Tafamidis (Monograph)

Brand names: Vyndamax ([Web], Vyndaqel
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: 2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Molecular formula: C₁₄H₇Cl₂NO₃C₁₄H₇Cl₂NO₃•C₇H₁₇NO₅
CAS number: 594839-88-0

Medically reviewed by Drugs.com on May 23, 2022. Written by ASHP.

Introduction

Benzoxazole derivative; transthyretin (TTR) stabilizer.

Uses for Tafamidis

Transthyretin-mediated Amyloidosis

Treatment of cardiomyopathy in adults with wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) to reduce cardiovascular mortality and cardiovascular-related hospitalization.

Has been used for the treatment of polyneuropathy of transthyretin-mediated amyloidosis^{† [off-label]}.

Transthyretin-mediated amyloidosis (ATTR) can be inherited as an autosomal dominant trait caused by pathogenic variants/mutations in the TTR gene (ATTRv) or by deposition of wild-type TTR protein (ATTRwt). Selection of an appropriate disease-modifying therapy in patients with ATTR is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis.

The American Heart Association (AHA) has issued a scientific statement on management of ATTR-CM. In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, AHA states that tafamidis is recommended in those with NYHA class I–III symptoms; the benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function.

Tafamidis Dosage and Administration

General

Dispensing and Administration Precautions

Tafamidis and tafamidis meglumine are not substitutable on a mg-per-mg basis.

Other General Considerations

Advise patients of availability of the Transthyretin Amyloidosis Outcome Survey (THAOS) registry. Participation is voluntary and may involve long-term follow-up. Information regarding the registry is available at [Web].

Administration

Oral Administration

Administer orally once daily.

Swallow capsules whole; do not crush or cut.

If a dose is missed, take the dose as soon as remembered or skip the missed dose and take next dose at the regularly scheduled time. Do not double the dose.

Dosage

Tafamidis and tafamidis meglumine are not substitutable on a mg-per-mg basis.

Adults

Transthyretin-mediated Amyloidosis

Tafamidis Meglumine (Vyndaqel)

Oral

80 mg (administered as four 20-mg tafamidis meglumine capsules).

Tafamidis (Vyndamax)

Oral

61 mg (administered as one 61-mg tafamidis capsule) orally once daily.

Special Populations

Hepatic Impairment

The manufacturer makes no dosage adjustment recommendations for patients with mild or moderate hepatic impairment.

Tafamidis has not been evaluated in patients with severe hepatic impairment; caution is recommended if given to patients with severe hepatic impairment.

Renal Impairment

The manufacturer makes no dosage adjustment recommendations for patients with renal impairment.

Geriatric Patients

The manufacturer states that no dosage adjustments are required for patients 65 years of age and older.

Cautions for Tafamidis

Contraindications

None.

Warnings/Precautions

Specific Populations

Pregnancy

May cause fetal harm. In animal studies, developmental toxicity (e.g., increased embryofetal mortality, decreased fetal body weight, fetal malformation, fetal skeletal variation, postnatal mortality, growth retardation, neurobehavioral impairment in offspring) observed.

Limited available human data have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Lactation

Distributed into milk in rats; not known whether tafamidis distributes into human milk, affects the breast-fed infant, or affects milk production.

Breast-feeding not recommended during treatment with tafamidis.

Pediatric Use

Safety and efficacy in pediatric patients not established.

Geriatric Use

In pivotal clinical trial, 90.5% of patients were ≥65 years of age; median age was 75 years. No dosage adjustment required in geriatric patients.

Hepatic Impairment

Decreased systemic exposure and increased clearance reported in patients with moderate hepatic impairment (Child-Pugh score of 7–9) compared to healthy subjects; however, because TTR levels are lower in patients with moderate hepatic impairment, exposure of tafamidis relative to amount of TTR is sufficient to maintain stabilization of the TTR tetramer in these patients.

Not studied in patients with severe hepatic impairment.

Renal Impairment

Systemic exposure to tafamidis does not appear to be altered in patients with renal impairment.

Common Adverse Effects

In clinical trials, similar incidence of adverse events reported in patients receiving tafamidis meglumine 20 mg or 80 mg and in those receiving placebo.

Interactions for Tafamidis

In vitro, induces CYP2B6 and CYP3A4 but does not induce CYP1A2. Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5, or CYP2D6.

Inhibits uridine 5′-diphospho-glucuronyltransferase (UGT) 1A1 but neither induces nor inhibits other UGT isoenzymes. Inhibits breast cancer resistance protein (BCRP). Low potential for inhibiting organic anion transporters (OAT) 1 and OAT3 at clinically relevant concentrations. Does not inhibit P-glycoprotein (P-gp), organic cation transporter (OCT) 2, multidrug and toxin extrusion transporters (MATE) 1 and MATE2/K, or organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.

Drugs Metabolized by Breast Cancer Resistance Protein

Concomitant use with drugs that are metabolized by BCRP may increase plasma concentrations of the substrate drug, potentially increasing the risk of adverse reactions.

Monitor patients for substrate drug-related toxicities and modify dosage of the substrate drug as clinically appropriate.

Specific Drugs

Drug	Interaction	Comments
Imatinib	Possible increase in plasma concentrations and risk of adverse reactions of imatinib (BCRP substrate)	Monitor patients for imatinib toxicity and decrease imatinib dosage as clinically appropriate
Methotrexate	Possible increase in plasma concentrations and risk of adverse reactions of methotrexate (BCRP substrate)	Monitor patients for methotrexate toxicity and decrease methotrexate dosage as clinically appropriate
Midazolam	No clinically important effects on pharmacokinetics of midazolam (CYP3A4 substrate) or on formation of its active metabolite (1-hydroxymidazolam) observed when a single 7.5-mg dose of midazolam was administered prior to and after a 14-day regimen of tafamidis meglumine 20 mg once daily
Rosuvastatin	AUC and peak plasma concentrations of rosuvastatin (BCRP substrate) increased by approximately 97 and 86%, respectively, following multiple doses of tafamidis 61 mg daily	Monitor patients for rosuvastatin toxicity and decrease rosuvastatin dosage as clinically appropriate

Tafamidis Pharmacokinetics

Absorption

Bioavailability

Tafamidis exposure increases dose-proportionally following single (up to 480 mg) or multiple (up to 80 mg once daily) dosing of tafamidis meglumine.

Similar apparent clearance observed following single- and repeated-dose administration of tafamidis meglumine 80 mg.

Degree of drug accumulation at steady state after repeated tafamidis daily dosing approximately 2.5-fold greater than that observed after a single dose.

No clinically important differences in steady-state peak plasma concentrations or AUC observed for tafamidis 61 mg and tafamidis meglumine 80 mg (administered as four 20-mg capsules).

Median tafamidis peak concentrations occur within 4 hours following dosing.

Food

No clinically important differences in pharmacokinetics of tafamidis observed following administration of a high-fat, high-calorie meal.

Distribution

Extent

Not known whether distributes into human milk.

Plasma Protein Binding

>99%, primarily to TTR.

Elimination

Metabolism

Not fully characterized; glucuronidation has been observed.

Phase II enzymes UGT1A9, UGT1A1, and UGT1A3 appear to be the major isoforms responsible for formation of the acyl glucuronide; UGT isoforms 1A6, 1A7, 1A8, and 2B7 appear to play minor role.

Elimination Route

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

Half-life

Effective half-life approximately 33 hours; terminal elimination half-life approximately 49 hours.

Special Populations

Systemic exposure decreased by approximately 40% and clearance increased by approximately 68% in patients with moderate hepatic impairment (Child-Pugh score 7–9).

No clinically important differences in pharmacokinetics of tafamidis observed based on age, race/ethnicity (Caucasian, Japanese), renal impairment, or mild hepatic impairment (Child Pugh score 5–6).

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted to 15–30°C).

Actions

Selective stabilizer of TTR.
Binds to TTR at thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
In a TTR stabilization assay, a dose-dependent trend for greater TTR tetramer stabilization observed with a tafamidis dosage of 80 mg daily compared to 20 mg daily; however, clinical relevance of higher TTR tetramer stabilization to cardiovascular outcomes not known.
May decrease serum concentrations of total thyroxine, without an accompanying change in thyroid stimulating hormone; no clinical findings consistent with hypothyroidism reported.

Advice to Patients

Importance of advising patients to read the FDA-approved patient labeling (patient information).
Importance of informing patients that tafamidis capsules should be swallowed whole and not crushed or cut.
If a dose is missed, instruct patients to take the dose as soon as remembered or, if it is almost time for the next dose, to skip the missed dose and take the next dose at the regularly scheduled time. Do not double the dose.
Importance of advising patients of the availability of the Transthyretin Amyloidosis Outcome Survey (THAOS) registry and that participation is voluntary and may involve long-term follow-up. Information regarding the registry is available at [Web].
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy and to report pregnancies to the Pfizer reporting line at 1-800-438-1985. Consider pregnancy planning and prevention for females of reproductive potential. Advise females not to breast-feed during tafamidis therapy.
Advise females not to breast-feed during tafamidis therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses (e.g., liver disease).
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tafamidis is available through a specialty pharmacy network. Clinicians may consult the Vyndamax website at [Web] for specific availability information.