Makindo Medical Notes

Tafamidis is a transthyretin (TTR) stabiliser used in the management of transthyretin amyloidosis, including both familial amyloid polyneuropathy (TTR-FAP) and transthyretin amyloid cardiomyopathy (ATTR-CM). It is used to delay neurological and cardiac deterioration by preventing amyloid fibril formation. Treatment is initiated and monitored by a specialist in amyloidosis or inherited neuropathy. Always 🔗 check the BNF entry here for current guidance.

🧬 Pathophysiology

• Transthyretin (TTR) is a serum transport protein for thyroxine and retinol-binding protein, produced mainly by the liver.
• Mutations in the TTR gene destabilise the tetramer → dissociation into monomers → misfolding → formation of insoluble amyloid fibrils.
• These amyloid fibrils deposit in nerves, myocardium, and other tissues, leading to progressive polyneuropathy or restrictive cardiomyopathy.
• Tafamidis binds to the TTR tetramer, stabilising it and preventing dissociation, thereby slowing amyloid formation.

⚙️ Mode of Action

• Selective transthyretin kinetic stabiliser.
• Binds non-covalently to the thyroxine-binding sites on the TTR tetramer.
• Prevents tetramer dissociation — the rate-limiting step in amyloidogenesis.
• Does not dissolve existing amyloid but reduces further deposition and progression.

📋 Indications & Dose

• Familial amyloid polyneuropathy (TTR-FAP):
  • Adults with stage 1 symptomatic polyneuropathy to delay neurological decline.
  • Tafamidis meglumine 20 mg PO once daily.
• Transthyretin amyloid cardiomyopathy (ATTR-CM):
  • Adults with wild-type or hereditary ATTR-CM to reduce mortality and cardiovascular-related hospitalisation.
  • Tafamidis 61 mg PO once daily (free acid formulation; not interchangeable mg-for-mg with the 20 mg meglumine form).
• May be taken with or without food; swallow whole with water.

🧪 Pharmacology

• Onset: gradual stabilisation — clinical benefit seen over months.
• Half-life: ~49 hours.
• Metabolism: hepatic (glucuronidation, not via CYP450).
• Elimination: faecal (major) and urinary (minor).

⚠️ Interactions

• Few significant interactions — not a CYP inhibitor or inducer.
• However, review co-prescribed agents for amyloid patients (anticoagulants, heart failure drugs, thyroid replacement).
• Check the BNF for updates.

🚧 Cautions

• Initiate only after confirmation of TTR amyloidosis by genetic or tissue diagnosis (to distinguish from AL amyloidosis).
• Not indicated for stage 2–3 polyneuropathy where neuronal loss is advanced.
• Monitor neurological function, cardiac status, and quality-of-life metrics at regular intervals.
• Limited safety data in severe hepatic impairment — use with caution.

⛔ Contraindications

• Pregnancy and breastfeeding (embryotoxic in animal studies).
• Women of child-bearing potential must use effective contraception during and for 1 month after treatment.
• Hypersensitivity to tafamidis or excipients.

💢 Side Effects

• Generally well tolerated.
• Common: abdominal pain, diarrhoea, urinary tract infection, vaginal infection, dizziness, fatigue.
• Uncommon: weight loss, increased liver enzymes.
• Long-term therapy may unmask cardiac progression despite stabilisation — requires specialist follow-up.

🧠 Clinical Pearls

• Tafamidis does not reverse existing amyloid but delays further fibril formation — early initiation gives best benefit.
• In cardiac amyloidosis, tafamidis improves survival and reduces heart failure admissions (ATTR-ACT trial, NEJM 2018).
• For advanced disease, management becomes supportive (diuretics, rate control, transplantation consideration).
• Alternative approaches: RNA-targeted therapies (e.g. patisiran, inotersen) act by silencing hepatic TTR production.

📚 References

• BNF: Tafamidis
• NICE TA766 (2022): Tafamidis for treating transthyretin amyloidosis with cardiomyopathy.
• Adams D. et al., NEJM 2018: "Patisiran and Tafamidis in Hereditary Transthyretin Amyloidosis".
• European Society of Cardiology (ESC) Position Paper: Amyloidosis 2023.