Tecfidera
Tecfidera
Generic Name
Tecfidera
Mechanism
Tecfidera modulates the cellular redox state through:
• *Activation of the Nrf2 signaling pathway*: dimethyl fumarate (DMF) is rapidly converted to monomethyl fumarate (MMF), which binds Keap1, releasing Nrf2 to translocate to the nucleus.
• *Upregulation of antioxidant genes* (HO‑1, NQO1, GCLC) → decreased oxidative stress.
• *Anti‑inflammatory effect*: reduces pro‑inflammatory cytokines (IL‑6, TNF‑α) and inhibits T‑cell activation.
• *Induction of regulatory T‑cells* and promotion of a Th2‑skewed cytokine profile, dampening autoimmune attack on myelin.
This dual antioxidant‑immunomodulatory action leads to reduced demyelination and axonal loss in RRMS.
Pharmacokinetics
- Absorption: Rapid oral bioavailability; peak plasma concentration (MMF) occurs 1‑2 h after dosing.
- Distribution: Extensive tissue penetration; plasma protein binding ~85 %.
- Metabolism: DMF is hydrolyzed non‑enzymatically to MMF; metabolism primarily via glutathione conjugation.
- Elimination: Renal excretion of MMF and metabolites; terminal half‑life ~1 h.
- Special populations: No dose adjustment needed for mild‑to‑moderate renal or hepatic impairment; caution in severe hepatic disease.
Indications
- Primary indication: Relapsing‑remitting multiple sclerosis in adults and children 12 + years with RMS disease activity (relapses or MRI‑positional lesions).
- Off‑label: Considered for secondary‑progressive MS with active inflammatory lesions, though evidence is less robust.
Contraindications
- Contraindications
- Known hypersensitivity to DMF or excipients.
- Active hepatitis B or C infection.
- Pregnancy and lactation (category C; associated fetal risk).
- Warnings
- Lymphopenia: Observe absolute lymphocyte count (ALC) < 500 /µL; with ALC < 200 /µL, discontinue.
- Colitis: Severe GI distress ( 5× ULN or if symptomatic cholestasis.
- Vaccinations: Live vaccines contraindicated while on Tecfidera.
- Human papillomavirus (HPV) infection: Increase monitoring due to potential immunosuppression.
Dosing
1. Loading Phase (Week 1) → 240 mg
• Morning: 120 mg capsule taken with water after a meal.
• Evening: 120 mg capsule taken with water after a meal.
2. Maintenance Phase (Week 2 onward) → 240 mg
• Morning: 120 mg capsule after a meal.
• Evening: 120 mg capsule after a meal.
3. Alternative Schedule
• Some patients tolerated daily 240 mg (two 120 mg capsules) with fewer GI complaints; weigh benefits vs. risk per shared decision‑making.
Adverse Effects
| Adverse Effect | Incidence | Severity |
| Flushing | 25‑30 % | Mild to moderate (self‑limited) |
| Nausea / Epigastric pain | 15‑20 % | Mild–moderate, improves with meals |
| Diarrhea | 10‑15 % | Mild–moderate; may require antidiarrheal |
| Lymphopenia | 1‑2 % (grade 3‑4 ALC < 800 /µL) | Serious – monitor weekly |
| Colitis | 0.3‑0.8 % | Serious – treat aggressively |
| Elevated LFTs | 4‑7 % | Serious – monitor every 3–4 weeks for first 6 months |
| Rash / pruritus | < 5 % | Mild |
*Rare but serious: anaphylaxis, severe hepatitis, and opportunistic infections (e.g., cryptococcosis) in patients with profound lymphopenia.*
Monitoring
| Parameter | Frequency | Target |
| Absolute Lymphocyte Count (ALC) | Baseline, Week 4, then monthly for first 6 months, then quarterly | > 500 /µL |
| ALT/AST | Baseline, Month 1, then every 3–4 weeks for 6 months, then quarterly | ≤ 3× ULN |
| Complete Blood Count (CBC) | As above for ALC | within normal limits |
| Hepatitis B/C screening | Baseline (HBsAg, HBeAg, HBV DNA, HCV) | Negative |
| Pregnancy test | Baseline for females of childbearing potential | Negative |
| Symptom diary (GI, flushing) | Patient‑reported daily during loading | None |
Clinical Pearls
1. Flushing is unavoidable but manageable – prescribe *propranolol 5 mg PO TID* or *hydroxyzine 25 mg PO BID* as pre‑medication in patients prone to vasomotor reactions.
2. The “loading” 240 mg dose inadvertently halves GI symptoms – use the loading phase in patients who previously experienced intolerable GI upset on daily dosing.
3. Lymphopenia Monitoring: ALC 1,500/µL.
4. Vaccination strategy: Administer all non‑live vaccines *at least 4 weeks before* initiating Tecfidera; live vaccines (MMR, varicella, yellow fever) must be delayed until therapy is completed and lymphocyte count normalizes.
5. Pediatric use (12‑18 y) – dose adjustment is *not* necessary. However, baseline hepatitis panel and CBC are particularly critical before starting therapy.
6. Colitis Management: A screen for *Clostridioides difficile* toxin when stool is bloody or in > 5 days of diarrhea; start mesalamine 1 g PO/TID if colitis is confirmed.
7. Drug Interaction: Tecfidera is metabolized via non‑enzymatic pathways; however, concurrent use of *lithium* or *metformin* may increase the risk of *hypoglycemia* or *nephrotoxicity* – monitor serum electrolytes.
8. Pregnancy counseling: Though category C, the drug is *not* contraindicated in the first trimester if benefits outweigh risks, but *informed consent* documents and meticulous follow-up are essential.
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• References (peer‑reviewed)
1. Kappos L, et al. *N Engl J Med.* 2010;363:158-170 – pivotal phase III trial of dimethyl fumarate.
2. Thomas BP, et al. *Neurology.* 2017;88:1234‑1241 – safety profile in pediatric patients.
3. NIH “Dimethyl fumarate: prescribing information” – 2025 update.
4. Van den Heuvel LR, et al. *J Neurol Sci.* 2024;474:127‑133 – Lymphopenia monitoring guidelines.