Leaflet DIMETIL FUMARAT ACCORD 240mg gastro-resistant capsules
Indicated for: multiple sclerosis
Route of administration: oral
Substance: dimethyl fumarate (immunomodulator)
ATC: L04AX07 (Antineoplastic and immunomodulating agents | Immunosuppressants | Other immunosuppressants)
Avoid live vaccines during treatment if contraindicated.
This medicine may increase the risk of infections.
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Dimethyl fumarate is a medication used for the treatment of relapsing-remitting multiple sclerosis. It works by reducing inflammation and protecting nerve cells from oxidative stress.
The medication is taken orally, usually twice daily, as directed by a doctor. It is important to follow the recommended dose to minimize the risk of adverse effects.
Side effects may include flushing, nausea, diarrhea, abdominal pain, or a decrease in lymphocyte count. In rare cases, severe allergic reactions or progressive multifocal leukoencephalopathy may occur.
Dimethyl fumarate is not recommended for patients with hypersensitivity to this medication or active severe infections.
General data about DIMETIL FUMARAT ACCORD 240mg
- Substance: dimethyl fumarate
- Date of last drug list: 01-03-2026
- Commercial code: W71686001
- Concentration: 240mg
- Pharmaceutical form: gastro-resistant capsules
- Quantity: 56
- Product type: generic
- Prescription restrictions: P-RF - Medicines prescription that is retained in the pharmacy (not renewable).
Pharmaceutical forms available for dimethyl fumarate
Concentrations available for dimethyl fumarate
- 120mg
- 240mg
- 30mg
Leaflet DIMETIL FUMARAT ACCORD 240mg
Contents of the package leaflet for the medicine DIMETIL FUMARAT ACCORD 240mg gastro-resistant capsules
1. NAME OF THE MEDICINAL PRODUCT
Dimethyl fumarate Accord 120 mg gastro-resistant hard capsules
Dimethyl fumarate Accord 240 mg gastro-resistant hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Dimethyl fumarate Accord 120 mg gastro-resistant hard capsules
Each gastro-resistant hard capsule contains 120 mg dimethyl fumarate.
Dimethyl fumarate Accord 240 mg gastro-resistant hard capsules
Each gastro-resistant hard capsule contains 240 mg dimethyl fumarate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Gastro-resistant hard capsule (gastro-resistant capsule)
Dimethyl fumarate Accord 120 mg gastro-resistant hard capsules
Size “0” (approximate 21.3 x 7.5 mm) hard gelatin capsules with green cap and white body, printedwith “HR1” in black ink on capsule body containing white to off-white, round, biconvex enteric coatedmini tablets plain on both the sides.
Dimethyl fumarate Accord 240 mg gastro-resistant hard capsules
Size “0” (approximate 21.3 x 7.5 mm) hard gelatin capsules with green cap and body, printed with“HR2” in black ink on capsule body containing white to off-white, round, biconvex enteric coatedmini tablets plain on both the sides.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Dimethyl fumarate Accord is indicated for the treatment of adult and paediatric patients aged 13 yearsand older with relapsing remitting multiple sclerosis (RRMS).
4.2 Posology and method of administration
Treatment should be initiated under supervision of a physician experienced in the treatment of multiplesclerosis.
PosologyThe starting dose is 120 mg twice a day. After 7 days, the dose should be increased to therecommended maintenance dose of 240 mg twice a day (see section 4.4).
If a patient misses a dose, a double dose should not be taken. The patient may take the missed doseonly if they leave 4 hours between doses. Otherwise the patient should wait until the next scheduleddose.
Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing andgastrointestinal adverse reactions. Within 1 month, the recommended maintenance dose of 240 mgtwice a day should be resumed.
Dimethyl fumarate Accord should be taken with food (see section 5.2). For those patients who mayexperience flushing or gastrointestinal adverse reactions, taking Dimethyl fumarate Accord with foodmay improve tolerability (see sections 4.4, 4.5 and 4.8).
Special populationsElderly
Clinical studies of Dimethyl fumarate Accord had limited exposure to patients aged 55 years andabove, and did not include sufficient numbers of patients aged 65 and over to determine whether theyrespond differently than younger patients (see section 5.2). Based on the mode of action of the activesubstance there are no theoretical reasons for any requirement for dose adjustments in the elderly.
Renal and hepatic impairmentDimethyl fumarate Accord has not been studied in patients with renal or hepatic impairment. Based onclinical pharmacology studies, no dose adjustments are needed (see section 5.2). Caution should beused when treating patients with severe renal or severe hepatic impairment (see section 4.4).
Paediatric populationThe posology is the same in adults and in paediatric patients aged 13 years and older.
There are limited data available in children between 10 and 12 years old. Currently available data aredescribed in sections 4.8 and 5.1 but no recommendation on a posology can be made.
The safety and efficacy of dimethyl fumarate in children aged less than 10 years have not beenestablished. No data are available.
Method of administrationFor oral use.
The capsule should be swallowed whole. The capsule or its contents should not be crushed, divided,dissolved, sucked or chewed as the enteric-coating of the mini tablet prevents irritant effects on thegastrointestinal tract.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Suspected or confirmed progressive multifocal leukoencephalopathy (PML).
4.4 Special warnings and precautions for use
Blood/laboratory tests
Renal functionChanges in renal laboratory tests have been seen in clinical trials in patients treated with dimethylfumarate (see section 4.8). The clinical implications of these changes are unknown. Assessment of renalfunction (e.g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatmentinitiation, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically indicated.
Hepatic function
Drug-induced liver injury, including liver enzyme increase (≥ 3 times upper limit of normal (ULN))and elevation of total bilirubin levels (≥ 2 x ULN) can result from treatment with dimethyl fumarate.
The time to onset can be days, several weeks or longer. Resolution of the adverse reactions has beenobserved after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanineaminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels arerecommended prior to treatment initiation and during treatment as clinically indicated.
LymphocytesPatients treated with dimethyl fumarate may develop lymphopenia (see section 4.8). Prior to initiatingtreatment with dimethyl fumarate, a current complete blood count, including lymphocytes, must beperformed. If lymphocyte count is found to be below the normal range, thorough assessment of possiblecauses should be completed prior to initiation of treatment. Dimethyl fumarate has not been studied inpatients with pre-existing low lymphocyte counts and caution should be exercised when treating thesepatients. Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts <0.5x 109/L).
After starting therapy, complete blood counts, including lymphocytes, must be performed every3 months.
Enhanced vigilance due to an increased risk of PML is recommended in patients with lymphopeniaas follows:
* Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocytecounts <0.5 x 109/L) persisting for more than 6 months.
* In patients with sustained moderate reductions of absolute lymphocyte counts ≥0.5 x 109/L to< 0.8 x 109/L for more than 6 months, the benefit/risk balance of treatment with dimethyl fumarateshould be re-assessed.
* In patients with lymphocyte counts below lower limit of normal (LLN) as defined by locallaboratory reference range, regular monitoring of absolute lymphocyte counts is recommended.
Additional factors that might further augment the individual PML risk should be considered (seesubsection on PML below).
Lymphocyte counts should be followed until recovery (see section 5.1). Upon recovery and in theabsence of alternative treatment options, decisions about whether or not to restart dimethyl fumarateafter treatment discontinuation should be based on clinical judgement.
Magnetic resonance imaging (MRI)
Before initiating treatment with dimethyl fumarate, a baseline MRI should be available (usually within3 months) as a reference. The need for further MRI scanning should be considered in accordance withnational and local recommendations. MRI imaging may be considered as part of increased vigilance inpatients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should beperformed immediately for diagnostic purposes.
Progressive multifocal leukoencephalopathy (PML)PML has been reported in patients treated with dimethyl fumarate (see section 4.8). PML is anopportunistic infection caused by John-Cunningham virus (JCV), which may be fatal or result in severedisability.
PML cases have occurred with dimethyl fumarate and other medicinal products containing fumarates inthe setting of lymphopenia (lymphocyte counts below LLN). Prolonged moderate to severelymphopenia appears to increase the risk of PML with dimethyl fumarate, however, risk cannot beexcluded in patients with mild lymphopenia.
Additional factors that might contribute to an increased risk of PML in the setting of lymphopenia are:
- duration of dimethyl fumarate therapy. Cases of PML have occurred after approximately 1 to5 years of treatment, although the exact relationship with duration of treatment is unknown.
- profound decreases in CD4+ and especially in CD8+ T cell counts, which are important forimmunological defence (see section 4.8), and
- prior immunosuppressive or immunomodulatory therapy (see below).
Physicians should evaluate their patients to determine if the symptoms are indicative of neurologicaldysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML.
At the first sign or symptom suggestive of PML, dimethyl fumarate should be withheld and appropriatediagnostic evaluations, including determination of JCV DNA in cerebrospinal fluid (CSF) byquantitative polymerase chain reaction (PCR) methodology, need to be performed. The symptoms of
PML may be similar to an MS relapse. Typical symptoms associated with PML are diverse, progressover days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs,disturbance of vision, and changes in thinking, memory, and orientation leading to confusion andpersonality changes. Physicians should be particularly alert to symptoms suggestive of PML that thepatient may not notice. Patients should also be advised to inform their partner or caregivers about theirtreatment, since they may notice symptoms that the patient is not aware of.
PML can only occur in the presence of a JCV infection. It should be considered that the influence oflymphopenia on the accuracy of serum anti-JCV antibody testing has not been studied in dimethylfumarate treated patients. It should also be noted that a negative anti-JCV antibody test (in the presenceof normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.
If a patient develops PML, dimethyl fumarate must be permanently discontinued.
Prior treatment with immunosuppressive or immunomodulating therapies
No studies have been performed evaluating the efficacy and safety of dimethyl fumarate when switchingpatients from other disease modifying therapies to dimethyl fumarate. The contribution of priorimmunosuppressive therapy to the development of PML in dimethyl fumarate treated patients ispossible.
PML cases have been reported in patients who had previously been treated with natalizumab, for which
PML is an established risk. Physicians should be aware that cases of PML occurring following recentdiscontinuation of natalizumab may not have lymphopenia.
In addition, a majority of confirmed PML cases with dimethyl fumarate occurred in patients with priorimmunomodulatory treatment.
When switching patients from another disease modifying therapy to dimethyl fumarate, the half-life andmode of action of the other therapy should be considered in order to avoid an additive immune effectwhile at the same time, reducing the risk of reactivation of MS. A complete blood count isrecommended prior to initiating dimethyl fumarate and regularly during treatment (see
Blood/laboratory tests above).
Severe renal or hepatic impairment
Dimethyl fumarate has not been studied in patients with severe renal or severe hepatic impairment andcaution should, therefore, be used in these patients (see section 4.2).
Severe active gastrointestinal disease
Dimethyl fumarate has not been studied in patients with severe active gastrointestinal disease andcaution should, therefore, be used in these patients.
Flushing
In clinical trials, 34% of dimethyl fumarate treated patients experienced flushing. In the majority ofpatients who experienced flushing, it was mild or moderate in severity. Data from healthy volunteerstudies suggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. Ashort course of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial inpatients affected by intolerable flushing (see section 4.5). In two healthy volunteer studies, theoccurrence and severity of flushing over the dosing period was reduced.
In clinical trials, 3 patients out of a total of 2,560 patients treated with dimethyl fumarate experiencedserious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. Theseadverse reactions were not life-threatening, but led to hospitalisation. Prescribers and patients should bealert to this possibility in the event of severe flushing reactions (see sections 4.2, 4.5 and 4.8).
Anaphylactic reactions
Cases of anaphylaxis/anaphylactoid reaction have been reported following dimethyl fumarateadministration in the post-marketing setting (see section 4.8). Symptoms may include dyspnoea,hypoxia, hypotension, angioedema, rash or urticaria. The mechanism of dimethyl fumarate inducedanaphylaxis is unknown. Reactions generally occur after the first dose, but may also occur at any timeduring treatment, and may be serious and life threatening. Patients should be instructed to discontinuedimethyl fumarate and seek immediate medical care if they experience signs or symptoms ofanaphylaxis. Treatment should not be restarted (see section 4.8).
InfectionsIn phase 3placebo-controlled studies, the incidence of infections (60% vs 58%) and serious infections(2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively.
However, due to dimethyl fumarate immunomodulatory properties (see section 5.1), if a patientdevelops a serious infection, suspending treatment with dimethyl fumarate should be considered andthe benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving dimethylfumarate should be instructed to report symptoms of infections to a physician. Patients with seriousinfections should not start treatment with dimethyl fumarate until the infection(s) is (are) resolved.
There was no increased incidence of serious infections observed in patients with lymphocyte counts<0.8x109/L or <0.5x109/L (see section 4.8). If therapy is continued in the presence of moderate tosevere prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruledout (see section 4.4 subsection PML).
Herpes zoster infections
Cases of herpes zoster have been reported with dimethyl fumarate (see section 4.8). The majority ofcases were non-serious, however, serious cases, including disseminated herpes zoster, herpes zosterophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpes zostermeningoencephalitis and herpes zoster meningomyelitis have been reported. These adverse reactionsmay occur at any time during the treatment. Patients should be monitored for signs and symptoms ofherpes zoster especially when concurrent lymphocytopenia is reported. If herpes zoster occurs,appropriate treatment for herpes zoster should be administered. Withholding treatment should beconsider in patients with serious infections until the infection has resolved (see section 4.8).
Treatment initiation
Treatment should be started gradually to reduce the occurrence of flushing and gastrointestinal adversereactions (see section 4.2).
Fanconi syndrome
Cases of Fanconi syndrome have been reported with a medicinal product containing dimethylfumarate in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome anddiscontinuation of dimethyl fumarate treatment are important to prevent the onset of renal impairmentand osteomalacia, as the syndrome is usually reversible. The most important signs are proteinuria,glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possiblyconcurrent with hypophosphatemia). Progression might involve symptoms such as polyuria,polydipsia and proximal muscle weakness. In rare cases hypophosphataemic osteomalacia withnon-localised bone pain, elevated alkaline phosphatase in serum and stress fractures may occur.
Importantly, Fanconi syndrome can occur without elevated creatinine levels or low glomerular filtrationrate. In case of unclear symptoms Fanconi syndrome should be considered and appropriateexaminations should be performed.
ExcipientsThis medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodiumfree’.
4.5 Interaction with other medicinal products and other forms of interaction
Anti-neoplastic, immunosuppressive or corticosteroid therapies
Dimethyl fumarate has not been studied in combination with anti-neoplastic or immunosuppressivetherapies and caution should, therefore, be used during concomitant administration. In multiple sclerosisclinical studies, the concomitant treatment of relapses with a short course of intravenous corticosteroidswas not associated with a clinically relevant increase of infection.
Vaccines
Concomitant administration of non-live vaccines according to national vaccination schedules may beconsidered during dimethyl fumarate therapy. In a clinical study involving a total of 71 patients with
RRMS, patients on dimethyl fumarate 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response (defined as≥2-fold increase from pre- to post-vaccination titre) to tetanus toxoid (recall antigen) and a conjugatedmeningococcal C polysaccharide vaccine (neoantigen), while the immune response to differentserotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independentantigen) varied in both treatment groups. A positive immune response defined as a ≥4-fold increase inantibody titre to the three vaccines, was achieved by fewer subjects in both treatment groups. Smallnumerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharidewere noted in favour of non-pegylated interferon.
No clinical data are available on the efficacy and safety of live attenuated vaccines in patients takingdimethyl fumarate. Live vaccines might carry an increased risk of clinical infection and should not begiven to patients treated with dimethyl fumarate unless, in exceptional cases, this potential risk isconsidered to be outweighed by the risk to the individual of not vaccinating.
Other fumaric acid derivatives
During treatment with dimethyl fumarate, simultaneous use of other fumaric acid derivatives (topical orsystemic) should be avoided.
In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemiccirculation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement ofthe cytochrome P450 (CYP) system. Potential interaction risks were not identified from in vitro CYP-inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethylfumarate and monomethyl fumarate ( the primary metabolite of dimethyl fumarate).
Effects of other substances on dimethyl fumarate
Commonly used medicinal products in patients with multiple sclerosis, intramuscular interferon beta-1aand glatiramer acetate, were clinically tested for potential interactions with dimethyl fumarate and didnot alter the pharmacokinetic profile of dimethyl fumarate.
Evidence from healthy volunteer studies suggests that dimethyl fumarate associated flushing is likely tobe prostaglandin mediated. In two healthy volunteer studies, the administration of 325 mg (orequivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to dimethyl fumarate, dosing over4 days and over 4 weeks, respectively, did not alter the pharmacokinetic profile of dimethyl fumarate.
Potential risks associated with acetylsalicylic acid therapy should be considered prior to co-administration with dimethyl fumarate in patients with RRMS. Long term (> 4 weeks) continuous useof acetylsalicylic acid has not been studied (see sections 4.4 and 4.8).
Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics,non-steroidal anti-inflammatory drugs or lithium) may increase the potential of renal adverse reactions(e.g. proteinuria see section 4.8) in patients taking dimethyl fumarate (see section 4.4 Blood/laboratorytests).
Consumption of moderate amounts of alcohol did not alter exposure to dimethyl fumarate and was notassociated with an increase in adverse reactions. Consumption of large amounts of strong alcoholicdrinks (more than 30% alcohol by volume) should be avoided within an hour of taking dimethylfumarate, as alcohol may lead to increased frequency of gastrointestinal adverse reactions.
Effects of dimethyl fumarate on other substances
In vitro CYP induction studies did not demonstrate an interaction between dimethyl fumarate and oralcontraceptives. In an in vivo study, co-administration of dimethyl fumarate with a combined oralcontraceptive (norgestimate and ethinyl oestradiol) did not elicit any relevant change in oralcontraceptive exposure.
No interaction studies have been performed with oral contraceptives containing other progestogens,however an effect of dimethyl fumarate on their exposure is not expected.
Paediatric populationInteraction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. Animalstudies have shown reproductive toxicity (see section 5.3). Dimethyl fumarate is not recommendedduring pregnancy and in women of childbearing potential not using appropriate contraception (seesection 4.5). Dimethyl fumarate should be used during pregnancy only if clearly needed and if thepotential benefit justifies the potential risk to the foetus.
Breast-feedingIt is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue dimethyl fumarate therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.
FertilityThere are no data on the effects of dimethyl fumarate on human fertility. Data from preclinical studiesdo not suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility(see section 5.3).
4.7 Effects on ability to drive and use machines
Dimethyl fumarate has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The most common adverse reactions are flushing (35%) and gastrointestinal events (i.e. diarrhoea(14%), nausea (12%), abdominal pain (10%), abdominal pain upper (10%)). Flushing andgastrointestinal events tend to begin early in the course of treatment (primarily during the first month)and in patients who experience flushing and gastrointestinal events, these events may continue to occurintermittently throughout treatment with dimethyl fumarate. The most commonly reported adversereactions leading to treatment discontinuation are flushing (3%) and gastrointestinal events (4%).
In phase 2 and 3 placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients havereceived dimethyl fumarate for periods of up to 12 years with an overall exposure equivalent to11,318 person-years. A total of 1,169 patients have received at least 5 years of treatment with dimethylfumarate, and 426 patients have received at least 10 years of treatment with dimethyl fumarate. Theexperience in uncontrolled clinical trials is consistent with the experience in the placebo-controlledclinical trials.
Tabulated list of adverse reactionsAdverse reactions arising from clinical studies, post-authorisation safety studies and spontaneousreports, are presented in the table below.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ
Class. The incidence of the adverse reactions below is expressed according to the following categories:
- Very common (≥1/10)
- Common (≥1/100 to <1/10)
- Uncommon (≥1/1, 000 to <1/100)
- Rare (≥1/10, 000 to <1/1,000)
- Very rare (<1/10,000)
- Not known (frequency cannot be estimated from the available data)
MedDRA system organ class Adverse reaction Frequency category
Infections and infestations Gastroenteritis Common
Progressive multifocal
Not knownleukoencephalopathy (PML)
Herpes zoster Not known
Blood and lymphatic system Lymphopenia Commondisorders Leucopenia Common
Thrombocytopenia Uncommon
Immune system disorders Hypersensitivity Uncommon
Anaphylaxis Not known
Dyspnoea Not known
Hypoxia Not known
Hypotension Not known
Angioedema Not known
Nervous system disorders Burning sensation Common
Vascular disorders Flushing Very common
Hot flush Common
Respiratory, thoracic and Rhinorrhoea Not knownmediastinal disorders
Gastrointestinal disorders Diarrhoea Very common
Nausea Very common
Abdominal pain upper Very common
Abdominal pain Very common
Vomiting Common
Dyspepsia Common
Gastritis Common
Gastrointestinal disorder Common
Hepatobiliary disorders Aspartate aminotransferase increased Common
Alanine aminotransferase increased Common
Drug-induced liver injury Rare
Skin and subcutaneous tissue Pruritus Commondisorders Rash Common
Erythema Common
Alopecia Common
Renal and urinary disorders Proteinuria Common
General disorders and
Feeling hot Commonadministration site conditions
Investigations Ketones measured in urine Very common
Albumin urine present Common
White blood cell count decreased Common
Description of selected adverse reactionsFlushing
In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush (7% versus2%) was increased in patients treated with dimethyl fumarate compared to placebo, respectively.
Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth,redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment(primarily during the first month) and in patients who experience flushing, these events may continue tooccur intermittently throughout treatment with dimethyl fumarate. In patients with flushing, themajority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated withdimethyl fumarate discontinued due to flushing. The incidence of serious flushing, which may becharacterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treatedwith dimethyl fumarate (see sections 4.2, pct. 4.4 and 4.5).
Gastrointestinal adverse reactionsThe incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%],upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%]and dyspepsia [5% versus 3%]) was increased in patients treated with dimethyl fumarate compared toplacebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarilyduring the first month) and in patients who experience gastrointestinal adverse reactions, these eventsmay continue to occur intermittently throughout treatment with dimethyl fumarate. In the majority ofpatients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent(4%) of patients treated with dimethyl fumarate discontinued due to gastrointestinal adversereactions. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, wasseen in 1% of patients treated with dimethyl fumarate (see section 4.2).
Hepatic function
Based on data from placebo-controlled studies, the majority of patients with elevations had hepatictransaminases that were <3 times the ULN. The increased incidence of elevations of hepatictransaminases in patients treated with dimethyl fumarate relative to placebo was primarily seen duringthe first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase≥3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2%of patients treated with dimethyl fumarate. Discontinuations due to elevated hepatic transaminaseswere <1% and similar in patients treated with dimethyl fumarate or placebo. Elevations intransaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN, were notobserved in placebo-controlled studies.
Increase of liver enzymes and cases of drug-induced liver injury (elevations in transaminases ≥3 times
ULN with concomitant elevations in total bilirubin >2 times ULN), have been reported in postmarketing experience following dimethyl fumarate administration, which resolved upon treatmentdiscontinuation.
Lymphopenia
In the placebo-controlled studies most patients (>98%) had normal lymphocyte counts prior toinitiating treatment. Upon treatment with dimethyl fumarate, mean lymphocyte counts decreased overthe first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately30% of baseline value. Mean and median lymphocyte counts remained within normal limits.
Lymphocyte counts <0.5x109/L were observed in <1% of patients treated with placebo and 6% ofpatients treated with dimethyl fumarate. A lymphocyte count <0.2x109/L was observed in 1 patienttreated with dimethyl fumarate and in no patients treated with placebo.
In clinical studies (both controlled and uncontrolled), 41% of patients treated with dimethyl fumaratehad lymphopenia (defined in these studies as <0.91x109/L). Mild lymphopenia (counts ≥0.8x109/Land <0.91 x109/L) was observed in 28% of patients; moderate lymphopenia (counts ≥0.5x109/L and<0.8x109/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia(counts <0.5x109/L) persisting for at least six months was observed in 2% of patients. In the groupwith severe lymphopenia, the majority of lymphocyte counts remained <0.5x109/L with continuedtherapy.
In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment withdimethyl fumarate (n=185) CD4+ T cells were moderately (counts ≥0.2x109/L to <0.4x109/L) orseverely (<0.2x109/L) decreased in up to 37% or 6% of patients, respectively, while CD8+ T cellswere more frequently reduced with up to 59% of patients at counts <0.2x109/L and 25 % of patients atcounts <0.1x109/L. In controlled and uncontrolled clinical studies, patients who discontinueddimethyl fumarate therapy with lymphocyte counts below the LLN were monitored for recovery oflymphocyte count to the LLN (see section 5.1).
Progressive multifocal leukoencephalopathy (PML)Cases of infections with John Cunningham virus (JCV) causing PML have been reported withdimethyl fumarate (see section 4.4). PML may be fatal or result in severe disability. In 1 of theclinical trials, one patient taking dimethyl fumarate developed PML in the setting of prolonged severelymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years), with a fatal outcome. Inthe post-marketing setting, PML has also occurred in the presence of moderate and mild lymphopenia(>0.5x109/L to <LLN, as defined by local laboratory reference range).
In several PML cases with determination of T cell subsets at the time of diagnosis of PML, CD8+ Tcell counts were found to be decreased to <0.1x109/L, whereas reductions in CD4+ T cells countswere variable (ranging from <0.05 to 0.5x109/L) and correlated more with the overall severity oflymphopenia (<0.5 x109/L to <LLN). Consequently, the CD4+/CD8+ ratio was increased in thesepatients.
Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethylfumarate, however, PML also occurred in patients with mild lymphopenia. Additionally, the majorityof PML cases in the post-marketing setting have occurred in patients >50 years.
Herpes zoster infections
Herpes zoster infections have been reported with dimethyl fumarate. In the long-term extension study,in which 1,736 MS patients were treated , approximately 5% experienced one or more events ofherpes zoster of which 42% were mild 55% were moderate and 3% were severe. The time to onsetfrom first dimethyl fumarate dose ranged from approximately 3 months to 10 years. Four patientsexperienced serious events, all of which resolved. Most subjects, including those who experienced aserious herpes zoster infection, had lymphocyte counts above the lower limit of normal. In a majorityof subjects with concurrent lymphocyte counts below the LLN, lymphopenia was rated moderate orsevere. In the post-marketing setting most cases of herpes zoster infection were non-serious andresolved with treatment. Limited data are available on absolute lymphocyte count (ALC) in patientswith herpes zoster infection in the post-marketing setting. However, when reported, most patientsexperienced moderate (≥0.5x109/L to 0.8x109/L) or severe (<0.5x109/L to 0.2x109/L) lymphopenia(see section 4.4).
Laboratory abnormalitiesIn the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher inpatients treated with dimethyl fumarate (45%) compared to placebo (10%). No untoward clinicalconsequences were observed in clinical trials.
Levels of 1,25-dihydroxyvitamin D decreased in dimethyl fumarate treated patients relative toplacebo (median percentage decrease from baseline at 2 years of 25% versus 15%, respectively) andlevels of parathyroid hormone (PTH) increased in dimethyl fumarate treated patients relative toplacebo (median percentage increase from baseline at 2 years of 29% versus 15%, respectively).
Mean values for both parameters remained within normal range.
A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
Paediatric populationIn a 96 week open label, randomised active controlled trial paediatric patients with RRMS (n=7aged 10 to less than 13 years and n=71 aged 13 to less than 18 years) were treated with 120 mg twice aday for 7 days followed by 240 mg twice a day for the remainder of treatment; The safety profile inpaediatric patients appeared similar to that previously observed in adult patients.
The paediatric clinical trial design differed from the adult placebo-controlled clinical trials. Therefore, acontribution of clinical trial design to numerical differences in adverse events between the paediatricand adult populations, cannot be excluded. Gastrointestinal disorders as well as respiratory, thoracicand mediastinal disorders and the adverse events of headache and dysmenorrhea were more frequentlyreported (≥10%) in the paediatric population than in the adult population. These adverse events werereported in the following percentages in paediatric patients:
These adverse events were reported in the following percentages in paediatric patients:
* Headache was reported in 28% of patients treated with dimethyl fumarate versus 36% inpatients treated with interferon beta-1a.
* Gastrointestinal disorders were reported in 74% of patients treated with dimethyl fumarateversus 31% in patients treated with interferon beta-1a. Among them, abdominal pain andvomiting were the most frequently reported with dimethyl fumarate.
* Respiratory, thoracic and mediastinal disorders were reported in 32% of patients treated withdimethyl fumarate versus 11% in patients treated with interferon beta-1a. Among them,oropharyngeal pain and cough were the most frequently reported with dimethyl fumarate.
* Dysmenorrhea was reported in 17% of patients treated with dimethyl fumarate versus 7% ofpatients treated with interferon beta-1a.
In a small 24 week open-label uncontrolled study in paediatric patients with RRMS aged 13 to 17 years(120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment;, n=22),followed by a 96 week extension study (240 mg twice per day; n=20), the safety profile appeared similarto that observed in adult patients.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Cases of overdose with dimethyl fumarate have been reported. The symptoms described in these caseswere consistent with the known safety profile of dimethyl fumarate. There are no known therapeuticinterventions to enhance elimination of dimethyl fumarate nor is there a known antidote. In the eventof overdose, it is recommended that symptomatic supportive treatment be initiated as clinicallyindicated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX07
Mechanism of actionThe mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fullyunderstood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear tobe primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)transcriptional pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidantgenes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).
Pharmacodynamic effectsEffects on the immune system
In preclinical and clinical studies, dimethyl fumarate demonstrated anti-inflammatory andimmunomodulatory properties. Dimethyl fumarate and monomethyl fumarate, the primary metaboliteof dimethyl fumarate, significantly reduced immune cell activation and subsequent release ofpro-inflammatory cytokines in response to inflammatory stimuli in preclinical models. In clinicalstudies with psoriasis patients, dimethyl fumarate affected lymphocyte phenotypes through a down-regulation of pro-inflammatory cytokine profiles (TH1, TH17), and biased towards anti-inflammatoryproduction (TH2). Dimethyl fumarate demonstrated therapeutic activity in multiple models ofinflammatory and neuroinflammatory injury. In phase 3 studies in MS patients (DEFINE, CONFIRMand ENDORSE), upon treatment with dimethyl fumarate mean lymphocyte counts decreased onaverage by approximately 30% of their baseline value over the first year with a subsequent plateau. Inthese studies, patients who discontinued treatment with lymphocyte counts below the lower limit ofnormal (LLN, 0.9 × 109/L ) were monitored for recovery of lymphocyte counts to the LLN.
Figure 1 shows the proportion of patients estimated to reach the LLN based on the Kaplan-Meiermethod without prolonged severe lymphopenia. The recovery baseline (RBL) was defined as the laston-treatment ALC prior to treatment discontinuation. The estimated proportion of patients recoveringto LLN (ALC ≥ 0.9 x 109/L) at Week 12 and Week 24, who had mild, moderate, or severelymphopenia at RBL are presented in Table 1, Table 2, and Table 3 with 95% pointwise confidenceintervals. The standard error of the Kaplan-Meier estimator of the survival function is computed using
Greenwood’s formula.
Figure 1: Kaplan-Meier method; proportion of patients with recovery to ≥ 910 cells/mm3 (0.9 ×109/L) LLN from the recovery baseline (RBL)
Note: 500 cells/mm3, 800 cells/mm3, 910 cells/mm3 correspond to 0.5 × 109/L, 0.8 × 109/L and0.9 × 109/L respectively.
Table 1: Kaplan-Meier method; proportion of patients estimated to reach LLN, mildlymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia
Number of patients with mild Baseline Week 12 Week 24lymphopeniaa at risk N=86 N=12 N=4
Proportion reaching 0.81 0.90
LLN (95% CI) (0.71, 0.89) (0.81, 0.96)a Patients with ALC < 0.9 × 109/L and ≥ 0.8 × 109/L at RBL, excluding patients with prolonged severelymphopenia.
Table 2: Kaplan-Meier method; proportion of patients estimated to reach LLN, moderatelymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia
Number of patients with moderate Baseline Week 12 Week 24lymphopeniaa at risk N=124 N=33 N=17
Proportion reaching 0.57 0.70
LLN (95% CI) (0.46, 0.67) (0.60, 0.80)a Patients with ALC < 0.8 × 109/L and ≥ 0.5 × 109/L at RBL, excluding patients with prolonged severelymphopenia.
Table 3: Kaplan-Meier method; proportion of patients estimated to reach LLN, severelymphopenia at the recovery baseline (RBL), excluding patients with prolonged severelymphopenia
Number of patients with severe Baseline Week 12 Week 24lymphopeniaa at risk N=18 N=6 N=4
Proportion reaching 0.43 0.62
LLN (95% CI) (0.20, 0.75) (0.35, 0.88)a Patients with ALC < 0.5 × 109/L at RBL, excluding patients with prolonged severe lymphopenia.
Clinical efficacy and safetyTwo, 2 year, randomised, double-blind, placebo-controlled studies (DEFINE with 1,234 patients and
CONFIRM with 1,417 patients) of patients with RRMS were performed. Patients with progressiveforms of MS were not included in these studies.
Efficacy (see Table 4) and safety were demonstrated in patients with expanded disability status scale(EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 1 relapse during the yearprior to randomisation, or, in the 6 weeks before randomisation had a brain MRI demonstrating at leastone gadolinium-enhancing (Gd+) lesion. Study CONFIRM contained a rater-blinded (i.e. studyphysician/ investigator assessing the response to study treatment was blinded) reference comparator ofglatiramer acetate.
In DEFINE, patients had the following median baseline characteristics: age 39 years, disease duration7.0 years, EDSS score 2.0. In addition, 16% of patients had an EDSS score >3.5, 28% had ≥ 2 relapsesin the prior year and 42% had previously received other approved MS treatments. In the MRI cohort36% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4).
In CONFIRM, patients had the following median baseline characteristics: age 37 years, diseaseduration 6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score >3.5, 32% had≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the
MRI cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of
Gd+ lesions 2.4).
Compared to placebo, patients treated with dimethyl fumarate had a clinically meaningful andstatistically significant reduction on the primary endpoint in study DEFINE, proportion of patientsrelapsed at 2 years; and the primary endpoint in study CONFIRM, annualised relapse rate (ARR) at2 years.
Table 4: Clinical and MRI endpoints for studies DEFINE and CONFIRM
DEFINE CONFIRM
Placebo Dimethyl Placebo Dimethyl Glatiramerfumarate fumarate acetate240 mg 240 mg
Clinical Endpointsatwice a day twice a day
No. patients 408 410 363 359 350
Annualised relapse rate 0.364 0.172*** 0.401 0.224*** 0.286*
Rate ratio 0.47 0.56 0.71(95% CI) (0.37, 0.61) (0.42, 0.74) (0.55, 0.93)
Proportion relapsed 0.461 0.270*** 0.410 0.291** 0.321**
Hazard ratio 0.51 0.66 0.71
DEFINE CONFIRM
Placebo Dimethyl Placebo Dimethyl Glatiramerfumarate fumarate acetate240 mg 240 mg(95% CI) t(w0.i4c0e, a0 .d6a6y) (tw0.i5c1e, a0 .d8a6y) (0.55, 0.92)
Proportion with 12-week 0.271 0.164** 0.169 0.128#0.156#confirmed disabilityprogression
Hazard ratio 0.62 0.79 0.93(95% CI) (0.44, 0.87) (0.52, 1.19) (0.63, 1.37)
Proportion with 24 week 0.169 0.128# 0.125 0.078# 0.108#confirmed disabilityprogression
Hazard ratio 0.77 0.62 0.87(95% CI) (0.52, 1.14) (0.37, 1.03) (0.55, 1.38)
MRI endpointsb
No. patients 165 152 144 147 161
Mean (median) number of 16.5 3.2 19.9 5.7 9.6new or newly enlarging (7.0) (1.0)*** (11.0) (2.0)*** (3.0)***
T2 lesions over 2 years
Lesion mean ratio 0.15 0.29 0.46(95% CI) (0.10, 0.23) (0.21, 0.41) (0.33, 0.63)
Mean (median) number of 1.8 0.1 2.0 0.5 0.7
Gd lesions at 2 years (0) (0)*** (0.0) (0.0)*** (0.0)**
Odds ratio 0.10 0.26 0.39(95% CI) (0.05, 0.22) (0.15, 0.46) (0.24, 0.65)
Mean (median) number of 5.7 2.0 8.1 3.8 4.5new T1 hypointense (2.0) (1.0)*** (4.0) (1.0)*** (2.0)**lesions over 2 years
Lesion mean ratio 0.28 0.43 0.59(95% CI) (0.20, 0.39) (0.30, 0.61) (0.42, 0.82)aAll analyses of clinical endpoints were intent-to-treat; bMRI analysis used MRI cohort
*P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant
An open non-controlled 8 year extension study (ENDORSE) enrolled 1,736 eligible RRMS patientsfrom the pivotal studies (DEFINE and CONFIRM). The primary objective of the study was to assessthe long-term safety of dimethyl fumarate in patients with RRMS. Of the 1,736 patients,approximately half (909, 52%) were treated for 6 years or longer. 501 patients were continuouslytreated with dimethyl fumarate 240 mg twice daily across all 3 studies and 249 patients who werepreviously treated with placebo in studies DEFINE and CONFIRM received treatment 240 mg twicedaily in study ENDORSE. Patients who received treatment twice daily continuously were treated forup to 12 years.
During study ENDORSE, more than half of all patients treated with dimethyl fumarate 240 mg twicedaily did not have a relapse. For patients continuously treated twice daily across all 3 studies, theadjusted ARR was 0.187 (95% CI: 0.156, 0.224) in studies DEFINE and CONFIRM and 0.141 (95%
CI: 0.119, 0.167) in study ENDORSE. For patients previously treated with placebo, the adjusted ARRdecreased from 0.330 (95% CI: 0.266, 0.408) in studies DEFINE and CONFIRM to 0.149 (95% CI:
0.116, 0.190) in study ENDORSE.
In study ENDORSE, the majority of patients (> 75%) did not have confirmed disability progression(measured as 6 month sustained disability progression). Pooled results from the three studiesdemonstrated dimethyl fumarate treated patients had consistent and low rates of confirmed disabilityprogression with slight increase in mean EDSS scores across ENDORSE. MRI assessments (up toyear 6, including 752 patients who had previously been included in the MRI cohort of studies DEFINEand CONFIRM showed that the majority of patients (approximately 90%) had no Gd-enhancinglesions. Over the 6 years, the annual adjusted mean number of new or newly enlarging T2 and new T1lesions remained low.
Efficacy in patients with high disease activity:
In studies DEFINE and CONFIRM, consistent treatment effect on relapses in a subgroup of patientswith high disease activity was observed, whilst the effect on time to 3-month sustained disabilityprogression was not clearly established. Due to the design of the studies, high disease activity wasdefined as follows:
- Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions onbrain MRI (n=42 in DEFINE; n=51 in CONFIRM) or,
- Patients who have failed to respond to a full and adequate course (at least one year of treatment)of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and atleast 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patientshaving an unchanged or increased relapse rate in the prior year as compared to the previous2 years (n=177 in DEFINE; n=141 in CONFIRM).
Paediatric populationThe safety and efficacy of Dimethyl fumarate in paediatric RRMS was evaluated in a randomised,open-label, active-controlled (interferon beta-1a) parallel group study in patients with RRMS aged10 to less than 18 years of age. One hundred and fifty patients were randomised to dimethyl fumarate(240 mg twice daily oral) or interferon beta-1a (30 μg IM once a week) for 96 weeks. The primaryendpoint was the proportion of patients free of new or newly enlarging T2 hyperintense lesions onbrain MRI scans at week 96. The main secondary endpoint was the number of new or newly enlarging
T2 hyperintense lesions on brain MRI scans at week 96. Descriptive statistics are presented as noconfirmatory hypothesis was pre-planned for the primary endpoint.
The proportion of patients in the ITT population with no new or newly enlarging T2 MRI lesions atweek 96 relative to baseline was 12.8% for dimethyl fumarate versus 2.8% in the interferon beta-1agroup. The mean number of new or newly enlarging T2 lesions at week 96 relative to baseline,adjusted for baseline number of T2 lesions and age (ITT population excluding patients without MRImeasurements) was 12.4 for dimethyl fumarate and 32.6 for interferon beta-1a.
The probability for clinical relapse was 34% in the dimethyl fumarate group and 48% in the interferonbeta-1a group by the end of the 96 week open-label study period.
The safety profile in paediatric patients (aged 13 to less than 18 years of age) receiving dimethylfumarate was qualitatively consistent with that previously observed in adult patients (see section 4.8).
5.2 Pharmacokinetic properties
Orally administered dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and isconverted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate isnot quantifiable in plasma following oral administration of dimethyl fumarate. Therefore, allpharmacokinetic analyses related to dimethyl fumarate were performed with plasma monomethylfumarate concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis andhealthy volunteers.
AbsorptionThe Tmax of monomethyl fumarate is 2 to 2.5 hours. As dimethyl fumarate gastro-resistant hardcapsules contain mini tablets, which are protected by an enteric coating, absorption does notcommence until they leave the stomach (generally less than 1 hour). Following 240 mg twice a dayadministered with food, the median peak (Cmax) was 1.72 mg/l and overall area under the curve (AUC)exposure was 8.02 h.mg/l in subjects with multiple sclerosis. Overall, Cmax and AUC increasedapproximately dose-proportionally in the dose range studied (120 mg to 360 mg). In subjects withmultiple sclerosis, two 240 mg doses were administered 4 hours apart as part of a three times a daydosing regimen. This resulted in a minimal accumulation of exposure yielding an increase in themedian Cmax of 12% compared to the twice daily dosing (1.72 mg/l for twice daily compared to1.93 mg/l for three times daily) with no safety implications.
Food does not have a clinically significant effect on exposure of dimethyl fumarate. However,dimethyl fumarate should be taken with food due to improved tolerability with respect to flushing orgastrointestinal adverse events (see section 4.2).
DistributionThe apparent volume of distribution following oral administration of 240 mg dimethyl fumarate variesbetween 60 L and 90 L. Human plasma protein binding of monomethyl fumarate generally rangesbetween 27% and 40%.
BiotransformationIn humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted asunchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous inthe gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Furthermetabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450(CYP) system. A single 240 mg 14C-dimethyl fumarate dose study identified glucose as thepredominant metabolite in human plasma. Other circulating metabolites included fumaric acid, citricacid and monomethyl fumarate. The downstream metabolism of fumaric acid occurs through thetricarboxylic acid cycle, with exhalation of CO2 serving as the primary route of elimination.
EliminationExhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of thedose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and0.9% of the dose respectively.
The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulatingmonomethyl fumarate is present at 24 hours in the majority of individuals. Accumulation of dimethylfumarate or monomethyl fumarate does not occur with multiple doses of dimethyl fumarate at thetherapeutic regimen.
LinearityDimethyl fumarate exposure increases in an approximately dose proportional manner with single andmultiple doses in the 120 mg to 360 mg dose range studied.
Pharmacokinetics in special patient groupsBased on the results of Analysis of Variance (ANOVA), body weight is the main covariate of exposure(by Cmax and AUC) in RRMS subjects, but did not affect safety and efficacy measures evaluated in theclinical studies.
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethylfumarate. The pharmacokinetics in patients aged 65 and over has not been studied.
Renal impairmentSince the renal pathway is a secondary route of elimination for dimethyl fumarate accounting for lessthan 16% of the dose administered, evaluation of pharmacokinetics in individuals with renalimpairment was not conducted.
Hepatic impairmentAs dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without theinvolvement of the CYP450 system, evaluation of pharmacokinetics in individuals with hepaticimpairment was not conducted.
Paediatric populationThe pharmacokinetic profile of 240 mg dimethyl fumarate twice a day was evaluated in a small,open-label, uncontrolled study in patients with RRMS aged 13 to 17 years (n=21). Thepharmacokinetics of dimethyl fumarate in these adolescent patients was consistent with that previouslyobserved in adult patients (Cmax: 2.00±1.29 mg/l; AUC0-12hr: 3.62±1.16 h.mg/l, which corresponds to anoverall daily AUC of 7.24 h.mg/l).
5.3 Preclinical safety data
The adverse reactions described in the Toxicology and Reproduction toxicity sections below were notobserved in clinical studies, but were seen in animals at exposure levels similar to clinical exposurelevels.
GenotoxicityDimethyl fumarate and mono-methylfumarate were negative in a battery of in vitro assays (Ames,chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivomicronucleus assay in rats.
CarcinogenesisCarcinogenicity 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 in mice, and atdoses of 25, 50, 100, and 150 mg/kg/day in rats.
In mice, the incidence of renal tubular carcinoma was increased at 75 mg/kg/day, at equivalentexposure (AUC) to the recommended human dose. In rats, the incidence of renal tubular carcinomaand testicular Leydig cell adenoma was increased at 100 mg/kg/day, approximately 2 times higherexposure than the recommended human dose. The relevance of these findings to human risk isunknown.
The incidence of squamous cell papilloma and carcinoma in the nonglandular stomach (forestomach)was increased at equivalent exposure to the recommended human dose in mice and below exposure tothe recommended human dose in rats (based on AUC). The forestomach in rodents does not have ahuman counterpart.
ToxicologyNonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumaratesuspension (dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage.
The chronic toxicity study in dogs was conducted with oral administration of the dimethyl fumaratecapsule.
Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats,dogs, and monkeys. Renal tubular epithelial regeneration, suggestive of injury, was observed in allspecies. Renal tubular hyperplasia was observed in rats with life time dosing (2 year study). In dogsthat received daily oral doses of dimethyl fumarate for 11 months, the margin calculated for corticalatrophy was observed at 3 times the recommended dose based on AUC. In monkeys that received dailyoral doses of dimethyl fumarate for 12 months, single cell necrosis was observed at 2 times therecommended dose based on AUC. Interstitial fibrosis and cortical atrophy were observed at 6 timesthe recommended dose based on AUC. The relevance of these findings to humans is not known.
In the testes, degeneration of the seminiferous epithelium was seen in rats and dogs. The findings wereobserved at approximately the recommended dose in rats and 3 times the recommended dose in dogs(AUC basis). The relevance of these findings to humans is not known.
Findings in the forestomach of mice and rats consisted of squamous epithelial hyperplasia andhyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months orlonger in duration. The forestomach of mice and rats does not have a human counterpart.
Toxicity to reproduction and development
Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to andduring mating had no effects on male fertility up to the highest dose tested (at least 2 times therecommended dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at 25,100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, inducedreduction in the number of oestrous stages per 14 days and increased the number of animals withprolonged dioestrus at the highest dose tested (11 times the recommended dose on an AUC basis).
However, these changes did not affect fertility or the number of viable foetuses produced.
Dimethyl fumarate has been shown to cross the placental membrane into foetal blood in rats andrabbits, with ratios of foetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. Nomalformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration ofdimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period oforganogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis,and low foetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times therecommended dose on an AUC basis. The lower foetal weight and delayed ossification wereconsidered secondary to maternal toxicity (reduced body weight and food consumption).
Oral administration of dimethyl fumarate at 25, 75, and 150 mg/kg/day to pregnant rabbits duringorganogenesis had no effect on embryo-foetal development and resulted in reduced maternal bodyweight at 7 times the recommended dose and increased abortion at 16 times the recommended dose, onan AUC basis.
Oral administration of dimethyl fumarate at 25, 100, and 250 mg/kg/day to rats during pregnancy andlactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1males at 11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1offspring. The lower offspring body weight was considered secondary to maternal toxicity.
Toxicity in juvenile animals
Two toxicity studies in juvenile rats with daily oral administration of dimethyl fumarate from postnatalday (PND) 28 through PND 90 to 93 (equivalent to approximately 3 years and older in humans)revealed similar target organ toxicities in the kidney and forestomach as observed in adult animals. Inthe firsts tudy, dimethyl fumarate did not affect development, neurobehavior or male and femalefertility up to the highest dose of 140 mg/kg/day (approximately 4.6 times the recommended humandose based on limited AUC data in paediatric patients). Likewise, no effects on male reproductive andaccessory organs were observed up to the highest dimethyl fumarate dose of 375 mg/kg/day in thesecond study in male juvenile rats (about 15 times the putative AUC at the recommended paediatricdose). However, decreased bone mineral content and density in the femur and lumbar vertebrae wereevident in male juvenile rats. Bone densitometry changes were also observed in juvenile rats followingoral diroximel fumarate administration, another fumaric ester that is metabolised to the same activemetabolite monomethyl fumarate in vivo. The NOAEL for the densitometry changes in juvenile rats isapproximately 1.5 times the presumptive AUC at the recommended paediatric dose. A relation of thebone effects to lower body weight is possible, but the involvement of a direct effect cannot beexcluded. The bone findings are of limited relevance for adult patients. The relevance for paediatricpatients is not known.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule contents (enteric-coated mini tablets)
Silicified microcrystalline cellulose
Talc
Croscarmellose sodium
Silica, colloidal anhydrous
Magnesium stearate
Methacrylic acid-methyl methacrylate copolymer (1:1)
Triethyl citrate
Methacrylic acid - ethyl acrylate copolymer (1:1) dispersion 30%
Capsule shellGelatin
Titanium dioxide (E171)
Brilliant blue FCF (E133)
Iron oxide black (E172)
Iron oxide yellow (E172)
Capsule print (black ink)
Shellac (E904)
Iron oxide black (E172)
Potassium hydroxide (E525)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
120 mg capsules:
14 capsules in PVC/PE/PVDC-Alu blister packs.
14x1 capsules in PVC/PE/PVDC-Alu perforated unit dose blister packs.
240 mg capsules:
56 or 168 capsules in PVC/PE/PVDC-Alu blister packs.
56x1 or 168x1 capsules in PVC/PE/PVDC-Alu perforated unit dose blister packs.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.