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.

BRIEF SUMMARY

TAFAMIDIS MEGLUMINE-(May 2019) 

Indn-   To treat heart disease (cardiomyopathy) caused by  transthyretin medicated amyloidsis

ADR-   Diarrhoea, abdominal pain, urinary tract infection, vaginal infectiuon

CI- ­ None. 

Pat Inform-                                                                                                                   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

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  10

 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 [see Use in Specific Populations (8.2)].

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

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.

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.

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.

 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.

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 [see Use in Specific Populations (8.1

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.