Vyndaqel · 4.5 Interaction with other medicinal products and other forms of interaction · 3

HOS-096000 · has-adverse-reaction-information · PDF-Seite 5

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). System Organ Class Very Common Infections and infestations Urinary tract infection Gastrointestinal disorders Diarrhoea Upper abdominal pain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-096012 · has-adverse-reaction-information · PDF-Seite 27

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 (see section 5.1). 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. System Organ Class Common Gastrointestinal disorders Diarrhoea Skin and subcutaneous tissue disorders Rash Pruritus Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 27

HOS-096006 · has-adverse-reaction-information · PDF-Seite 15

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 (see section 5.1). 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. System Organ Class Common Gastrointestinal disorders Diarrhoea Skin and subcutaneous tissue disorders Rash Pruritus Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-096002 · has-contraindication-information · PDF-Seite 13

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096008 · has-contraindication-information · PDF-Seite 25

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-095996 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096001 · has-indication-information · PDF-Seite 12

Vyndaqel is indicated for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

HOS-096007 · has-indication-information · PDF-Seite 24

Vyndaqel is indicated for the treatment of wild-type transthyretin amyloidosis in adult patients with cardiomyopathy (ATTRwt-CM).

HOS-095995 · has-indication-information · PDF-Seite 2

Vyndaqel is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

HOS-095998 · has-interaction-information · PDF-Seite 3

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 with IC50=1.16 µM and may cause drug-drug interactions at clinically relevant concentrations with substrates of this transporter (e.g. methotrexate, rosuvastatin, atorvastatin, apixaban, rivaroxaban, imatinib). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple 3 daily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate related adverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substrate may be considered (see section 4.4). 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 meglumine 20 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 meglumine. 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 transthyretin (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.

HOS-096004 · has-interaction-information · PDF-Seite 14

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 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, atorvastatin, apixaban, rivaroxaban, imatinib). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple daily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate related adverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substrate may be considered (see section 4.4). 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.

HOS-096010 · has-interaction-information · PDF-Seite 26

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 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, atorvastatin, apixaban, rivaroxaban, imatinib). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple daily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate related adverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substrate may be considered (see section 4.4). 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.

HOS-096011 · has-pregnancy-information · PDF-Seite 26

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. 26 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).

HOS-096005 · has-pregnancy-information · PDF-Seite 14

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

HOS-095999 · has-pregnancy-information · PDF-Seite 4

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. Pregnancy There are no data on the use of tafamidis meglumine in pregnant women. Studies in animals have shown developmental toxicity (see section 5.3). Tafamidis meglumine 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 meglumine should not be used during breast-feeding. Fertility No impairment of fertility has been observed in nonclinical studies (see section 5.3).

HOS-096003 · has-warning-information · PDF-Seite 13

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). Co-administration of tafamidis with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5). This medicinal product contains no more than 44 mg sorbitol in each capsule. Sorbitol is a source of fructose. 13 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.

HOS-095997 · has-warning-information · PDF-Seite 3

Women of childbearing potential should use appropriate contraception when taking tafamidis meglumine and continue to use appropriate contraception for 1-month after stopping treatment with tafamidis meglumine (see section 4.6). Tafamidis meglumine should be added to the standard of care for the treatment of patients with ATTR-PN. Physicians should monitor patients and continue to assess the need for other therapy, including the need for liver transplantation, as part of this standard of care. As there are no data available regarding the use of tafamidis meglumine post-liver transplantation, tafamidis meglumine should be discontinued in patients who undergo liver transplantation. Co-administration of tafamidis meglumine with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5). 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.

HOS-096009 · has-warning-information · PDF-Seite 25

Women of childbearing potential should use appropriate contraception when taking tafamidis and continue to use appropriate contraception for one-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). Co-administration of tafamidis with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5). 25 Excipients Lactose monohydrate This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.