Chemical formula: C₁₁H₁₃NO₆ Molecular mass: 255.226 g/mol
Diroximel fumarate interacts in the following cases:
No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking diroximel fumarate. 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.
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) in patients taking diroximel fumarate.
No dose adjustment is necessary for patients with hepatic impairment. Diroximel fumarate has not been studied in patients with hepatic impairment. Therefore, caution should be used when considering treatment in these patients.
No dose adjustment is necessary in patients with renal impairment. 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.
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 diroximel fumarate, 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.
During treatment, simultaneous use of other fumaric acid esters (topical or systemic) should be avoided.
Diroximel fumarate should not be administered concomitantly with dimethyl fumarate.
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.
Patients receiving diroximel fumarate 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 diroximel fumarate therapy is continued in the presence of moderate to severe prolonged lymphopenia, the risk of an opportunistic infection, including PML, cannot be ruled out.
There are no or limited amount of data from the use of diroximel fumarate in pregnant women. Animal studies have shown reproductive toxicity. Diroximel fumarate is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception. Diroximel fumarate should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus.
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 diroximel fumarate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data on the effects of diroximel fumarate on human fertility. Data from animal studies with diroximel fumarate showed no impairment of male or female fertility.
Diroximel fumarate has no or negligible influence on the ability to drive and use machines.
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%).
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:
| MedDRA System Organ Class | Adverse reaction | Frequency category |
|---|---|---|
| Infections and infestations | Gastroenteritis | Common |
| Progressive multifocal leukoencephalopathy (PML)1 | Not known | |
| Herpes zoster1,2 | Not known | |
| Blood and lymphatic system disorders | Lymphopenia1,3 | Common |
| Leukopenia | Common | |
| Thrombocytopenia | Uncommon | |
| Immune system disorders | Hypersensitivity | Uncommon |
| Anaphylaxis2 | Not known | |
| Dyspnoea2 | Not known | |
| Hypoxia2 | Not known | |
| Hypotension2 | Not known | |
| Angioedema2 | Not known | |
| Nervous system disorders | Burning sensation | Common |
| Vascular disorders | Flushing1 | Very common |
| Hot flush | Common | |
| Respiratory, thoracic and mediastinal disorders | Rhinorrhoea2 | Not known |
| Gastrointestinal disorders2 | 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 increased1 | Common |
| Alanine aminotransferase increased1 | Common | |
| Drug-induced liver injury2 | Not known | |
| Skin and subcutaneous tissue disorders | Pruritus | Common |
| Rash | Common | |
| Erythema | Common | |
| Renal and urinary disorders | Proteinuria | Common |
| General disorders and administration site conditions | Feeling hot | Common |
| Investigations2 | Ketones measured in urine | Very common |
| Albumin urine present | Common | |
| White blood cell count decreased | Common |
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
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.
In the diroximel fumarate phase 3 double-blind trial, 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.
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.
Gastrointestinal adverse reactions reported in the clinical study with diroximel fumarate and dimethyl fumarate are presented in section 5.1.
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.
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.
Cases of infections with JCV causing PML have been reported with dimethyl fumarate. 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.
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.
The safety of diroximel fumarate in paediatric patients has not yet been established.
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