DRUG INTERACTIONS

1. BCRP Substrates

Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of substrates of this transporter (e.g., methotrexate, rosuvastatin, imatinib) following VYNDAQEL 80 mg or VYNDAMAX 61 mg.

Dose adjustment may be needed for these substrates.

U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-10

 ADVERSE REACTIONS

1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. No specific advere reactions reported

CONTRAINDICATIONS

None. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy

Report pregnancies to the Pfizer reporting line at 1-800-438-1985.

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 

 Lactation

Advise females not to breastfeed during treatment with VYNDAQEL or VYNDAMAX 

Transthyretin Amyloidosis Outcome Survey (THAOS)

Advise all patients prescribed VYNDAQEL or VYNDAMAX of the availability of the Transthyretin Amyloidosis Outcome Survey (THAOS) registry, that their participation is voluntary, and may involve long-term follow-up.

THAOS is an international disease registry designed to assess disease progression, genotype/phenotype relationships, and the impact of interventions, including VYNDAQEL and VYNDAMAX on disease progression.

For information regarding the registry, visit www.thaos.net. This product’s label may have been updated.

For full prescribing information, please visit www.pfizer.com. LAB-0497-0.7 14 Reference ID: 4428838

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 d

 CLINICAL PHARMACOLOGY

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.

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.

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. 

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 is approximately 18.5 liters. 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 is 0.263 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. 

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 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

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

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on findings from animal studies, VYNDAQEL and VYNDAMAX may cause fetal harm when administered to a pregnant woman.

However, limited available human data with VYNDAQEL use in pregnant women (at a dose of 20 mg per day) have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus. 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary 

There are no available data on the presence of tafamidis in human milk, the effect on the breastfed infant, or the effect on milk production. Tafamidis is present in rat milk 

When a drug is present in animal milk, it is likely the drug will be present in human milk.

Based on findings from animal studies which suggest the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with VYNDAQEL or VYNDAMAX.

3. Females and Males of Reproductive Potential

Contraception Females Based on findings from animal studies, VYNDAQEL and VYNDAMAX may cause fetal harm when administered to a pregnant woman 

Consider pregnancy planning and prevention for females of reproductive potential.

4. Pediatric Use

The safety and effectiveness of VYNDAQEL and VYNDAMAX have not been established in pediatric patients.

5. Geriatric Use

No dosage adjustment is required for elderly patients (=65 years)

Of the total number of patients in the clinical study (n=441), 90.5% were 65 and over, with a median age of 75 years.

 OVERDOSAGE

There is minimal clinical experience with overdose. During clinical trials, two patients accidentally ingested a single VYNDAQEL 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. There was one reported adverse event of mild hordeolum at this dose.