VUMERITY Gastro-resistant hard capsule Ref.[28088] Active ingredients: Diroximel fumarate

Diroximel fumarate and dimethyl fumarate are metabolised to monomethyl fumarate upon oral administration (see section 5.2). The risks associated with diroximel fumarate are expected to be similar to those reported for dimethyl fumarate even though not all the risks listed below have been observed specifically for diroximel fumarate.

Blood/laboratory tests

Changes in renal laboratory tests have been seen in clinical trials in patients treated with dimethyl fumarate (see section 4.8). The clinical implications of these changes are unknown. Assessment of renal function (e.g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment initiation with Vumerity, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically indicated.

Drug-induced liver injury, including liver enzyme increase (≥3 x 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 directly, several weeks or longer. Resolution of the adverse reactions has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

Patients treated with diroximel fumarate may develop lymphopenia (see section 4.8). Prior to initiating treatment, a current complete blood count, including lymphocytes, must be performed. If the lymphocyte count is found to be below the normal range, a thorough assessment of possible causes should be completed prior to initiation of treatment. Vumerity has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients. Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts <0.5 × 10⁹/L).

After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months.

Enhanced vigilance due to an increased risk for Progressive Multifocal Leukoencephalopathy (PML) is recommended in patients with lymphopenia as follows:

• Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocyte counts <0.5 × 10⁹/L) persisting for more than 6 months.
• In patients with sustained moderate reductions of absolute lymphocyte counts ≥0.5 × 10⁹/L and <0.8 × 10⁹/L for more than 6 months, the benefit/risk of treatment should be re-assessed.
• In patients with lymphocyte counts below LLN, as defined by local laboratory reference range, regular monitoring of absolute lymphocyte counts is recommended. Additional factors that might further augment the individual PML risk should be considered (see subsection on PML).

Lymphocyte counts should be followed until recovery. Upon recovery and in the absence of alternative treatment options, decisions about whether or not to restart Vumerity after treatment discontinuation should be based on clinical judgement.

Magnetic resonance imaging (MRI)

Before initiating treatment, a baseline MRI should be available (usually within 3 months) as a reference. The need for further MRI scanning should be considered in accordance with national and local recommendations. MRI imaging may be considered as part of increased vigilance in patients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should be performed immediately for diagnostic purposes.

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in patients treated with dimethyl fumarate. PML is an opportunistic infection caused by John Cunningham virus (JCV), which may be fatal or result in severe disability.

PML cases have occurred with dimethyl fumarate and other medicinal products containing fumarates in the setting of lymphopenia (lymphocyte counts below lower limit of normal [LLN]). Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate, however, risk cannot be excluded in patients with mild lymphopenia.

Additional factors that might contribute to an increased risk for PML in the setting of lymphopenia are:

• duration of Vumerity therapy. Cases of PML have occurred after approximately 1 to 5 years of dimethyl fumarate 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 for immunological defense (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 neurological dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML.

At the first sign or symptom suggestive of PML, Vumerity should be withheld and appropriate diagnostic evaluations, including determination of JCV DNA in cerebrospinal fluid (CSF) by quantitative 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, progress over 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 and personality changes. Physicians should be particularly alert to symptoms suggestive of PML that the patient may not notice. Patients should also be advised to inform their partner or caregivers about their treatment, 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 of lymphopenia on the accuracy of serum anti-JCV antibody testing has not been studied in dimethyl fumarate or Vumerity treated patients. It should also be noted that a negative anti-JCV antibody test (in the presence of normal lymphocyte counts) does not preclude the possibility of subsequent JCV infection.

If a patient develops PML, Vumerity must be permanently discontinued.

Prior treatment with immunosuppressive or immunomodulating therapies

No studies have been performed evaluating the efficacy and safety of diroximel fumarate when switching patients from other disease modifying therapies. The contribution of prior immunosuppressive therapy to the development of PML is possible.

PML cases have occurred 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 recent discontinuation of natalizumab may not have lymphopenia.

In addition, a majority of confirmed PML cases with dimethyl fumarate occurred in patients with prior immunomodulatory treatment.

When switching patients from another disease modifying therapy to Vumerity, the half-life and mechanism of action of the other therapy should be considered in order to avoid an additive immune effect while at the same time, reducing the risk of reactivation of MS. A complete blood count is recommended prior to treatment initiation and regularly during treatment (see Blood/laboratory tests above).

Severe renal impairment

The long-term safety of diroximel fumarate has not been studied in patients with moderate or severe renal impairment. Therefore, caution should be used when considering treatment in these patients (see sections 4.2 and 5.2).

Severe hepatic impairment

Diroximel fumarate has not been studied in patients with severe hepatic impairment. Therefore, caution should be used when considering treatment in these patients (see sections 4.2 and 5.2).

Severe active gastrointestinal disease

Diroximel fumarate has not been studied in patients with severe active gastrointestinal disease. Therefore, caution should be used when considering treatment in these patients.

Flushing

In dimethyl fumarate pivotal clinical trials, 3 patients out of a total of 2,560 patients treated with dimethyl fumarate experienced serious flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. These adverse reactions were not life-threatening but led to hospitalisation. Prescribers and patients should be alert to this possibility in the event of severe flushing reactions with Vumerity (see sections 4.2, 4.5 and 4.8).

Data from healthy volunteer studies suggest that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. A short course of treatment with 75 mg non-enteric coated acetylsalicylic acid may be beneficial in patients affected by intolerable flushing (see section 4.5). In two healthy volunteer studies, the occurrence and severity of flushing over the dosing period was reduced.

Anaphylactic reactions

Cases of anaphylaxis/anaphylactoid reaction have been reported following dimethyl fumarate administration in the post-marketing setting. Symptoms may include dyspnoea, hypoxia, hypotension, angioedema, rash or urticaria. The mechanism of dimethyl fumarate induced anaphylaxis is unknown. Reactions generally occur after the first dose, but may also occur at any time during treatment, and may be serious and life threatening. Patients should be instructed to discontinue Vumerity and seek immediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted (see section 4.8).

Infections

In the phase 3 placebo-controlled studies with dimethyl fumarate, the incidence of infections (60% versus 58%) and serious infections (2% versus 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively.

Diroximel fumarate exerts immunomodulatory properties (see section 5.1).

Patients receiving Vumerity should be instructed to report symptoms of infections to a physician. If a patient develops a serious infection, suspending treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients with serious infections should not start treatment until the infection(s) is resolved.

There was no increased incidence of serious infections observed in patients treated with dimethyl fumarate with lymphocyte counts <0.8 × 10⁹/L or <0.5 × 10⁹/L. If Vumerity therapy is continued in the presence of moderate to severe prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruled out (see subsection on PML).

Herpes zoster infections

Cases of herpes zoster have occurred with diroximel fumarate and dimethyl fumarate. The majority of cases with dimethyl fumarate were non-serious, however, serious cases, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster oticus, herpes zoster infection neurological, herpes zoster meningoencephalitis and herpes zoster meningomyelitis have been reported. These events may occur at any time during treatment. Patients should be monitored for signs and symptoms of herpes zoster especially when concurrent lymphocytopenia is reported. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered. Withholding treatment should be considered 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 adverse reactions (see section 4.2).

Fanconi syndrome

Cases of Fanconi syndrome have been reported for a medicinal product containing dimethyl fumarate in combination with other fumaric acid esters. Early diagnosis of Fanconi syndrome and discontinuation of Vumerity treatment are important to prevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. The most important signs are: proteinuria, glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possibly concurrent with hypophosphatemia). Progression might involve symptoms such as polyuria, polydipsia and proximal muscle weakness. In rare cases hypophosphataemic osteomalacia with non-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 filtration rate. In case of unclear symptoms Fanconi syndrome should be considered and appropriate examinations should be performed.

During treatment, simultaneous use of other fumaric acid esters (topical or systemic) should be avoided.

Vumerity should not be administered concomitantly with dimethyl fumarate.

Potential interaction risks were not identified from in vitro and/or in vivo inhibition studies of transporters, from in vitro CYP-inhibition and induction studies, or studies of the protein binding of diroximel fumarate and its major metabolites, active metabolite monomethyl fumarate (MMF) and inactive metabolite 2-hydroxyethyl succinimide (HES).

Although not studied with diroximel fumarate, in vitro CYP induction studies did not demonstrate an interaction between dimethyl fumarate and oral contraceptives. In an in vivo study, co-administration of dimethyl fumarate with a combined oral contraceptive (norgestimate and ethinyl estradiol) did not elicit any relevant change in oral contraceptive exposure. No interaction studies have been performed with oral contraceptives containing other progestogens, however an effect of diroximel fumarate on their exposure is not expected.

Diroximel fumarate has not been studied in combination with anti-neoplastic or immunosuppressive therapies and caution should, therefore, be used during concomitant administration. In MS clinical studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase of infection.

Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during Vumerity therapy. In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis (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 conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups. A positive immune response defined as a ≥4-fold increase in antibody titre to the three vaccines, was achieved by fewer patients in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon.

No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking Vumerity. Live vaccines might carry an increased risk of clinical infection and should not be given to patients unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

Evidence from healthy volunteer studies suggests that dimethyl fumarate-associated flushing is likely to be prostaglandin mediated. In two healthy volunteer studies with dimethyl fumarate, the administration of 325 mg (or equivalent) non enteric coated acetylsalicylic acid, 30 minutes prior to dimethyl fumarate, dosing over 4 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 Vumerity in patients with relapsing remitting MS. Long term (>4 weeks) continuous use of 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 Vumerity (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are no or limited amount of data from the use of diroximel fumarate in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Vumerity is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception (see section 4.5). Vumerity should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether diroximel fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Vumerity therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of Vumerity on human fertility. Data from animal studies with diroximel fumarate showed no impairment of male or female fertility (see section 5.3).

Vumerity has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Upon oral administration, diroximel fumarate and dimethyl fumarate are rapidly metabolised to monomethyl fumarate before they reach the systemic circulation, adverse reactions are similar once metabolised.

The most common adverse reactions for dimethyl fumarate were flushing (35%) and gastrointestinal events (i.e. diarrhoea 14%, nausea 12%, abdominal pain 10% and abdominal pain upper 10%). The most commonly reported adverse reactions leading to discontinuation in patients treated with dimethyl fumarate were flushing (3%) and gastrointestinal events (4%).

Tabulated list of adverse reactions

The adverse reactions which were more frequently reported in dimethyl fumarate-treated patients as compared to placebo-treated patients from two pivotal phase 3 placebo controlled clinical trials and post marketing experience are presented in Table 1.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organ class (SOC). 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), and not known (frequency cannot be estimated from the available data).

Table 1. Adverse reactions:

¹ See ‘Description of selected adverse reactions’ for further information
² Adverse reactions derived during post marketing experience
³ Lymphopenia was reported with the frequency “very common” in a phase 3, open-label, uncontrolled study with diroximel fumarate

Description of selected adverse reactions

Flushing

In the placebo-controlled dimethyl fumarate studies, the incidence of flushing (34% versus 5%) and hot flush (7% versus 2%) was increased in patients treated with dimethyl fumarate 240 mg twice daily 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 to occur intermittently throughout treatment with dimethyl fumarate. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with dimethyl fumarate discontinued due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with dimethyl fumarate (see sections 4.2, 4.4 and 4.5).

In the diroximel fumarate phase 3 double-blind trial (see section 5.1), flushing and hot flush were reported in 32.8% and 1.6% of diroximel fumarate-treated patients and in 40.6% and 0.8% of dimethyl fumarate-treated patients. There were no serious events of flushing or discontinuations due to flushing.

Gastrointestinal

The 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 to placebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience gastrointestinal events, these events may continue to occur intermittently throughout treatment with dimethyl fumarate. In the majority of patients 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 events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with dimethyl fumarate (see section 4.4).

Gastrointestinal adverse reactions reported in the clinical study with diroximel fumarate and dimethyl fumarate are presented in section 5.1.

Hepatic function

Based on data from placebo-controlled studies with dimethyl fumarate, the majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥3 x 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 transaminases were <1% and similar in patients treated with dimethyl fumarate or placebo. Elevations in transaminases ≥3 x ULN with concomitant elevations in total bilirubin >2 x ULN indicative of drug-induced liver injury were not observed during placebocontrolled studies, but have been reported in post marketing experience following dimethyl fumarate administration, which resolved upon treatment discontinuation.

Lymphopenia

In the diroximel fumarate phase 3, open-label, uncontrolled trial, treatment was discontinued in patients with confirmed lymphocyte counts <0.5 × 10⁹/L which persisted for ≥4 weeks.

In the placebo-controlled studies for dimethyl fumarate, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with dimethyl fumarate, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5 × 10⁹/L were observed in <1% of patients treated with placebo and 6% of patients treated with dimethyl fumarate. A lymphocyte count <0.2x10⁹/l was observed in 1 patient treated with dimethyl fumarate and in no patients treated with placebo.

In clinical studies (both controlled and uncontrolled), 41% of patients treated with dimethyl fumarate had lymphopenia (defined in these studies as <0.91 × 10⁹/L). Mild lymphopenia (counts ≥0.8 × 10⁹/L and <0.91 × 10⁹/L) was observed in 28% of patients; moderate lymphopenia (counts ≥0.5 × 10⁹/L and <0.8 × 10⁹/L) persisting for at least six months was observed in 11% of patients; severe lymphopenia (counts <0.5 × 10⁹/L) persisting for at least six months was observed in 2% of patients. In the group with severe lymphopenia, the majority of lymphocyte counts remained <0.5 × 10⁹/L with continued therapy.

In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with dimethyl fumarate (n=185) CD4+ T cells were moderately (counts ≥0.2 × 10⁹/L to <0.4 × 10⁹/L) or severely (<0.2 × 10⁹/L) decreased in up to 37% or 6% of patients, respectively, while CD8+ T cells were more frequently reduced with up to 59% of patients at counts <0.2 × 10⁹/L and 25% of patients at counts <0.1 × 10⁹/L.

Infections, including PML and opportunistic infections

Cases of infections with JCV causing PML have been reported with dimethyl fumarate (see section 4.4). PML may be fatal or result in severe disability. In one of the clinical trials, one patient taking dimethyl fumarate developed PML in the setting of prolonged severe lymphopenia (lymphocyte counts predominantly <0.5 × 10⁹/L for 3.5 years), with a fatal outcome. In the post-marketing setting, PML has also occurred in the presence of moderate and mild lymphopenia (>0.5 × 10⁹/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+ T cell counts were found to be decreased to <0.1 × 10⁹/L, whereas reductions in CD4+ T cells counts were variable (ranging from <0.05 to 0.5 × 10⁹/L) and correlated more with the overall severity of lymphopenia (<0.5 × 10⁹/L to <LLN). Consequently, the CD4+/CD8+ ratio was increased in these patients.

Prolonged moderate to severe lymphopenia appears to increase the risk of PML with dimethyl fumarate and likewise diroximel fumarate, however, PML also occurred in patients treated with dimethyl fumarate with mild lymphopenia. Additionally, the majority of PML cases in the postmarketing setting have occurred in patients >50 years.

Herpes zoster infections have been reported with dimethyl fumarate use. In the long-term extension study, in which 1,736 MS patients were treated with dimethyl fumarate, 5% experienced one or more events of herpes zoster, the majority of which were mild to moderate in severity. Most patients, including those who experienced a serious herpes zoster infection, had lymphocyte counts above the lower limit of normal. In a majority of patients with concurrent lymphocyte counts below the LLN, lymphopenia was rated moderate or severe. In the post-marketing setting most cases of herpes zoster infection were non-serious and resolved with treatment. Limited data is available on ALC in patients with herpes zoster infection in the post-marketing setting. However, when reported, most patients experienced moderate (<0.8 × 10⁹/L to 0.5 × 10⁹/L) or severe (<0.5 × 10⁹/L to 0.2 × 10⁹/L) lymphopenia (see section 4.4).

Laboratory abnormalities

In the placebo-controlled studies for dimethyl fumarate, measurement of urinary ketones (1+ or greater) was higher in patients treated with dimethyl fumarate (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.

Levels of 1,25-dihydroxyvitamin D decreased in dimethyl fumarate treated patients relative to placebo (median percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of parathyroid hormone (PTH) increased in dimethyl fumarate treated patients relative to placebo (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 dimethyl fumarate therapy.

Paediatric population

The safety of Vumerity in paediatric patients has not yet been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.