Product Information
Registration Status: ActiveVYNDAQEL SOFT GELATIN CAPSULE 20MG is approved to be sold in Singapore with effective from 2020-02-27. It is marketed by PFIZER PTE LTD, with the registration number of SIN15893P.
This product contains Tafamidis 20mg in the form of CAPSULE. It is approved for ORAL use.
This product is manufactured by Catalent Pharma Solutions in UNITED STATES, andCatalent Pharma Solutions in UNITED STATES, and.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
Tafamidis is a novel specific transthyretin (TTR) stabilizer or dissociation inhibitor. TTR ordinarily assumes a tetramer configuration that primarily serves to transport retinol-binding protein-vitamin A complex as well as thyroxine (to a small degree) in the blood. In TTR-related disorders such as TTR familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated and results in unregulated amyloidogenesis and amyloid fibril formation. The unwanted deposition of such formations in various tissues eventually contributes to the failure of autonomic and peripheral nervous system functions. Tafamidis was approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. Tafamidis is an investigational drug under the FDA and - despite prior approval rejections in 2012 - in June 2017, Pfizer received FDA Fast Track Designation for tafamidis. Tafamidis was developed by Jeffery W. Kelly in the company FoldRx that he had co-founded with Susan Lindquist of MIT and the Whitehead Institute. FoldRx was eventually acquired by Pfizer, who - despite the approval of tafamidis for use by the European Medicines Agency as well as in Japan - continues to run clinical trials to obtain formal FDA approval in the United States.
Indication
Tafamidis is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment [FDA Label].
Mechanism of Action
Transthyretin (TTR) amyloid polyneuropathy (also known as TTR familial amyloid polyneuropathy, TTR-FAP) results from genetic mutations in the TTR gene that cause destabilization of ordinary TTR tetramers and/or speed up TTR tetramer dissociation into monomers [A27206]. TTR-FAP itself is a multi-faceted, progressive, axonal degenerative neuropathy characterized by sensory, motor, and autonomic impairment [FDA Label]. The dissociation of TTR tetramers to monomers is, in fact, the rate-limiting step in the pathogenesis of TTR-FAP [FDA Label]. The folded monomers that comprise ordinary TTR tetramers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates [FDA Label]. These intermediates then misassemble into a variety of soluble oligomers, profilaments, filaments, and amyloid fibrils [FDA Label]. These various undesired, soluble aggregates subsequently deposit upon tissues where they ultimately are not expected to be present or needed [A27206]. In particular, studies demonstrating TTR's ability to influence nerve physiology by enhancing nerve regeneration in mouse models [A32598] emphasizes a potential function of TTR for nerve biology and repair that may assist in explaining why mutant TTR aggregrates preferentially deposit in the peripheral nervous system of patients with TTR-FAP [A27206]. Tafamidis is subsequently a rationally designed pharmaceutical that specifically binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of TTR to prevent its dissociation into monomers [FDA Label]. Tafamidis is consequently formally considered to be a specific stabilizer of TTR, and its inhibition of TTR tetramer dissociation forms the rationale for its use as a treatment to slow - but not cure - the disease progression of TTR-FAP [FDA Label].
Pharmacokinetics
- Absorption
- After oral administration of tafamidis soft capsule, the maximum plasma concentration (Cmax) is achieved at a median time (tmax) of 2 hours after dosing in the fasted state [FDA Label]. Concomitant administration of food decreased the rate of absorption, but not the extent of absorption [FDA Label]. These results support the administration of tafamidis with or without food [FDA Label].
- Distribution
- The apparent steady-state volume of distribution is reported to be 25.7 liters [FDA Label].
- Metabolism
- Based on preclinical data, it is believed that tafamidis is primarily metabolized by glucuronidation and then excreted by way of the bile [FDA Label].
- Elimination
Clearance
After daily administration of a 20mg tafamidis dose for fourteen days in healthy subjects, the mean total clearance observed was 0.42 L/h [FDA Label].
Toxicity
The most common adverse effects associated with taking tafamidis include urinary tract infection, vaginal infection, diarrhea, and upper abdominal pain [FDA Label]. No cases of acute overdose have yet been reported [FDA Label]. In clinical trials of healthy volunteers, the highest dose of tafamidis administrated was 480 mg in a single dose and 60 mg once daily for two weeks [FDA Label]. The reported treatment-related adverse events were mild to moderate and included headache, somnolence, myalgia, insomnia, hordeolum, photosensitivity reaction, and presyncope [FDA Label].
Active Ingredient/Synonyms
tafamidis | tafamidisum | Tafamidis |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.