Special populations : אוכלוסיות מיוחדות

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.

4.3   Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4   Special warnings and precautions for use

Women of childbearing potential should use appropriate contraception when taking tafamidis and continue to use appropriate contraception for 1-month after stopping treatment with tafamidis (see section 4.6).

Tafamidis should be added to the standard of care for the treatment of patients with transthyretin amyloidosis. Physicians should monitor patients and continue to assess the need for other therapy, including the need for organ transplantation, as part of this standard of care. As there are no data available regarding the use of tafamidis in organ transplantation, tafamidis should be discontinued in patients who undergo organ transplantation.

Increase in liver function tests and decrease in thyroxine may occur (see section 4.5 and 4.8).

This medicinal product contains no more than 44 mg sorbitol in each capsule. Sorbitol is a source of fructose.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

4.5   Interaction with other medicinal products and other forms of interaction

In a clinical study in healthy volunteers, 20 mg tafamidis meglumine did not induce or inhibit the cytochrome P450 enzyme CYP3A4.

In vitro tafamidis inhibits the efflux transporter BCRP (breast cancer resistant protein) at the 61 mg/day tafamidis dose 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. Likewise, 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 61 mg dose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to result in clinically significant interactions.

No interaction studies have been performed evaluating the effect of other medicinal products on tafamidis.

Laboratory test abnormality

Tafamidis may decrease serum concentrations of total thyroxine, without an accompanying change in free thyroxine (T4) or thyroid stimulating hormone (TSH). This observation in total thyroxine values may likely be the result of reduced thyroxine binding to or displacement from TTR due to the high binding affinity tafamidis has to the TTR thyroxine receptor. No corresponding clinical findings consistent with thyroid dysfunction have been observed.



4.6    Fertility, pregnancy and lactation

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

Pregnancy

There are no data on the use of tafamidis in pregnant women. Studies in animals have shown developmental toxicity (see section 5.3). Tafamidis is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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

Fertility

No impairment of fertility has been observed in nonclinical studies (see section 5.3).