VYNDAQEL 2 Contraindications

INDICATIONS

VYNDAQEL (tafamidis meglumine) is indicated for:

• the treatment of adult patients with cardiomyopathy due to transthyretin-mediated amyloidosis, wildtype or hereditary, to reduce cardiovascular mortality and cardiovascular-related hospitalization.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥65 years of age): Safety and efficacy were demonstrated in this population.

VYNDAQEL is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4.1 Dosing Considerations

• VYNDAQEL (tafamidis meglumine) capsules and VYNDAMAX (tafamidis) capsules are different formulations with the active moiety tafamidis. To avoid dosing errors, it is important that prescriptions should specify VYNDAQEL (tafamidis meglumine) or VYNDAMAX (tafamidis) and the prescribed dose. VYNDAQEL and VYNDAMAX are not interchangeable on a per mg basis (see 10.3 Pharmacokinetics, 14.3 Comparative Bioavailability Studies of the Product Monograph for VYNDAMAX). The recommended dose of VYNDAMAX (tafamidis) is 61 mg tafamidis (administered as one 61 mg tafamidis capsule) orally once daily.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose is VYNDAQEL (tafamidis meglumine) 80 mg administered as four 20 mg tafamidis meglumine capsules (equivalent to 48.8 mg tafamidis) orally once daily.  The dose may be reduced to one capsule of 20 mg VYNDAQEL if not tolerated (see 14 CLINICAL TRIALS).

Special populations

Pregnant Women: VYNDAQEL should not be used during pregnancy (see 7 WARNINGS AND PRECAUTIONS, 7.1.1 Pregnant Women).

Women of childbearing potential should use appropriate contraception when taking VYNDAQEL and continue to use contraception for 1‑month after stopping treatment.

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥65 years of age): No dosage adjustment is required for elderly patients (≥65 years). 

Renal or hepatic impairment: VYNDAQEL has not been studied in patients with severe hepatic impairment and use is not recommended in these patients. No dosage adjustment is required for patients with mild or moderate hepatic impairment. Data are limited in patients with severe renal impairment. No dosage adjustment is required for patients with renal impairment.

4.4 Administration

The capsules should be swallowed whole and not crushed or cut. VYNDAQEL may be taken with or without food.

4.5 Missed Dose

If a dose is missed, the patient should take the dose as soon as remembered. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regularly scheduled time.

There is minimal clinical experience with overdose. During clinical trials, two patients diagnosed with ATTR-CM accidentally ingested a single tafamidis meglumine dose of 160 mg without adverse events. The highest dose of tafamidis meglumine given to healthy volunteers in a clinical trial was 480 mg as a single dose.  

VYNDAQEL 20 mg: yellow, opaque, oblong (approximately 21 mm) capsule printed with “VYN 20” in red.  120 capsules (one month supply) supplied in 4 intermediary cartons.  Each intermediary carton contains 3 blister cards, with 10 capsules each. 

General

No studies have been conducted in organ transplant patients. The efficacy and safety of VYNDAQEL in organ transplant patients has not been established.  Tafamidis is not recommended in these patients.

Carcinogenesis and Mutagenesis

Carcinogenesis: There was no evidence of an increased incidence of neoplasia in the transgenic (Tg)‑rasH2 mouse following repeated daily administration for 26 weeks at daily doses of 0, 10, 30 or 90 mg/kg. There was no evidence of increased incidence of neoplasia in a 2‑year carcinogenicity study in rats at exposures 18‑times the human AUC at the clinical dose of 80 mg tafamidis meglumine (see 16 NON-CLINICAL TOXICOLOGY).

Mutagenesis: There was no evidence of mutagenicity or clastogenicity in vitro, and an in vivo rat micronucleus study was negative.

Driving and Operating Machinery

VYNDAQEL has not been shown to influence the ability to drive and use machines.

Hepatic/Biliary/Pancreatic

VYNDAQEL has not been studied in patients with severe hepatic impairment and use is not recommended in these patients.

Renal

Limited data are available in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min).

Reproductive Health: Female and Male Potential

• Teratogenic Risk

Studies in animals have shown developmental toxicity (see 16 NON-CLINICAL TOXICOLOGY). The potential risk for humans is unknown. VYNDAQEL should not be used during pregnancy.

Women of childbearing potential should use appropriate contraception when taking VYNDAQEL and continue to use contraception for 1‑month after stopping treatment.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled clinical studies with the use of VYNDAQEL in pregnant women. Studies in animals have shown developmental toxicity (see 16 NON-CLINICAL TOXICOLOGY).  The potential risk for humans is unknown. VYNDAQEL should not be used during pregnancy.

7.1.2 Breast-feeding

There are no clinical data available to support the presence of tafamidis in human breast milk. Nonclinical data demonstrates that tafamidis is secreted in the milk of lactating rats (see 16 NON-CLINICAL TOXICOLOGY).  When a drug is present in animal milk, it is likely the drug will be present in human milk. The effect of VYNDAQEL on nursing infants after administration to the mother has not been studied. Based on findings from animal studies which suggest the potential for serious adverse reactions in the breastfed infant, VYNDAQEL should not be used by nursing women.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥65 years of age): Safety and efficacy were demonstrated in this population.

8.1 Adverse Reaction Overview

The most frequently reported Treatment emergent Serious Adverse Events (TESAEs) in the tafamidis 80 mg, 20 mg and placebo groups respectively were condition aggravated (22.7%, 23.9% and 32.8%); cardiac failure (19.3%, 18.2%, and 22.6%), cardiac failure congestive (11.9%, 15.9% and 17.5%), cardiac failure acute (13.1%, 4.5% and 9.6%), fall (5.1%, 5.7% and 2.8%) and syncope (3.4%, 0%, 5.6%).

Treatment emergent Adverse Events (TEAEs) with a higher incidence in the tafamidis 80 mg and 20 mg treatment group than placebo (≥2x placebo and reported by ≥4 patients) respectively, included cystitis (3.4%, 2.3% and 0%), sinusitis (5.7%, 5.7% and 0.6%), asthenia (10.2%, 12.5% and 6.2%), balance disorder (8.5%, 2.3% and 1.1%) and cataract (5.1%, 3.4% and 1.1%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The data across clinical trials reflect exposure of 377 ATTR‑CM patients to either 20 mg or 80 mg (administered as four 20 mg capsules) of VYNDAQEL daily for an average of 24.5 months (ranging from 1 day to 111 months). The population included adult patients diagnosed with ATTR‑CM with baseline NYHA (New York Heart Association) Class I, Class II or Class III respectively at 9.1%, 61.4%, and 29.5% in the pooled tafamidis arm and at 7.3%, 57.1% and 35.6%, respectively on placebo. The mean age was approximately 75 years (ranging from 46 years to 91 years of age); >90% were male, and approximately 82% were Caucasian (see Study Results Table 6: Patient Demographics and Baseline Characteristics).

Adverse events were assessed from ATTR‑CM clinical trials with VYNDAQEL including a 30‑month placebo‑controlled trial in patients diagnosed with ATTR‑CM.  The frequency of adverse events in patients treated with VYNDAQEL 20 mg (n=88) or 80 mg (n=176; administered as four 20 mg capsules) was comparable to placebo (n=177).  Listed below are all causality adverse events reported in the pivotal clinical trial.

A similar proportion of VYNDAQEL‑treated patients compared to placebo discontinued due to an adverse event in the 30‑month placebo‑controlled trial in patients diagnosed with ATTR‑CM [12 (6.8%), 5 (5.7%), and 11 (6.2%)] from the tafamidis meglumine 80 mg, tafamidis meglumine 20 mg, and placebo groups, respectively].

The reported incidence of hypothyroidism was 6.8%, 5.7% and 5.6% in patients in the tafamidis 80 mg, 20 mg and placebo groups, respectively.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The incidence of thyroxine abnormality <0.8 x LLN was greater in the tafamidis 80 mg group (29.7%) than in the tafamidis 20 mg (12.3%) and placebo (4.5%) groups. No clinically meaningful shifts in free thyroxine or thyroid stimulating hormone values were observed, and no corresponding signal in thyroid dysfunction was observed in the analysis of TEAEs (see 8.2 Clinical Trial Adverse Reactions for rates of hypothyroidism reported in clinical trials).

Low neutrophil count (<0.8 x LLN) was more frequent with tafamidis treatment than with placebo (1.9% tafamidis 80 mg, 1.2% tafamidis 20 mg, 0.6% placebo).

Elevated liver function tests were more frequent in the tafamidis 80 mg group (3.4%) than in the tafamidis 20 mg (2.3%) and placebo (1.1%) groups.

9.2 Drug Interactions Overview

In vitro studies:

Cytochrome P450 Enzymes: Tafamidis induces CYP2B6 and CYP3A4 and does not induce CYP1A2.  Tafamidis does not inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and moderately inhibits CYP2C8.

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

Transporter Systems: Tafamidis inhibits breast cancer resistant protein (BCRP).   

In vitro studies and model predictions show that tafamidis has a potential to inhibit the 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.  

Clinical studies: 

Transporter Systems: Tafamidis inhibits breast cancer resistant protein (BCRP).  In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple doses of 61 mg tafamidis daily dosing. 

In a clinical study (n=12) using healthy participants, the renal clearance of the OAT3 substrate rosuvastatin did not change following multiple doses of 61 mg tafamidis daily dosing. This suggests that any inhibition of OAT3 by tafamidis may not result in clinically significant interactions with OAT3 substrates. 

9.4 Drug-Drug Interactions

The drugs listed in Table 3 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

9.5 Drug-Food Interactions

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

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10.1 Mechanism of Action

Tafamidis is a selective stabilizer of transthyretin (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.

10.2 Pharmacodynamics

A TTR stabilization assay was utilized as a pharmacodynamic marker and assessed the stability of the TTR tetramer under denaturation conditions. Tafamidis 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 an additional 26 variants tested ex vivo.

The tafamidis 80 mg dose was selected based on maximal TTR % stabilization data from PK studies.  The clinical relevance of a higher TTR stabilization is not known.

Cardiac Electrophysiology

At single dose of 400 mg, approximately 2.2 times the steady state peak plasma concentration (C_max) at the recommended dose, tafamidis does not prolong the QTc interval to any clinically relevant extent.

10.3 Pharmacokinetics

The pharmacokinetic profile of tafamidis was characterized in healthy volunteers (n = 333) and patients with transthyretin amyloidosis (n = 427).  Steady-state PK parameters were estimated by a population PK analysis.  Tafamidis apparent oral clearance was affected by age and body weight. Over the range of 57.5 to 93 kg (corresponding to the 10^th and 90^th percentile of the observed weights) the clearance changed from 0.85-fold to 1.14-fold relative to the median weight and it decreased by 14.5% in subjects ≥ 65 years of age compared to younger subjects.

Absorption:

After oral administration of VYNDAQEL once daily, the maximum peak concentration (C_max) is achieved at a median time (t_max) within 4 hours after dosing in the fasted state. 

Concomitant administration of a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of VYNDAQEL with or without food.

Distribution:

Tafamidis is highly protein bound (>99%) in plasma. The apparent steady‑state volume of distribution is 16 liters.

Metabolism:

While there is no explicit evidence of biliary excretion of tafamidis in humans, based on preclinical data, it is suggested that tafamidis is metabolized by glucuronidation and excreted via the bile. This route of metabolism and excretion is likely in humans, as approximately 59% of the total administered dose is recovered in feces mostly as unchanged drug, and approximately 22% recovered in urine mostly as the glucuronide metabolite.

Elimination:

The mean half‑life of tafamidis is approximately 49 hours. The apparent oral clearance of tafamidis is 0.228 L/hr. 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.

Special Populations and Conditions

Ethnic origin: No clinically significant differences in the pharmacokinetics of tafamidis were observed based on race/ethnicity (Caucasian and Japanese).

Pediatrics: Tafamidis has not been studied and is not indicated in this population.

Hepatic Insufficiency: Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and approximately 68% increase of total clearance (0.52 L/h versus 0.31 L/h) of tafamidis meglumine in subjects with moderate hepatic impairment (Child‑Pugh Class B) compared to healthy subjects.  As TTR levels are lower in patients with moderate hepatic impairment than in healthy subjects, the exposure of VYNDAQEL relative to the amount of TTR would be sufficient for stabilization of the TTR tetramer in these patients.

Exposure to VYNDAQEL was similar between subjects with mild hepatic impairment (Child-Pugh Class A) and healthy subjects.

The pharmacokinetics of VYNDAQEL in patients with severe hepatic impairment (Child-Pugh Class C) is unknown.

Renal Insufficiency: VYNDAQEL has not specifically been evaluated in patients with renal impairment.  Limited data are available in patients with severe renal impairment (CrCl ≤30 mL/min).

Store VYNDAQEL at room temperature 15°C to 25°C. Keep out of the reach and sight of children.

There are no special handling instructions for this drug product.

Control #: 258993
OCT 7, 2022