Fumarox
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUMAROX (FUMAROX)
Composition:
Active substance: dimethyl fumarate;
One modified-release capsule contains 120 mg or 240 mg of dimethyl fumarate;
Excipients:
Mini-tablet core: silicified microcrystalline cellulose, sodium croscarmellose, talc, colloidal anhydrous silicon dioxide, magnesium stearate;
Primary coating: isopropyl alcohol, purified water, "Opadry enteric white 940580021" [methacrylate copolymer (type A), triethyl citrate, titanium dioxide (E 171), talc], polysorbates;
Secondary coating: purified water, "Acryl ESE II white 493Z180022" [methacrylate copolymer (type C), talc, titanium dioxide (E 171), poloxamer, calcium silicate, sodium bicarbonate, sodium lauryl sulfate], trimethyl citrate;
Hard gelatin capsule shell: for 120 mg (size "0") — gelatin, yellow iron oxide (E 172), titanium dioxide (E 171), indigo carmine FCF (E 133), black iron oxide (E 172), black ink (SW-9008); for 240 mg (size "0el") — gelatin, titanium dioxide (E 171), black ink (SW-9008);
One capsule contains 2 mini-tablets of 60 mg (120 mg dose) or 4 mini-tablets of 60 mg (240 mg dose).
Pharmaceutical form. Modified-release capsules.
Main physicochemical characteristics:
120 mg capsules: opaque blue hard gelatin capsules (size "0") with "H" printed on the cap and "D12" on the body, filled with white or almost white tablets;
240 mg capsules: opaque white hard gelatin capsules (size "0el") with "H" printed on the cap and "D15" on the body, filled with white or almost white tablets.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents.
ATC code L04AX07.
Pharmacological Properties.
Mechanism of action
The mechanism of therapeutic action of dimethyl fumarate in multiple sclerosis has not been fully elucidated. Preclinical studies have shown that the pharmacodynamic effects of dimethyl fumarate are primarily mediated through activation of nuclear factor (erythroid-derived 2) (Nrf2) transcription. Dimethyl fumarate has been shown to activate Nrf2-dependent antioxidant genes in patients (e.g., NAD(P)H dehydrogenase, quinone 1 [NQO1]).
Pharmacodynamics.
Effects on the immune system
In preclinical and clinical studies, dimethyl fumarate has demonstrated anti-inflammatory and immunomodulatory effects. Dimethyl fumarate and its primary metabolite, monomethyl fumarate, have been shown to significantly reduce immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli. In clinical studies in patients with psoriasis, dimethyl fumarate affected lymphocyte phenotype by suppressing pro-inflammatory cytokine profiles (TH1, TH17) and shifting towards anti-inflammatory production (TH2). Dimethyl fumarate has demonstrated therapeutic activity in several models of inflammatory and neuroinflammatory conditions. In Phase III studies in patients with multiple sclerosis, treatment with dimethyl fumarate resulted in a mean reduction in lymphocyte count of approximately 30% from baseline during the first year, followed by stabilization. In these studies, patients who discontinued dimethyl fumarate therapy with lymphocyte counts below the lower limit of normal (LLN) of 910 cells/mm³ showed recovery of lymphocyte counts to LLN.
Pharmacokinetics.
Following oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted into its primary metabolite, monomethyl fumarate, which is also pharmacologically active. Since dimethyl fumarate is not detectable in plasma after oral administration, all pharmacokinetic parameters are determined for its active metabolite, monomethyl fumarate.
The pharmacokinetics of dimethyl fumarate have been studied in patients with multiple sclerosis and in healthy volunteers.
Absorption
The time to reach maximum concentration (Tmax) of monomethyl fumarate is 2–2.5 hours. Since the enteric-coated hard capsules contain mini-tablets protected by an enteric coating, absorption occurs only after gastric emptying (typically within less than 1 hour). After administration of 240 mg twice daily with food, the mean peak concentration (Cmax) in patients with multiple sclerosis was 1.72 mg/L, and the total area under the curve (AUC) was 8.02 h × mg/L. Overall, Cmax and AUC increased approximately dose-proportionally within the studied dose range (120 to 360 mg). Administration of two 240 mg doses separated by 4 hours as part of a three-times-daily regimen in patients with multiple sclerosis was associated with minimal accumulation of monomethyl fumarate in blood and did not affect the safety profile of the drug (median Cmax increased by 12% compared to twice-daily dosing: 1.72 mg/L and 1.93 mg/L for twice- and three-times-daily dosing, respectively).
Administration of the drug with food does not affect the plasma concentration of dimethyl fumarate. Dimethyl fumarate should be taken with food to improve tolerability of adverse reactions (flushing or gastrointestinal adverse reactions) (see section "Dosage and administration").
Distribution
The apparent volume of distribution after oral administration of 240 mg dimethyl fumarate ranges from 60 to 90 L. The binding of monomethyl fumarate to human plasma proteins is typically between 27% and 40%.
Biotransformation
In humans, dimethyl fumarate is extensively metabolized, with less than 0.1% of the dose excreted unchanged in urine. It is initially metabolized by esterases in the gastrointestinal tract, blood, and tissues before reaching systemic circulation. Further metabolism occurs via the tricarboxylic acid (TCA) cycle without involvement of the cytochrome P450 (CYP) system. In one study using a 240 mg dose of 14C-dimethyl fumarate, glucose was identified as the primary metabolite in human plasma. Other circulating metabolites include fumaric acid, citric acid, and monomethyl fumarate. Further metabolism of fumaric acid proceeds via the TCA cycle, with CO2 release as the primary elimination pathway.
Excretion
Exhalation of CO2 is the primary route of elimination of dimethyl fumarate, accounting for 60% of the dose. Renal and fecal excretion are secondary elimination pathways, accounting for 15.5% and 0.9% of the dose, respectively.
The elimination half-life (T½) of monomethyl fumarate is short (approximately 1 hour), and monomethyl fumarate is not detectable in blood in most patients after 24 hours. No accumulation of unchanged dimethyl fumarate or monomethyl fumarate occurs with repeated administration of dimethyl fumarate under therapeutic dosing regimens.
Linearity
The concentration of dimethyl fumarate increases approximately dose-proportionally over the range of 120 to 360 mg, both after single and multiple doses.
Pharmacokinetics in special patient populations
According to results from an analysis of variance (ANOVA), body weight is a key covariate influencing exposure (Cmax and AUC) in patients with relapsing-remitting multiple sclerosis, but it does not affect safety and efficacy outcomes as assessed in clinical trials.
Age and sex of the patient do not have a clinically significant effect on the pharmacokinetics of dimethyl fumarate. Pharmacokinetics in patients aged 65 years and older has not been studied.
Children
The pharmacokinetic profile of dimethyl fumarate at a dose of 240 mg twice daily was evaluated in a small, open-label, uncontrolled study in patients with relapsing-remitting multiple sclerosis aged 13 to 17 years (n = 21). The pharmacokinetics of dimethyl fumarate in adolescent patients were similar to those in adults (Cmax 2.00 ± 1.29 mg/L; AUC0–12h 3.62 ± 1.16 h × mg/L, corresponding to total daily AUC of 7.24 h × mg/L).
Renal impairment
Since renal excretion is a secondary elimination pathway for dimethyl fumarate and accounts for less than 16% of the administered dose, pharmacokinetic evaluation in patients with renal impairment has not been performed.
Hepatic impairment
Since dimethyl fumarate and monomethyl fumarate are metabolized by esterases without involvement of the CYP450 system, pharmacokinetic evaluation in individuals with hepatic impairment has not been performed.
Clinical characteristics.
Indications.
Fumarox is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS).
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Suspected or confirmed progressive multifocal leukoencephalopathy (PML).
Interaction with other medicinal products and other types of interactions.
Studies on the use of dimethyl fumarate in combination with antineoplastic or immunosuppressive agents have not been conducted; therefore, caution should be exercised when co-administering these drugs. Concomitant short-term intravenous administration of corticosteroids for the prevention of multiple sclerosis relapses during clinical trials of dimethyl fumarate was not associated with a clinically significant increase in the frequency of infections.
Administration of inactivated vaccines according to national vaccination schedules may be considered during dimethyl fumarate therapy. In a clinical study (involving a total of 71 patients with relapsing-remitting multiple sclerosis), comparable immune responses (defined as ≥2-fold increase from pre-vaccination titer) to tetanus toxoid (a T-cell-dependent antigen) and to conjugated meningococcal group C polysaccharide vaccine (a neoantigen) were observed in patients receiving 240 mg dimethyl fumarate twice daily for at least 6 months (n = 38) or non-pegylated interferon for at least 3 months (n = 33). However, immune responses to various serotypes of the unconjugated 23-valent pneumococcal polysaccharide vaccine (a T-cell-independent antigen) varied between the two treatment groups. A positive immune response, defined as a 4-fold increase in antibody titer to three vaccines, was achieved in fewer patients in both treatment groups. Small quantitative differences in response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were observed in favor of non-pegylated interferon.
There are no clinical data on the safety and efficacy of administering live attenuated vaccines to patients taking this medicinal product. Live vaccines may increase the risk of infectious diseases and therefore should not be administered to patients receiving Fumarox, except in cases where the potential benefit of vaccination outweighs the associated risk.
During treatment with this drug, concomitant use of other fumaric acid derivatives (for topical or systemic use) should be avoided.
In humans, dimethyl fumarate is extensively metabolized by esterases before reaching systemic circulation; further metabolism occurs via the tricarboxylic acid cycle without involvement of the cytochrome P450 (CYP) enzyme system. In vitro studies showed no potential risk of inhibition or induction of cytochrome P450 enzymes, nor any significant interaction with P-glycoprotein, and studies on binding of dimethyl fumarate and monomethyl fumarate to plasma proteins were unremarkable.
Clinical studies have shown that medicinal products commonly used in the treatment of multiple sclerosis (intramuscular interferon beta-1a and glatiramer acetate) do not interact with dimethyl fumarate and do not alter its pharmacokinetic profile.
Data from studies in healthy volunteers suggest that flushing associated with dimethyl fumarate is likely mediated by prostaglandins. Administration of 325 mg acetylsalicylic acid (or equivalent) in non-enteric-coated formulation 30 minutes before dimethyl fumarate for more than 4 days and more than 4 weeks did not alter the pharmacokinetic profile of dimethyl fumarate. Potential risks associated with acetylsalicylic acid therapy should be considered before concomitant use with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis. Long-term (>4 weeks) continuous use of acetylsalicylic acid has not been studied (see sections "Special precautions for use", "Adverse reactions").
Concomitant therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, or lithium) may increase the risk of renal and urinary system adverse reactions (e.g., proteinuria, see section "Adverse reactions") in patients taking dimethyl fumarate (see subsection "Blood/laboratory tests" in section "Special precautions for use").
Moderate alcohol consumption did not affect the therapeutic effect of dimethyl fumarate and was not associated with an increased incidence of adverse reactions. However, consumption of large amounts of strong alcoholic beverages (more than 30% alcohol by volume) should be avoided within one hour after administration of Fumarox, as alcohol may increase the frequency of gastrointestinal adverse reactions.
In vitro studies on possible induction of cytochrome P450 enzymes showed no interaction between dimethyl fumarate and oral contraceptives. An in vivo study showed that concomitant administration of dimethyl fumarate with combined oral contraceptives (norgestimate and ethinylestradiol) did not result in any clinically significant changes in exposure. No interaction studies have been conducted with oral contraceptives containing other progestogens; no effect of dimethyl fumarate on their efficacy is expected.
Children
Interaction studies have been conducted only in adults.
Special precautions for use.
Blood/laboratory tests
Changes in certain kidney function parameters were observed in clinical trials in patients receiving dimethyl fumarate. The clinical significance of these changes is unknown. Assessment of kidney function (serum creatinine, blood urea nitrogen, and urinalysis) is recommended before starting treatment, at 3 and 6 months of treatment, and every 6–12 months thereafter, as clinically indicated.
Dimethyl fumarate may cause drug-induced liver injury, including elevations in liver enzymes (≥ 3 ULN [upper limit of normal]) and increased total bilirubin levels (≥ 2 ULN). Liver function abnormalities may occur immediately after initiation of the drug, several weeks after starting therapy, or later. Adverse reactions resolved after discontinuation of dimethyl fumarate. Monitoring of serum aminotransferase levels (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and total bilirubin levels is recommended before starting dimethyl fumarate and during treatment as clinically indicated.
Lymphopenia may develop in patients receiving dimethyl fumarate (see section "Special precautions for use"). A complete blood count, including lymphocyte count, should be performed before initiating dimethyl fumarate therapy. If lymphocyte count is below normal, a thorough evaluation of possible causes should be conducted before starting treatment with dimethyl fumarate. The effect of dimethyl fumarate has not been studied in patients who had low lymphocyte counts at baseline; therefore, caution is required when treating such patients. Treatment with dimethyl fumarate should not be initiated in patients with severe lymphopenia (lymphocyte count < 0.5 × 10⁹/L). A complete blood count, including lymphocyte count, should be performed every 3 months after starting therapy.
Close monitoring of patients with lymphopenia is required due to an increased risk of progressive multifocal leukoencephalopathy (PML), and the following recommendations should be followed:
- If lymphocyte count is < 0.5 × 10⁹/L for more than 6 months, consider interrupting treatment.
- If there is persistent moderate reduction in absolute lymphocyte count ≥ 0.5 × 10⁹/L and < 0.8 × 10⁹/L lasting more than 6 months, reassess the benefit-risk balance of dimethyl fumarate therapy.
- For patients with lymphocyte counts below the laboratory's lower limit of normal (LLN), regular monitoring of absolute lymphocyte count is recommended. Additional factors increasing individual risk of PML should be considered (see PML subsection below).
Lymphocyte counts should be monitored regularly until normalization (see section "Pharmacodynamics"). After lymphocyte count normalization and in the absence of alternative therapy, the decision to resume dimethyl fumarate after prior discontinuation should be based on clinical assessment.
Magnetic resonance imaging (MRI)
Before initiating Fumaroxx, an MRI should be performed (typically within 3 months) for baseline comparison. The need for further MRIs should be considered according to national and local guidelines. MRI may be considered as part of enhanced monitoring in patients at increased risk of progressive multifocal leukoencephalopathy (PML). In case of clinical suspicion of PML, diagnostic MRI should be performed immediately.
Progressive multifocal leukoencephalopathy (PML)
Cases of PML have been reported in patients receiving dimethyl fumarate (see section "Adverse reactions").
PML is an opportunistic infection caused by the John Cunningham virus (JCV) that may lead to severe disability or death.
Cases of PML have occurred with dimethyl fumarate and other fumarate-containing drugs in the context of prolonged moderate to severe lymphopenia; however, the risk of PML cannot be excluded in patients with mild lymphopenia.
Additional risk factors for PML in the setting of lymphopenia include:
- Duration of dimethyl fumarate therapy. Cases of PML occurred approximately 1–5 years after starting treatment, although the exact relationship with treatment duration is unknown;
- Marked reduction in CD4+ and especially CD8+ T-lymphocytes, which are important for immunological defense (see section "Adverse reactions");
- Prior immunosuppressive or immunomodulatory therapy (see below).
Physicians should evaluate their patients for symptoms suggesting neurological dysfunction and determine whether these symptoms are typical of multiple sclerosis (MS) or possibly indicative of PML.
At the first sign or symptom suggestive of PML, dimethyl fumarate should be withheld and appropriate diagnostic investigations initiated, including quantitative polymerase chain reaction (PCR) testing for JCV DNA in cerebrospinal fluid (CSF). Symptoms of PML may resemble those of an MS relapse. Typical symptoms of PML are variable, progress over days to weeks, and include progressive weakness on one side of the body or limb stiffness, blurred vision, changes in thinking, memory, and orientation leading to personality changes.
Patients should also be advised to inform their partner or caregivers about their treatment, as they may notice symptoms the patient is unaware of.
PML can only occur in the presence of JCV infection. When testing for JCV, it should be noted that the impact of lymphopenia on the accuracy of JCV antibody testing has not been studied in patients taking dimethyl fumarate. A negative JCV antibody test (with normal lymphocyte count) does not exclude the possibility of future JCV infection.
If a patient develops PML, the drug must be completely discontinued.
Prior treatment with immunosuppressive or immunomodulatory agents
No studies have evaluated the efficacy and safety of switching from other medications to dimethyl fumarate. Prior immunosuppressive therapy may influence the risk of PML in patients receiving dimethyl fumarate. Cases of PML have occurred in patients previously treated with natalizumab, for which PML is a known risk. Physicians should be aware of cases of PML occurring after recent discontinuation of natalizumab, which may occur without lymphopenia.
Furthermore, most confirmed cases of PML with dimethyl fumarate occurred in patients who had previously received immunomodulatory therapy.
When switching disease-modifying therapies to dimethyl fumarate, the half-life and mechanism of action of other agents should be considered to avoid additive immune effects while minimizing the risk of multiple sclerosis reactivation.
A complete blood count is recommended before starting dimethyl fumarate therapy and regularly during treatment (see "Blood / laboratory tests" above).
Severe renal or hepatic impairment
The effect of dimethyl fumarate has not been studied in patients with severe renal or hepatic impairment; therefore, the drug should be used with caution in these patient groups (see section "Dosage and administration").
Active gastrointestinal disorders
The use of dimethyl fumarate has not been studied in patients with active gastrointestinal disorders; therefore, the drug should be used with caution in these patients.
Flushing
During clinical trials, flushing occurred in 34% of patients receiving dimethyl fumarate. In most cases, flushing intensity was mild or moderately severe. Data from studies suggest that flushing associated with dimethyl fumarate is likely mediated by prostaglandins. A short course of 75 mg of non-enteric-coated acetylsalicylic acid may be beneficial for patients experiencing flushing (see section "Interaction with other medicinal products and other forms of interaction"). In two studies involving healthy volunteers, the frequency and severity of flushing decreased over the treatment period.
During clinical trials, three out of 2560 patients receiving dimethyl fumarate experienced serious flushing symptoms, possibly due to hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but led to hospitalization. Physicians and patients should be informed about the potential for severe flushing symptoms (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions").
Anaphylactic reactions
Post-marketing reports have described cases of anaphylaxis/anaphylactoid reactions during treatment with dimethyl fumarate. Symptoms may include dyspnea, hypoxia, hypotension, angioedema, rash, or urticaria. The mechanism of anaphylaxis caused by dimethyl fumarate is unknown. Reactions usually occur after the first dose but may occur at any time during treatment and may be serious and life-threatening. Patients should discontinue dimethyl fumarate and seek immediate medical attention if they experience signs or symptoms of anaphylaxis and should not restart treatment (see section "Adverse reactions").
Infections
In phase III placebo-controlled trials, the incidence of infections (60% vs. 58%) and serious infections (2% vs. 2%) was similar in patients receiving dimethyl fumarate and placebo. However, if a patient develops a serious infection, the drug should be discontinued due to the immunomodulatory properties of dimethyl fumarate (see section "Pharmacodynamics"). The benefit-risk balance should be evaluated before considering resumption of therapy. Patients taking Fumaroxx should inform their physician about symptoms of infection. Patients with serious infections should not start treatment until the infection has resolved.
No increase in the frequency of serious infections was observed in patients with lymphocyte counts < 0.8 × 10⁹/L or < 0.5 × 10⁹/L (see section "Adverse reactions"). However, when therapy continues in the presence of moderate or severe prolonged lymphopenia, the risk of opportunistic infections, including PML, cannot be excluded (see section "Special precautions for use").
Herpes zoster infections
Cases of herpes zoster infections have been reported during dimethyl fumarate treatment. Most cases were mild, but serious cases have been reported, including disseminated herpes zoster, herpes zoster with ocular involvement, herpes zoster affecting ears, otalgia due to herpesvirus infection of the seventh cranial nerve and geniculate ganglion, neurological herpesvirus infections, herpesviral meningoencephalitis, and herpesviral meningo-myelitis. These adverse reactions may occur at any time during treatment. Signs and symptoms of herpes zoster should be monitored, especially in patients with lymphocytopenia receiving dimethyl fumarate. Appropriate treatment should be initiated if herpes zoster occurs. Discontinuation of the drug should be considered in patients with serious infections until resolved (see section "Adverse reactions").
Initiation of treatment
Treatment with the drug should be initiated gradually to reduce the risk of flushing and gastrointestinal adverse reactions (see section "Dosage and administration").
Fanconi syndrome
Cases of Fanconi syndrome have been reported with dimethyl fumarate-containing drugs in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome and discontinuation of dimethyl fumarate treatment are important to prevent kidney dysfunction and osteomalacia, as the syndrome is usually reversible. Key signs include proteinuria, glucosuria (with normal blood glucose), hyperaminoaciduria, and phosphaturia (possibly with hypophosphatemia). Progression may include polyuria, polydipsia, and proximal muscle weakness. In rare cases, hypophosphatemic osteomalacia may occur, characterized by diffuse bone pain, elevated serum alkaline phosphatase, and stress fractures. Importantly, Fanconi syndrome may occur without elevated creatinine or reduced glomerular filtration rate. In the presence of unexplained symptoms, Fanconi syndrome should be suspected and appropriate investigations performed.
Paediatric population
Safety and efficacy in the paediatric population have not been established.
Use during pregnancy or breastfeeding.
Pregnancy
Data on the use of dimethyl fumarate in pregnant women are lacking or limited. Reproductive toxicity has been observed in animal studies. The drug is not recommended for use in pregnant women or in women of childbearing potential who are not using appropriate contraception (see section "Interaction with other medicinal products and other forms of interaction"). The drug may be prescribed during pregnancy only in cases of extreme necessity, when the potential benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
It is unknown whether dimethyl fumarate or its metabolites are excreted in human breast milk; therefore, a risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue therapy with the drug should be made after careful consideration of the benefit to the mother and the risk to the infant.
Fertility
There are no data on the effect of dimethyl fumarate on human fertility. Preclinical data do not suggest that dimethyl fumarate may reduce fertility.
Ability to drive and use machines
The medicinal product has no or negligible influence on the ability to drive or use machines. No studies have been conducted on the effect on driving or operating machinery, but clinical trials have not revealed any potential impact of dimethyl fumarate on this ability.
Method of Administration and Dosage
Treatment with Fumarox should be initiated under the supervision of a physician experienced in the management of multiple sclerosis.
Method of Administration
For oral use.
The capsule should be swallowed whole. The capsule or its contents must not be crushed, divided, dissolved, sucked, or chewed, as the enteric coating of the mini-tablets prevents intestinal irritation.
Dosage
The initial dose of the medicinal product is 120 mg twice daily. After 7 days, the dose should be increased to the recommended maintenance dose of 240 mg twice daily.
If a dose is missed, a double dose should not be taken. The patient may take the missed dose only if the time interval until the next scheduled dose is at least 4 hours. Otherwise, the patient should wait until the next scheduled dose.
A temporary reduction of the dose to 120 mg twice daily may reduce the likelihood of flushing and gastrointestinal adverse reactions. The recommended maintenance dose of 240 mg twice daily should be restored within 1 month.
Fumarox should be taken with food. For patients who may experience flushing or gastrointestinal adverse reactions, taking dimethyl fumarate with food may improve tolerability.
Special Populations
Elderly Patients
A limited number of patients aged 55 years and older participated in clinical studies of dimethyl fumarate. An insufficient number of patients aged 65 years and older were included in the studies to draw conclusions regarding differences in tolerability between elderly and younger patients. Based on the mechanism of action of dimethyl fumarate, there are no theoretical grounds to justify dose adjustment in elderly patients.
Renal and Hepatic Impairment
The use of dimethyl fumarate in patients with renal or hepatic impairment has not been studied. Based on clinical pharmacology data, dose adjustment in this patient population is not required. However, treatment of patients with severe renal or hepatic impairment should be undertaken with caution.
Children
Safety and efficacy in the pediatric population have not been established.
Overdose
There have been reports of dimethyl fumarate overdose. The symptoms described in these cases were consistent with the known adverse reaction profile of dimethyl fumarate. There are no known therapeutic measures to enhance the elimination of dimethyl fumarate, and no known antidotes. In the event of overdose, symptomatic and supportive treatment should be initiated according to clinical indications.
Adverse reactions.
Summary of safety profile
In patients receiving dimethyl fumarate treatment, the most common adverse reactions (occurring in > 10% of patients) were flushing and gastrointestinal adverse reactions (diarrhea, nausea, abdominal pain, upper abdominal pain). Flushing and gastrointestinal adverse reactions occurred more frequently at the beginning of therapy (mostly within the first month). These symptoms may also occur intermittently throughout the entire treatment period. The most common adverse reactions leading to treatment discontinuation (incidence > 1%) in patients treated with dimethyl fumarate were flushing (3%) and gastrointestinal adverse reactions (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2468 patients received dimethyl fumarate and were observed for up to 4 years, with overall exposure equivalent to 3588 patient-years. Of these, 1056 patients received dimethyl fumarate treatment for more than 2 years. The experience from uncontrolled clinical trials is consistent with that from placebo-controlled clinical trials.
List of adverse reactions in tabular form
Adverse reactions identified during clinical studies, post-marketing safety studies, and spontaneous reports are listed in the table below.
The frequency of adverse reactions is categorized as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).
| MedDRA System Organ Classes [Medical Dictionary for Regulatory Activities] |
Adverse reaction |
Frequency |
| Infections and infestations |
gastroenteritis |
common |
| progressive multifocal leukoencephalopathy (PML) |
frequency unknown |
|
| herpes zoster |
frequency unknown |
|
| Blood and lymphatic system disorders |
lymphopenia |
common |
| leukopenia |
common |
|
| thrombocytopenia |
uncommon |
|
| Immune system disorders |
hypersensitivity |
uncommon |
| anaphylaxis |
frequency unknown |
|
| dyspnea |
frequency unknown |
|
| hypoxia |
frequency unknown |
|
| hypotension |
frequency unknown |
|
| angioneurotic edema |
frequency unknown |
|
| Nervous system disorders |
burning sensation |
common |
| Vascular disorders |
flushing |
very common |
| hot flush |
common |
|
| Respiratory, thoracic and mediastinal disorders |
rhinorrhea |
frequency unknown |
| Gastrointestinal disorders |
diarrhea |
very common |
| nausea |
very common |
|
| upper abdominal pain |
very common |
|
| abdominal pain |
very common |
|
| vomiting |
common |
|
| dyspepsia |
common |
|
| gastritis |
common |
|
| gastrointestinal disorder |
common |
|
| acute pancreatitis |
frequency unknown |
|
| Hepatobiliary disorders |
elevation of AST levels |
common |
| elevation of ALT levels |
common |
|
| drug-induced liver injury |
frequency unknown |
|
| Skin and subcutaneous tissue disorders |
pruritus |
common |
| rash |
common |
|
| erythema |
common |
|
| alopecia |
common |
|
| Renal and urinary disorders |
proteinuria |
common |
| General disorders and administration site conditions |
sensation of heat |
common |
| Investigations |
ketonuria |
very common |
| albuminuria |
common |
|
| decreased white blood cell count |
common |
Description of individual adverse reactions
Flushing
During clinical studies, an increased frequency of flushing episodes (34 % compared to 4 %) and hot flush sensations (7 % compared to 2 %) was observed in patients receiving dimethyl fumarate compared to those receiving placebo. Flushing sensations are typically described as a rush of blood or warmth, but may also include other phenomena (e.g., feeling of warmth, redness, itching, and burning sensation). Flushing usually occurs at the beginning of dimethyl fumarate treatment (predominantly within the first month) and may occur intermittently during therapy. In most patients, flushing episodes were of mild or moderate severity. Overall, 3 % of patients receiving dimethyl fumarate discontinued treatment due to flushing. Cases of severe flushing, characterized by generalized erythema, rash, and/or pruritus, were observed in less than 1 % of patients receiving dimethyl fumarate (see sections “Dosage and administration”, “Special precautions”, “Interaction with other medicinal products and other forms of interaction”).
Gastrointestinal adverse reactions
The incidence of gastrointestinal disorders was higher in patients receiving dimethyl fumarate compared to placebo (e.g., diarrhea [14 % vs. 10 %], nausea [12 % vs. 9 %], upper abdominal pain [10 % vs. 6 %], abdominal pain [9 % vs. 4 %], vomiting [8 % vs. 5 %], and dyspepsia [5 % vs. 3 %]). Gastrointestinal events typically occur at the beginning of dimethyl fumarate treatment (predominantly within the first month) and may occur intermittently during therapy. In most cases, the intensity of gastrointestinal symptoms was reported by patients as mild or moderate. 4 % of patients receiving dimethyl fumarate discontinued treatment due to gastrointestinal adverse events. Serious gastrointestinal adverse events, including gastroenteritis and gastritis, were observed in 1 % of patients receiving dimethyl fumarate (see section “Dosage and administration”).
Liver function
According to data from placebo-controlled studies, in most patients, the elevation of liver transaminase levels did not exceed three times the upper limit of normal (ULN). An increased frequency of elevated liver transaminase levels in patients receiving dimethyl fumarate compared to placebo was observed predominantly during the first 6 months of treatment. Elevations of ALT and AST activity to 3 times or more the ULN were observed in 5 % and 2 % of patients receiving placebo, and in 6 % and 2 % of patients receiving dimethyl fumarate, respectively. Treatment with dimethyl fumarate was discontinued due to elevated liver transaminases in < 1 % of cases.
No cases of concomitant elevations of liver transaminases to 3 times or more the ULN and total bilirubin to 2 times or more the ULN were observed.
During post-marketing use of dimethyl fumarate, elevations in liver transaminases and drug-induced liver injury (elevation of transaminases to 3 times the ULN and concomitant increase in total bilirubin to 2 times the ULN) have been reported, which resolved after discontinuation of treatment.
Lymphopenia
In placebo-controlled studies, the majority of patients (> 98 %) had normal lymphocyte counts prior to starting treatment. Following dimethyl fumarate administration, a decrease in mean lymphocyte count was observed during the first year, followed by a plateau. On average, lymphocyte count decreased by approximately 30 % from baseline. Mean and median lymphocyte counts remained within the normal range. Lymphocyte counts < 0.5 × 10⁹/L were observed in less than 1 % of patients receiving placebo and in 6 % of patients receiving dimethyl fumarate. A lymphocyte count < 0.2 × 10⁹/L was observed in one patient receiving dimethyl fumarate, but not in patients receiving placebo.
In clinical studies (both controlled and uncontrolled), lymphopenia (< 0.91 × 10⁹/L) was observed in 41 % of patients receiving dimethyl fumarate treatment; mild lymphopenia (≥ 0.8 × 10⁹/L to < 0.91 × 10⁹/L) in 28 %; moderate lymphopenia (≥ 0.5 × 10⁹/L to < 0.8 × 10⁹/L) in 10 % for at least 6 months; and severe lymphopenia (< 0.5 × 10⁹/L) in 2 % of patients for at least 6 months. In most patients in this group, lymphocyte counts remained below 0.5 × 10⁹/L during continued therapy.
Additionally, in an uncontrolled prospective post-marketing study at week 48 of dimethyl fumarate treatment (n = 185), reductions in CD4+ T-cells were moderate (≥ 0.2 × 10⁹/L to < 0.4 × 10⁹/L) or marked (< 0.2 × 10⁹/L) in 37 % and 6 % of patients, respectively, while CD8+ T-cell counts decreased to < 0.2 × 10⁹/L in 59 % of patients and to < 0.1 × 10⁹/L in 25 % of patients. In controlled and uncontrolled clinical studies, recovery of lymphocyte counts to normal levels was observed in patients with lymphocyte counts below the lower limit of normal (LLN) after discontinuation of the medicinal product.
Infections, including PML and opportunistic infections
Cases of infection with John Cunningham virus (JCV), which causes progressive multifocal leukoencephalopathy (PML), have been reported during treatment with dimethyl fumarate (see section “Special precautions”). PML may lead to fatal outcome or severe disability. In one clinical trial, a patient receiving dimethyl fumarate developed PML on the background of prolonged severe lymphopenia (lymphocyte count predominantly < 0.5 × 10⁹/L for 3.5 years), resulting in death. In post-marketing settings, PML has also occurred in patients with moderate and mild lymphopenia (from > 0.5 × 10⁹/L to < LLN).
In several PML cases with determination of T-lymphocyte subsets at the time of PML diagnosis, CD8+ T-cell counts were reduced to < 0.1 × 10⁹/L, while reductions in CD4+ T-cell counts varied (ranging from < 0.05 to 0.5 × 10⁹/L) and correlated more with the overall severity of lymphopenia (from < 0.5 × 10⁹/L to < LLN). Thus, an increased CD4+/CD8+ ratio was observed in these patients.
Prolonged moderate or severe lymphopenia is associated with an increased risk of PML during dimethyl fumarate treatment; however, PML has also occurred in patients with mild lymphopenia. Furthermore, most post-marketing PML cases have been observed in patients aged 50 years and older.
Cases of herpes zoster have been reported during treatment with dimethyl fumarate. In a long-term extension study in which 1736 patients with MS received dimethyl fumarate, approximately 5 % experienced one or more episodes of herpes zoster, most of which were mild or moderate in severity. In most subjects, including those who experienced a serious herpes zoster infection, lymphocyte counts were above the lower limit of normal. In most patients with recurrent herpes zoster, lymphopenia was assessed as moderate or severe. In post-marketing settings, most cases of herpes zoster were not serious and responded to treatment. Data from post-marketing surveillance on absolute lymphocyte count (ALC) in patients with herpes zoster are limited. However, according to reports, most patients had moderate (from < 0.8 × 10⁹/L to 0.5 × 10⁹/L) or severe (from < 0.5 × 10⁹/L to 0.2 × 10⁹/L) lymphopenia (see section “Special precautions”).
Laboratory abnormalities
In placebo-controlled studies, urinary ketone levels (1+ or higher) were higher in patients receiving dimethyl fumarate (45 %) compared to placebo (10 %). No adverse clinical consequences of this phenomenon were observed.
Levels of 1,25-dihydroxyvitamin D decreased in patients receiving dimethyl fumarate compared to placebo (median percentage decrease from baseline at 2 years was 25 % vs. 15 %, respectively), while parathyroid hormone levels increased in patients receiving dimethyl fumarate compared to placebo (mean percentage increase from baseline at 2 years was 29 % vs. 15 %, respectively). Mean values for both parameters remained within the normal range.
A transient increase in mean eosinophil count was observed during the first 2 months of therapy.
Children
Safety and efficacy in the paediatric population have not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.
Shelf life.
2 years.
Storage conditions.
Store in the original packaging to protect from light at a temperature not exceeding 25 ºC. Keep out of the reach of children.
Packaging.
10 capsules in a blister; 3 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Hetero Labs Limited.
Manufacturer's address and location of operations.
Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.