 3,588 person-years. Approximately 1,056 patients received more than 2 years of therapy. with Tecfidera. Experience in uncontrolled clinical trials is consistent with experience in placebo-controlled clinical trials.
Table of adverse reactions
The table below lists the adverse reactions that were reported more frequently in patients treated with Tecfidera than in patients treated with placebo. These data are derived from 2 pivotal Phase 3, double-blind, placebo-controlled clinical trials with a total of 1,529 patients treated with Tecfidera for up to 24 months, with an overall exposure of 2,371 person-years (see section 5.1 The frequencies described in the table below are based on 769 patients treated with Tecfidera 240 mg twice daily and 771 patients treated with placebo.
Adverse reactions are presented according to the MedDRA recommended terminology in the MedDRA System Organ Class. The incidence of the adverse reactions listed below is expressed according to the following convention:
- Very common (≥1 / 10)
- Common (≥1 / 100,
- Uncommon (≥1 / 1,000,
- Rare (≥1 / 10,000,
- Very rare (
- Not known (frequency cannot be estimated from the available data)
Description of selected adverse reactions
Redness (flushing)
In placebo-controlled clinical trials, the incidence of redness (flushing) (34% vs 4%) and hot flashes (7% vs 2%) were increased in patients treated with Tecfidera compared with those treated with placebo, respectively. Flushing is typically described as redness or hot flashes, but may include other events (e.g., warmth, redness, itching, and a burning sensation). Flushing events tend to occur early in therapy (especially during the first month) and, in affected patients, these events may continue to occur intermittently throughout treatment with Tecfidera. In patients with flushing, most experienced mild or moderate flushing events. Overall, 3% of patients treated with Tecfidera discontinued treatment due to flushing. The incidence of severe flushing, which may be characterized by generalized erythema, rash and / or pruritus, was observed in less than 1% of patients treated with Tecfidera (see sections 4.2, 4.4 and 4.5).
Gastrointestinal
The incidence of gastrointestinal events (eg, diarrhea [14% vs 10%], nausea [12% vs 9%], upper abdominal pain [10% vs 6%], abdominal pain [9% vs 4%], vomiting [8% versus 5%] and dyspepsia [5% versus 3%]) was increased in patients treated with Tecfidera compared to those treated with placebo, respectively. Gastrointestinal events tend to occur early in therapy (especially during the first month ) and, in affected patients, these events may continue to occur intermittently throughout treatment with Tecfidera. In the majority of patients who experienced gastrointestinal events, these were mild or moderate in severity. 4% of patients treated with Tecfidera discontinued therapy due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was observed in 1% of patients treated with Tecfidera (see section 4.2).
Hepatic transaminases
In placebo-controlled studies, elevations in hepatic transaminases were observed. In the majority of patients in whom these elevations occurred, hepatic transaminases were alanine aminotransferase and aspartate aminotransferase (AST) ≥3 times ULN, were observed in 5% and 2% of placebo-treated patients, respectively. and in 6% and 2% of patients treated with Tecfidera. No transaminase elevations ≥3-fold ULN with concomitant elevations in total bilirubin> 2-fold ULN were observed. Discontinuation of therapy due to elevated hepatic transaminases were
Renal
In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with Tecfidera (9%) compared to placebo (7%). The overall incidence of renal and urinary adverse events was similar for patients treated with Tecfidera. and with placebo. No cases of severe renal insufficiency have been reported. Urinalysis shows that the percentage of patients with protein values of 1+ or higher is similar for patients treated with Tecfidera (43%) and patients treated with placebo (40%). Typically, laboratory observations of proteinuria they were not progressive.Compared to patients treated with placebo, an increase in estimated glomerular filtration rate (eGFR) was observed in patients treated with Tecfidera, including those who experienced 2 consecutive episodes of proteinuria (≥1 +).
Hematological
In placebo-controlled clinical trials, lymphocyte values were normal in the majority of patients (> 98%) prior to initiation of therapy. Once treatment with Tecfidera was initiated, mean lymphocyte counts decreased over the first year and subsequently stabilized. On average, lymphocyte counts decreased approximately 30% from baseline. Mean and median lymphocyte counts remained within normal limits. Eosinophilic lymphocyte counts were observed during the first 2 months of therapy.
Laboratory abnormalities
In placebo-controlled clinical trials, measurement of urine ketones (1+ or higher) was superior in patients treated with Tecfidera (45%) compared to placebo (10%). No unexpected consequences were observed in clinical studies.
1,25-dihydroxyvitamin D levels decreased in patients treated with Tecfidera compared to those treated with placebo (median percentage decrease from baseline to 2 years by 25% compared to 15%, respectively) and parathyroid hormone (PTH) levels were increased in patients treated with Tecfidera compared to those treated with placebo (increase in median percentage from baseline to 2 years of 29% compared to 15%, respectively). Mean values for both parameters remained within the normal range.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. . Website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No cases of overdose have been reported.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other nervous system drugs.
ATC code: N07XX09.
Mechanism of action
The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that the pharmacodynamic responses of dimethyl fumarate are mainly mediated through the activation of the transcription pathway of nuclear factor Nrf2 (erythroid nuclear factor 2 2-related). Dimethyl fumarate has been shown to cause upregulation in patients (upregulation) of Nrf2-dependent antioxidant genes (eg NAD (P) H dehydrogenase, quinone 1; [NQO1]).
Pharmacodynamic effects
Effects on the immune system
In preclinical and clinical studies, Tecfidera demonstrated anti-inflammatory and immunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the major metabolite of dimethyl fumarate, significantly reduced the activation of immune cells and the subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinical studies in psoriasis patients , dimethyl fumarate affected lymphocyte phenotypes by downregulation (down-regulation) of pro-inflammatory cytokine profiles (TH1, TH17), and favored the production of anti-inflammatory cytokines (TH2). Dimethyl fumarate demonstrated "therapeutic activity in multiple inflammatory and neuroinflammatory lesion models. In Phase 3 studies, during treatment with Tecfidera, the mean lymphocyte count decreased by an average of about 30% from baseline over the first year" , with a subsequent stabilization phase.
Effect on the cardiovascular system
In a QT corrected interval (QTc) study, single doses of Tecfidera 240 mg or 360 mg compared versus placebo had no effect on the QTc interval.
Clinical efficacy and safety
Two randomized, double-blind, placebo-controlled, 2-year studies were conducted [Study 1 (DEFINE) with 1,234 subjects and Study 2 (CONFIRM) with 1,417 subjects] in subjects with relapsing-remitting multiple sclerosis (MS -RR). No subjects with progressive forms of multiple sclerosis were included in these studies. Efficacy (see table below) and safety were demonstrated in subjects with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5 inclusive, who had had at least 1 relapse during "year prior to randomization or, within 6 weeks of randomization, they had magnetic resonance imaging of the brain (MRI) showing at least one gadolinium-enhancing (Gd +) lesion. Study 2 included a single-blind comparator arm (rater-blinded, i.e. the study physician / investigator evaluating the treatment response in the study was in a blind condition) of treatment with glatiramer acetate (GA).
In Study 1, patients had the following median baseline characteristics: age 39 years, disease duration 7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score> 3.5, 28% had ≥2 relapses in the previous year, and 42% had previously received other approved treatments for multiple sclerosis. In the MRI cohort, 36 % of patients included in the study had gadolinium enhancing lesions (Gd +) at baseline (mean number of Gd lesions + 1.4).
In Study 2, patients had the following baseline characteristics: age 37 years, disease duration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score> 3.5, 32% had ≥2 relapses in the previous year, and 30% had previously received other approved treatments for multiple sclerosis. In the MRI cohort, 45% of patients included in the study had gadolinium enhancing lesions (Gd +) at baseline (mean number of Gd + lesions 2.4).
Compared to placebo, subjects treated with Tecfidera had a clinically relevant and statistically significant reduction in: the proportion of subjects with relapse at 2 years, primary endpoint of Study 1; the 2-year annualized relapse rate, primary endpoint of Study 2.
The annualized relapse rate for glatiramer acetate and placebo was 0.286 and 0.401 in Study 2, respectively, corresponding to a reduction of 29% (p = 0.013), which is consistent with approved prescribing information.
a All clinical endpoint analyzes were by intent-to-treat (ITT);
b MRI analysis used the MRI cohort
* P value
Efficacy in patients with high disease activity:
A consistent effect of treatment on relapse was observed in a subgroup of patients with high disease activity, while the effect on time to sustained progression of disability at 3 months was not clearly established. Due to the study design, the " high disease activity was defined as follows:
- Patients with 2 or more relapses in a year and with one or more Gadolinium-enhancing (Gd) lesions on magnetic resonance imaging (MRI) of the brain (n = 42 in the DEFINE study; n = 51 in the CONFIRM study) or,
- Patients who have not responded to a complete and adequate course (at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year on therapy and at least 9 hyperintense T2 lesions on magnetic resonance imaging (MRI) of the skull or at least one Gadolinium-enhancing lesion (Gd), or patients with an unchanged or greater relapse rate in the previous year compared to the previous 2 years (n = 177 in the DEFINE study; n = 141 in the CONFIRM study).
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Tecfidera in one or more subsets of the pediatric population in multiple sclerosis (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Administered orally, Tecfidera (dimethyl fumarate) undergoes rapid presystemic esterase-mediated hydrolysis and is converted to monomethyl fumarate, its major metabolite, which is also active. Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. all pharmacokinetic analyzes related to dimethyl fumarate were performed with plasma concentrations of monomethyl fumarate Pharmacokinetic data were obtained in subjects with multiple sclerosis and in healthy volunteers.
Absorption
The Tmax of monomethyl fumarate is between 2 and 2.5 hours. Since Tecfidera hard gastro-resistant capsules contain micro tablets, which are protected by an enteric coating, absorption does not begin until they leave the stomach (typically less than 1 hour). After administration with food of 240 mg two times per day, the median peak (Cmax) was 1.72 mg / l and the overall exposure (AUC, area under the curve) was 8.02 h.mg/l in subjects with multiple sclerosis. Overall, the C
max and AUC increased approximately dose proportionally over the dose range studied (120 mg to 360 mg). In subjects with multiple sclerosis, two doses of 240 mg were administered 4 hours apart over a period of 4 hours. dosage regimen of administration three times a day. This resulted in minimal accumulation of exposure resulting in a 12% increase in median Cmax compared to twice daily dosing (1.72 mg / L twice daily vs 1.93 mg / L three times daily). with no security implications.
Food has no clinically significant effect on dimethyl fumarate exposure. However Tecfidera should be taken with food due to improved tolerability of redness or gastrointestinal adverse events (see section 4.2).
Distribution
The apparent volume of distribution following oral administration of Tecfidera 240 mg varies between 60 L and 90 L. Binding of monomethyl fumarate to human plasma proteins is generally between 27% and 40%.
Biotransformation
In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted in the urine as unmodified dimethyl fumarate. Dimethyl fumarate is initially metabolised by esterases, which are ubiquitous in the gastrointestinal tract, blood and tissues, prior to achieve systemic circulation. Further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. A single dose study of 240 mg of 14C-dimethyl fumarate identified glucose as the predominant metabolite in human plasma. Other metabolites circulating included fumaric acid, citric acid and monomethyl fumarate. The metabolism of fumaric acid downstream of the aforementioned metabolic path takes place through the tricarboxylic acid cycle, with the exhalation of carbon dioxide (CO2) which acts as the main route of elimination.
Elimination
Exhalation of CO2 is the major route of elimination for dimethyl fumarate and accounts for 60% of the dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose, respectively.
The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulating monomethyl fumarate is present at 24 hours in most subjects. Accumulation of parent drug or monomethyl fumarate does not occur with multiple doses of dimethyl fumarate on the therapeutic regimen.
Linearity
Exposure to dimethyl fumarate increases in an approximately dose proportional manner with single and multiple doses over the studied dose range of 120 mg to 360 mg.
Pharmacokinetics in special patient groups
Based on the results of the analysis of variance (ANOVA), body weight is the main exposure covariate (according to Cmax and AUC) in subjects with relapsing-remitting multiple sclerosis (RRMS), but did not affect the measurements. safety and efficacy evaluated in clinical trials.
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl fumarate. Pharmacokinetics in patients 65 years of age and older have not been studied.
Pediatric population
Pharmacokinetics in patients under the age of 18 have not been studied.
Renal impairment
Since the renal pathway is a secondary route of elimination for dimethyl fumarate representing less than 16% of the administered dose, no evaluation of the pharmacokinetics in subjects with renal impairment has been performed.
Hepatic impairment
Since dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without involvement of the CYP450 system, no evaluation of the pharmacokinetics in subjects with hepatic impairment has been performed.
05.3 Preclinical safety data
The adverse reactions described in the Toxicology and Reproductive Toxicity sections below were not observed in clinical studies, but were observed in animals at exposure levels similar to clinical exposure levels.
Mutagenesis
Dimethyl fumarate and mono-methyl fumarate were negative in one battery of tests in vitro (Ames test, test for chromosomal aberrations in mammalian cells). Dimethyl fumarate was negative in the rat micronucleus test in vivo.
Carcinogenesis
Carcinogenicity studies of dimethyl fumarate were conducted for up to 2 years in mice and rats. Dimethyl fumarate was administered orally at doses of 25, 75, 200, and 400 mg / kg / day to mice, and at doses of 25, 50, 100, and 150 mg / kg / day to rats. In mice, the incidence of renal tubular carcinoma was increased at the dose of 75 mg / kg / day, an equivalent exposure (AUC) at the recommended human dose. In rats, the incidence of renal tubular carcinoma was increased at a dose of 100 mg / kg / day, an exposure approximately 3 times the recommended human dose. The relevance of these findings to human risk is unknown.
The incidence of papilloma and squamous cell carcinoma in the non-glandular part of the stomach (forestomach) was increased at an exposure equivalent to the recommended human dose in mice and at an exposure below the recommended human dose in rats (based on at "AUC). There is no human counterpart to the rodent forestomach.
Toxicology
Preclinical studies were conducted in rodents, rabbits and monkeys with a suspension of dimethyl fumarate (dimethyl fumarate in 0.8% hydroxypropylmethylcellulose) administered by oral gavage. The chronic dog study was conducted with oral administration of the dimethyl fumarate capsule.
Renal changes were observed after repeated oral administration of dimethyl fumarate in mice, rats, dogs and monkeys. Regeneration of renal tubular epithelium indicative of injury was observed in all species. Renal tubular hyperplasia was observed in rats that received lifelong treatment (2-year study). Cortical atrophy was observed in dogs and monkeys, and single cell necrosis and interstitial fibrosis were observed in monkeys who received daily oral doses of dimethyl fumarate for 12 months, at 6 times the recommended dose based on AUC. knows the relevance of these findings to human risk.
Degeneration of the seminiferous epithelium was observed in the testes of rats and dogs. Results were observed at approximately the recommended dose in rats and at 6 times the recommended dose in dogs (based on AUC). The relevance of these findings to human risk is unknown.
The findings in the forestomach of mice and rats were squamous epithelial hyperplasia coupled with hyperkeratosis; inflammation; and papilloma and squamous cell carcinoma in studies lasting 3 months or longer. There is no human counterpart to the forestomach of mice and rats.
Reproductive toxicity
Oral administration of dimethyl fumarate to male rats at 75, 250 and 375 mg / kg / day before and during mating had no effect on male fertility up to the highest dose tested (at least 2x the recommended AUC dose. ).Oral administration of dimethyl fumarate to female rats at 25, 100 and 250 mg / kg / day before and during mating, and continuing until day 7 of gestation, resulted in a reduction in the number of estrus cycles for 14 days. and increased the number of animals on prolonged diestrus at the highest dose tested (11 times the recommended dose based on AUC). However, these changes had no effect on fertility or the number of viable fetuses produced.
Dimethyl fumarate has been shown to cross the placental membrane and enter the fetal blood of rats and rabbits, with fetal-to-maternal plasma concentration ratios ranging from 0.48 to 0.64 and 0.1, respectively. No malformations were observed in rats or rabbits at any dose of dimethyl fumarate. Administration of dimethyl fumarate at oral doses of 25, 100 and 250 mg / kg / day to pregnant rats during the period of organogenesis produced maternal adverse effects at 4 times the recommended dose based on AUC, and low fetal weight and delayed "ossification (metatarsal and hind limb phalanges) at 11 times the recommended dose based on AUC. Lower fetal weight and delayed ossification were considered secondary to maternal toxicity (decreased body weight and food consumption) .
Oral administration of dimethyl fumarate at 25, 75 and 150 mg / kg / day to pregnant rabbits during organogenesis had no effect on embryo-fetal development and resulted in a reduced maternal weight at 7 times the recommended dose and increased abortion. to 16 times the recommended dose, based on AUC.
Oral administration of dimethyl fumarate at 25, 100 and 250 mg / kg / day to rats during pregnancy and lactation resulted in reduced body weights in F1 litters, and delays in sexual maturation in F1 males at 11 times the recommended dose based on "AUC. There was no effect on fertility in the F1 litters. Lower body weight of litters was considered secondary to maternal toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Micro-tablets with enteric coating
Microcrystalline cellulose
Croscarmellose sodium
Talc
Anhydrous colloidal silica
Magnesium stearate
Triethyl citrate
Methacrylic acid - methyl methacrylate copolymer (1: 1)
Methacrylic acid - ethyl acrylate copolymer (1: 1) dispersion 30%
Simethicone
Sodium lauryl sulfate
Polysorbate 80
Capsule shell
Jelly
Titanium dioxide (E171)
Brilliant Blue FCF (E133)
Yellow iron oxide (E172)
Capsule print (black ink)
Shellac
Potassium hydroxide
Black iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
120 mg gastro-resistant hard capsules: 4 years.
240 mg gastro-resistant hard capsules: 3 years.
06.4 Special precautions for storage
Do not store above 30 ° C.
Keep the blisters in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
120 mg capsules: 14 capsules in PVC / PE / PVDC-PVC aluminum blister packs.
240 mg capsules: 56 or 168 capsules in PVC / PE / PVDC-PVC aluminum blister packs.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Biogen Idec Ltd
Innovation House
70 Norden Road
Maidenhead
Berkshire
SL6 4AY
UK
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 043217013 / E
A.I.C. n. 043217025 / E
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 30 January 2014
10.0 DATE OF REVISION OF THE TEXT
12/2015
