VYNDAQEL® OR VYNDAMAX® (tafamidis meglumine or tafamidis) 12. CLINICAL PHARMACOLOGY

(tafamidis meglumine or tafamidis)

Prescribing Information

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tafamidis is a selective stabilizer of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.

12.2 Pharmacodynamics

A proprietary TTR stabilization assay was utilized as a pharmacodynamic marker and assessed the stability of the TTR tetramer ex vivo. The TTR stabilization assay quantifies immunoturbidimetric measurement of the stable TTR tetramer in plasma pre- and post-treatment with 2-day in vitro denaturation with urea. Using this proprietary assay, a dose-dependent trend for greater TTR tetramer stabilization is observed for VYNDAQEL 80-mg compared to VYNDAQEL 20-mg. However, the clinical relevance of a higher TTR tetramer stabilization towards cardiovascular outcomes is not known.

VYNDAQEL stabilized both the wild-type TTR tetramer and the tetramers of 14 TTR variants tested clinically after once-daily dosing. Tafamidis also stabilized the TTR tetramer for 25 variants tested ex vivo.

VYNDAQEL and VYNDAMAX may decrease serum concentrations of total thyroxine, without an accompanying change in thyroid stimulating hormone (TSH). This reduction in total thyroxine values is probably the result of reduced thyroxine binding to or displacement from transthyretin (TTR) due to the high binding affinity of tafamidis to the TTR thyroxine receptor. No corresponding clinical findings consistent with hypothyroidism have been observed.

Biomarkers associated with heart failure (NT-proBNP and Troponin I) favored VYNDAQEL over placebo.

Cardiac Electrophysiology

At approximately 2.2 times the steady state peak plasma concentration (Cmax) at the recommended dose, tafamidis does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

No clinically significant differences in steady state Cmax and area under the plasma concentration over time curve (AUC) of tafamidis were observed for VYNDAMAX 61-mg capsule compared to VYNDAQEL administered as four 20-mg capsules.

Tafamidis exposure increases proportionally over single (up to 480 mg) or multiple (up to 80 mg) (1 to 6 times the approved recommended dosage) once daily dosing.

The apparent clearance were similar after single and repeated administration of VYNDAQEL 80 mg.

Absorption

Median tafamidis peak concentrations occurred within 4 hours following dosing.

Effect of Food

No clinically significant differences in the pharmacokinetics of tafamidis were observed following administration of a high fat, high calorie meal.

Distribution

The apparent steady state volume of distribution of tafamidis meglumine is 16 liters and 18.5 liters for tafamidis. Plasma protein binding of tafamidis is >99% in vitro. Tafamidis primarily binds to TTR.

Elimination

The mean half-life of tafamidis is approximately 49 hours. The apparent oral clearance of tafamidis meglumine is 0.228 L/h (0.263 L/h for tafamidis). The degree of drug accumulation at steady state after repeated tafamidis daily dosing is approximately 2.5-fold greater than that observed after a single dose.

Metabolism

The metabolism of tafamidis has not been fully characterized. However, glucuronidation has been observed.

Excretion

After a single oral dose of tafamidis meglumine 20 mg, approximately 59% of the dose was recovered in feces (mostly as the unchanged drug) and approximately 22% of the dose was recovered in urine (mostly as the glucuronide metabolite).

Specific Populations

No clinically significant differences in the pharmacokinetics of tafamidis were observed based on age, race/ethnicity (Caucasian and Japanese) or renal impairment.

Patients with Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Score of 7 to 9) had decreased systemic exposure (approximately 40%) and increased clearance (approximately 68%) of tafamidis compared to healthy subjects. As TTR levels are lower in subjects with moderate hepatic impairment than in healthy subjects, the exposure of tafamidis relative to the amount of TTR is sufficient to maintain stabilization of the TTR tetramer in these patients. No clinically significant differences in the pharmacokinetics of tafamidis were observed in patients with mild hepatic impairment (Child Pugh Score of 5 to 6) compared to healthy subjects. The effect of severe hepatic impairment on tafamidis is unknown.

Drug Interaction Studies

Clinical Studies

CYP3A4 substrates: No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A4 substrate) or on the formation of its active metabolite (1-hydroxymidazolam) were observed when a single 7.5-mg dose of midazolam was administered prior to and after a 14-day regimen of VYNDAQEL 20-mg once daily.

BCRP substrates: Tafamidis inhibits breast cancer resistant protein (BCRP). In a clinical study in healthy participants, AUCinf and Cmax of the BCRP substrate rosuvastatin increased by 96.75% and 85.59%, respectively following multiple doses of VYNDAMAX 61 mg daily dosing.

In Vitro Studies

Cytochrome P450 Enzymes: Tafamidis induces CYP2B6 and CYP3A4 and does not induce CYP1A2. Tafamidis does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5 or CYP2D6.

UDP glucuronosyltransferase (UGT): Tafamidis inhibits intestinal activities of UGT1A1 but neither induces nor inhibits other UDP glucuronosyltransferase (UGT) systemically.

Transporter Systems: In vitro studies and model predictions show that tafamidis has a low potential to inhibit organic anion transporters OAT1 and OAT3 at clinically relevant concentrations. Tafamidis did not show a potential to inhibit Multi-Drug Resistant Protein (MDR1) (also known as P-glycoprotein; P-gp), organic cation transporter OCT2, multidrug and toxin extrusion transporters MATE1 and MATE2K and, organic anion transporting polypeptide OATP1B1 and OATP1B3.

Medication Guide

MEDICATION GUIDE

This Patient Information has been approved by the U.S. Food and Drug Administration	Issued: 10/2023
PATIENT INFORMATION
VYNDAQEL® (VIN-duh-kel) (tafamidis meglumine) capsules	VYNDAMAX™ (VIN-dah-max) (tafamidis) capsules
What is VYNDAQEL and VYNDAMAX? VYNDAQEL and VYNDAMAX are prescription medicines used to treat adults with cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) to reduce death and hospitalization related to heart problems. It is not known if VYNDAQEL and VYNDAMAX are safe and effective in children.
Before taking VYNDAQEL or VYNDAMAX, tell your healthcare provider about all your medical conditions, including if you: • have liver problems. • are pregnant or plan to become pregnant. VYNDAQEL and VYNDAMAX may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with VYNDAQEL or VYNDAMAX. You may also report your pregnancy by calling the Pfizer reporting line at 1-800-438-1985. • are breastfeeding or plan to breastfeed. It is not known if VYNDAQEL or VYNDAMAX passes into your breast milk. You should not breastfeed during treatment with VYNDAQEL or VYNDAMAX. Talk to your healthcare provider about the best way to feed your baby during treatment with VYNDAQEL or VYNDAMAX. Tell your healthcare provider about all the medicines you take including any prescription or over-the-counter medicines, vitamins, and herbal supplements.
How should I take VYNDAQEL or VYNDAMAX? • Take either VYNDAQEL or VYNDAMAX exactly as your healthcare provider tells you to. • Take either VYNDAQEL or VYNDAMAX capsule(s) 1 time a day. • VYNDAQEL or VYNDAMAX capsule(s) should be swallowed whole and not crushed or cut. • If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regularly scheduled time. Do not take 2 doses at the same time.
What are the possible side effects of VYNDAQEL and VYNDAMAX? There were no known side effects that happened during treatment with VYNDAQEL or VYNDAMAX in people with cardiomyopathy of transthyretin-mediated amyloidosis. You may report side effects to FDA at 1-800-FDA-1088.
How should I store VYNDAQEL and VYNDAMAX? • Store VYNDAQEL and VYNDAMAX capsules at room temperature between 68°F to 77°F (20°C to 25°C). • Keep VYNDAQEL and VYNDAMAX and all medicines out of the reach of children.
General information about the safe and effective use of VYNDAQEL and VYNDAMAX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VYNDAQEL or VYNDAMAX for a condition for which it was not prescribed. Do not give VYNDAQEL or VYNDAMAX to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about VYNDAQEL or VYNDAMAX that is written for healthcare professionals.
What are the ingredients in VYNDAQEL and VYNDAMAX? VYNDAQEL: Active ingredient: tafamidis meglumine Inactive ingredients: ammonium hydroxide 28%, brilliant blue FCF, carmine, gelatin, glycerin, iron oxide (yellow), polyethylene glycol 400, polysorbate 80, polyvinyl acetate phthalate, propylene glycol, sorbitan monooleate, sorbitol, and titanium dioxide VYNDAMAX: Active ingredient: tafamidis Inactive ingredients: ammonium hydroxide 28%, butylated hydroxytoluene, gelatin, glycerin, iron oxide (red), polyethylene glycol 400, polysorbate 20, povidone (K-value 90), polyvinyl acetate phthalate, propylene glycol, sorbitol, and titanium dioxide LAB-0573-5.0 For more information, go to www.vyndaqel.com or call 1-800-438-1985.

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