tafamidis

Action and Spectrum

Actions and Spectrum: 

• tafamidis is a medication used to treat transthyretin-mediated amyloidosis (ATTR), a rare disease caused by the buildup of misfolded transthyretin protein in various tissues, including the heart and nerves. 
• The mechanism of action of tafamidis is to stabilize the tetrameric structure of transthyretin, which prevents its misfolding and aggregation into amyloid fibrils. By stabilizing the tetramer, tafamidis reduces the amount of misfolded transthyretin available to form tissue amyloid deposits. 
• The spectrum of activity of tafamidis is limited to ATTR, specifically to ATTR with polyneuropathy. It has been shown to slow the progression of neurological impairment in patients with early-stage ATTR polyneuropathy. tafamidis is ineffective in treating other types of amyloidosis or neuropathy. 

Drug Interaction

Adverse Reaction

Black Box Warning

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

None 

Caution: 

• Liver function: tafamidis is primarily metabolized by the liver, so caution is advised in patients with liver dysfunction. Patients with moderate to severe hepatic impairment should be monitored closely for adverse effects. 

• Pregnancy and breastfeeding: There is limited data on the safety of tafamidis use during pregnancy and breastfeeding, so caution should be exercised. 

• Drug interactions: tafamidis is not known to interact with other medications. However, caution should be used when combined with drugs primarily metabolized by the liver or that may have hepatotoxic effects. 

• Allergic reactions: Allergic reactions, including anaphylaxis, have been reported in patients taking tafamidis. Patients who develop signs of an allergic reaction should discontinue the medication and seek medical attention. 

• Immunogenicity: There is a potential for patients to develop antibodies against tafamidis, which may reduce its effectiveness. Patients should be monitored for signs of decreased efficacy and the potential need for dose adjustments. 

• Geriatric patients: While there are no specific cautions, they may be more likely to experience adverse effects due to age-related changes in drug metabolism and elimination. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.   

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology:

tafamidis is a small molecule that selectively binds to transthyretin (TTR), a protein that plays a role in the transport of thyroid hormones and retinol-binding protein. In patients with TTR-mediated amyloidosis, mutations in the TTR gene can lead to unstable TTR tetramers, which can dissociate and form amyloid fibrils that accumulate in various tissues.

tafamidis binds to the thyroxine-binding sites of TTR, stabilizing the tetrameric structure of the protein and preventing its dissociation into monomers, which is a critical step in the formation of amyloid fibrils. By stabilizing the tetrameric structure, tafamidis reduces the misfolded TTR available to form tissue amyloid deposits.

Pharmacodynamics:

The pharmacodynamics of tafamidis is related to its mechanism of action, which is to stabilize the tetrameric structure of transthyretin (TTR) and prevent its dissociation into monomers. By doing so, tafamidis reduces the amount of misfolded TTR available to form amyloid fibrils, which can accumulate in various tissues and cause organ damage.

tafamidis has been shown to stabilize TTR tetramers in vitro and in vivo and reduce the dissociation rate of tetramers into monomers. In clinical studies, tafamidis has been shown to slow the progression of neuropathy in patients with TTR-mediated amyloidosis, with reductions in nerve impairment scores observed compared to placebo.

Pharmacokinetics:

Absorption

tafamidis is well-absorbed orally, and the peak plasma concentration is achieved 4 hours after administration. There are no clinically significant differences in the steady-state peak plasma concentration and AUC between the 61-mg capsule and the four 20-mg tafamidis meglumine capsules.

Distribution

tafamidis has a Vd (steady-state) of 18.5 L, indicating that it is widely distributed throughout the body. Over 99% of tafamidis is bound to plasma proteins, primarily to TTR.

Metabolism

The metabolism of tafamidis is not fully characterized, but it is known to undergo glucuronidation, a process by which glucuronic acid is added to the drug molecule, making it more water-soluble and easier to eliminate from the body.

Elimination and Excretion

tafamidis has a half-life of approximately 49 hours and an oral clearance of 0.263 L/hr. It is primarily eliminated through the feces, with about 59% of the drug being excreted unchanged in the feces. About 22% of the drug is eliminated in the urine, mainly as a glucuronide conjugate.

Adminstartion

Administration:

Oral administration:

• It may be consumed either with or without food
• Swallow the pill whole; do not crush or cut it.
• If a dosage is missed, either give it as soon as possible or skip it and take the following dose at the usually scheduled time; do not double the dose.

Storage:

Keep at room temperature (20-25°C [68-77°F]); excursions to 15-30°C (59-86°F) are acceptable.

Patient Information Leaflet

Patient information leaflet

Generic Name: tafamidis

Why do we use tafamidis?

tafamidis is a medication used to treat a rare genetic disorder called transthyretin amyloidosis (ATTR), characterized by the buildup of abnormal proteins called amyloids in various tissues and organs throughout the body.

• tafamidis is specifically approved for treating ATTR with cardiomyopathy, a disease that affects the heart.
• tafamidis works by stabilizing the tetrameric structure of the transthyretin protein, which is the protein misfolded in ATTR. By stabilizing the protein, tafamidis helps to prevent the formation of amyloids and the subsequent damage to tissues and organs