Tafamidis

Tafamidis inhibits the uptake transporters OAT1 and OAT3 (organic anion transporters) with IC₅₀=2.9 μM and IC₅₀=2.36 μM, respectively, and may cause drug-drug interactions at clinically relevant concentrations with substrates of these transporters (e.g. non-steroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine). Based on in vitro data, the maximal predicted changes in AUC of OAT1 and OAT3 substrates were determined to be less than 1.25 for the tafamidis meglumine 20 mg dose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to result in clinically significant interactions.

In vitro tafamidis inhibits the efflux transporter BCRP (breast cancer resistant protein) with IC₅₀=1.16 μM and may cause drug-drug interactions at clinically relevant concentrations with substrates of this transporter (e.g. methotrexate, rosuvastatin, imatinib). 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.

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

Tafamidis meglumine has not been studied in patients with severe hepatic impairment and caution is recommended.

There are no data on the use of tafamidis meglumine in pregnant women. Studies in animals have shown developmental toxicity. Tafamidis meglumine is not recommended during pregnancy and in women of childbearing potential not using contraception.

Available data in animals have shown excretion of tafamidis in milk. A risk to the newborns/infants cannot be excluded. Tafamidis meglumine should not be used during breast-feeding.

Women of childbearing potential

Contraceptive measures should be used by women of childbearing potential during treatment with tafamidis meglumine, and for one month after stopping treatment, due to the prolonged half-life.

Fertility

No impairment of fertility has been observed in nonclinical studies.

On the basis of the pharmacodynamic and pharmacokinetic profile, tafamidis meglumine is believed to have no or negligible influence on the ability to drive or use machines.

Transthyretin amyloid polyneuropathy (ATTR-PN)

Summary of the safety profile

The overall clinical data reflect exposure of 127 patients with ATTR-PN to 20 mg of tafamidis meglumine administered daily for an average of 538 days (ranging from 15 to 994 days). The adverse reactions were generally mild or moderate in severity.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common (≥1/10), Common (≥1/100 to <1/10), and Uncommon (≥1/1,000 to <1/100). Within the frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme in the tabular listing below reflect the rates at which they occurred in the Phase 3, double-blind, placebo-controlled study (Fx-005).

Transthyretin amyloid cardiomyopathy (ATTR-CM)

Summary of the safety profile

The safety data reflect exposure of 176 patients with ATTR-CM to 80 mg (administered as 4 x 20 mg) of tafamidis meglumine administered daily in a 30-month placebo-controlled trial in patients diagnosed with ATTR-CM.

The frequency of adverse events in patients treated with 80 mg tafamidis meglumine was generally similar and comparable to placebo.

The following adverse events were reported more often in patients treated with tafamidis meglumine 80 mg compared to placebo: flatulence [8 patients (4.5%) versus 3 patients (1.7%)] and liver function test increased [6 patients (3.4%) versus 2 patients (1.1%)]. A causal relationship has not been established.

Safety data for tafamidis 61 mg are available from its open-label long-term extension study.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common (≥1/10), Common (≥1/100 to <1/10), and Uncommon (≥1/1,000 to <1/100). Within the frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions listed in the table below are from cumulative clinical data in ATTR-CM participants.