Dimethyl Fumarate

Registered South African indications:

• Relapsing remitting multiple sclerosis

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Suspected or confirmed progressive multifocal leukoencephalopathy (PML)

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment 
• Pre-existing low lymphocyte counts​​​​​​
• Increased risk of PML
  - John-Cunningham virus (JCV)
  - Presence of moderate to severe lymphopenia (South African manufacturer recommendation)
  - Presence of lymphopenia (International manufacturer recommendation)
• Severe active gastrointestinal disease
• Prior treatment with immunosuppressive or immunomodulating agents
• Prior treatment with natalizumab (International manufacturer recommendation)
• Coadministration with antineoplastic or immunosuppressive agents
• Coadministration with live vaccines
• Coadministration with acetylsalicylic acid (See additional prescribing points)

Forms avail. in SA and covered in this monograph: cap

Treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis

Relapsing remitting multiple sclerosis (MS)

•  Oral (cap): Initial: 120mg, 12hrly; After 7 days increase to: Maintenance: 240mg, 12hrly

- Upon occurrence of flushing and gastrointestinal adverse reactions (temporary dose reduction)

• Oral (cap): 120mg, 12hrly;  Within 1 month increase to: Maintenance: 240mg, 12hrly

Capsule should be taken with food and swallowed whole

The capsule or its contents should not be crushed, divided, dissolved, sucked or chewed

For those patients who may experience flushing or gastrointestinal adverse reactions, taking with food may improve tolerability

If a patient misses a dose, a double dose should not be taken. The patient may take the missed dose only if they leave 4 hours between doses. Otherwise the patient should wait until the next scheduled dose

Not established for use in children between 10-18 years
No relevant use in children below 10 years 

Pregnancy

South African manufacturer recommendations

• Caution; not recommended
• There are no or limited data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity
• Dimethyl fumarate is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception
• Dimethyl fumarate should not be used during pregnancy

International manufacturer recommendations

• Caution; not recommended
• There are no or limited data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity
• Dimethyl fumarate is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception
• Dimethyl fumarate should not be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus

Breastfeeding

• Caution; not recommended
• It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue dimethyl fumarate therapy. The benefit of breastfeeding for the child and the benefit of therapy for the woman should be taken into account

Fertility

• There are no data on the effects of dimethyl fumarate on human fertility. Data from preclinical studies do not suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility​​

Renal Impairment

• Caution; no dose adjustment recommended 
  Dimethyl fumarate has not been studied in patients with renal impairment. Based on clinical pharmacology studies, no dose adjustments are needed.
  Caution should be used when treating patients with severe renal impairment

Hepatic Impairment

• Caution; no dose adjustment recommended 
  Dimethyl fumarate has not been studied in patients with hepatic impairment. Based on clinical pharmacology studies, no dose adjustments are needed
  Caution should be used when treating patients with severe hepatic impairment

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Burning sensation
• Progressive multifocal leukoencephalopathy (PML) (See additional prescribing points)

Cardiovascular Disorders

• Flushing
  - Hot flush
  - Warmth
  - Redness
  - Itching
  - Serious flushing (characterised by generalised erythema rash and/or pruritus)
• Hypotension

Respiratory Disorders

• Rhinorrhoea
• Dyspnoea
• Hypoxia

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
  - Upper abdominal pain
• Gastroenteritis
• Dyspepsia
• Gastritis

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Drug-induced liver injury

Genitourinary Disorders

• Proteinuria
• Ketones in urine
• Albumin in urine
• Fanconi syndrome (See additional prescribing points)

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Erythema
• Alopecia

Immune, Blood and Lymphatic System Disorders

• Lymphopenia
• Leucopenia
• Thrombocytopenia
• Hypersensitivity
• Herpes zoster
• Anaphylaxis (See additional prescribing points)
• Angioedema
• Decreased white blood cell count

Others

• Feeling hot

• Other fumaric acid derivates (topical or systemic)
• Nephrotoxic agents
• Aminoglycosides
• Diuretics
• Non-steroidal anti-inflammatory agents
• Lithium

Other interactions

• Strong alcoholic drinks (See additional prescribing points)

• Full blood count (prior to initiation, every 3 months and as clinically needed)
  - Lymphocytes
• Hepatic function (prior to initiation and as clinically indicated)
  - Transaminases
  - Alkaline phosphatase
  - Total bilirubin
• Renal function (prior to initiation, after 3 and 6 months, every 6-12 months thereafter and as clinically indicated)
  - Creatinine
  - Blood urea nitrogen (BUN)
  - Urinalysis
• Magnetic Resonance Imaging (baseline and as clinically indicated) 

Specific cases may require

• Latent infection screening (e.g. hepatitis, tuberculosis) 

Additional observations

• Grade 3 lymphopenia (at intervals <3 months)
• Signs/symptoms of hypersensitivity, infections, and/or PML

Progressive multifocal leukoencephalopathy (PML) 

• 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
• PML cases have occurred with dimethyl fumarate and other medicinal products containing fumarates in the setting of lymphopenia (lymphocyte counts below 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 dimethyl fumarate therapy. Cases of PML have occurred after approximately 1-5 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 for immunological defence, and
  - Prior immunosuppressive or immunomodulatory therapy
• If a patient develops PML, dimethyl fumarate must be permanently discontinued

Anaphylactic reactions

• Symptoms may include dyspnoea, hypoxia, hypotension, angioedema, rash or urticaria
• 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 and seek immediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted

Coadministration with acetylsalicylic acid

• Short course with 75mg non-enteric coated acetylsalicylic acid may be beneficial in patients affected by intolerable flushing
• Administration of 325mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to dosing over 4 days and over 4 weeks, respectively, did not alter the pharmacokinetic profile. Potential risks associated with acetylsalicylic acid therapy should be considered prior to coadministration with dimethyl fumarate
• Long term (>4 weeks) continuous use of acetylsalicylic acid has not been studied

Coadministration with strong alcoholic drinks

• Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided within an hour of taking dimethyl fumarate, as alcohol may lead to increased frequency of gastrointestinal adverse reactions

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 dimethyl fumarate 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

The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to be 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 antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]).

Capsule 120mg

• Tecfidera 120mg (Acino Pharma) originator

Capsule 240mg

• Tecfidera 240mg (Acino Pharma) originator