Tecfidera ™ (dimethyl fumarate)

1. Tecfidera™(dimethyl fumarate) Manufacturer: Biogen/Idec FDA Approval Date: March 27, 2013

2. Tecfidera™ (dimethyl fumarate)Clinical Application • Indications: • First line therapy for relapsing-remitting forms of multiple sclerosis (RRMS) • Place in therapy: • Oral, possibly mildest ADE profile of all oral and non-oral alternatives; efficacy testing vs other agents is required

3. Tecfidera™ (dimethyl fumarate)Clinical Application • Contraindications: • none • Warnings/Precautions • Lymphopenia – 30% reduction in lymphocyte count over 1st year, then stable • Flushing – similar to niacin; can be alleviated with food, Canadian labeling recommends premedication with aspirin for first week of therapy

4. Tecfidera™ (dimethyl fumarate)Clinical Application • Pregnancy: • Category C – some evidence of harm in animals • Lactation: • Excretion in breast milk unknown; not recommended

5. Tecfidera™ (dimethyl fumarate)Drug Facts • Pharmacology: • Exact mechanism unknown • Activates antioxidant pathways that protect CNS cells from autoimmune attack • May also directly inhibit pro-inflammatory pathways

6. Tecfidera™ (dimethyl fumarate)Drug Facts • Pharmacokinetics • A – rapidly converted to monomethyl fumarate during absorption; high fat/calorie meal slows absorption but no change in AUC. • D – moderate protein binding and lipophilicity • M – No CYP involvement; metabolized to endogenous substrates via Krebs cycle • E – primarily via exhaled CO2, some renal

7. Tecfidera™ (dimethyl fumarate)Drug Interactions • Drug Interactions – Object Drugs • May increase infection from live vaccines • May decrease ability to form humoral immunity from live vaccines • Drug Interactions – Precipitant Drugs • None observed

9. Tecfidera™ (dimethyl fumarate)Monitoring Parameters • Efficacy Monitoring • Prevention of relapse • Toxicity Monitoring • Baseline CBC (lymphocyte count); recheck annually

10. Tecfidera™ (dimethyl fumarate)Prescription Information • Twice daily dosing • Initiation: 120 mg BID • Maintenance 240 mg BID • Cost - $5400/month (Medi-Span; accessed 08/01/2013)

11. Tecfidera™ (dimethyl fumarate)Literature Review: DEFINE • 2-year, multi-center, randomized, double-blind, placebo-controlled trial • [240 mg BID] [240 mg TID] [placebo] • Outcomes • Proportion relapsed at 2 years (primary) • MRI changes • Annualized relapse rate • Time to progression of disability Gold R, et al. N Engl J Med. 2012;367:1098-107.

12. Tecfidera™ (dimethyl fumarate)Literature Review: DEFINE • N = 1234 • Age 18-55 yr • No progressive disease • Documented relapse within past year • Disability score 0-5 (out of 10), expanded disability status scale Gold R, et al. N Engl J Med. 2012;367:1098-107.

13. Tecfidera™ (dimethyl fumarate)Literature Review: DEFINE Gold R, et al. N Engl J Med. 2012;367:1098-107.

14. Tecfidera™ (dimethyl fumarate)Literature Review: DEFINE Primary Outcome: Gold R, et al. N Engl J Med. 2012;367:1098-107.

15. Tecfidera™ (dimethyl fumarate)Literature Review: DEFINE Secondary Outcomes: Gold R, et al. N Engl J Med. 2012;367:1098-107.

16. Tecfidera™ (dimethyl fumarate)Summary • New first-line oral agent for relapsing-remitting MS • Dosing: initial 120 mg BID x 7d, then 240 mg BID; no dose adjustments • Flushing is most common side effect; need baseline & annual CBC • Appears to be of similar efficacy to alternative agents, but comparative data is needed

17. Tecfidera™ (dimethyl fumarate)References • Tecfidera™package insert. Biogen/Idec. March 2013. Accessed at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=665d7e74-036c-5f68-5b67-ab84b9b49151 • Gold R, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-107. • Fox R, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367;1087-97.