4.1. Therapeutic indications

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

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy.

When there is a suspicion in patients presenting with specific medical history or signs of heart failure or cardiomyopathy, etiologic diagnosis must be done by a physician knowledgeable in the management of amyloidosis or cardiomyopathy to confirm ATTR-CM and exclude AL amyloidosis before starting tafamidis, using appropriate assessment tools such as: bone scintigraphy and blood/urine assessment, and/or histological assessment by biopsy, and transthyretin (TTR) genotyping to characterise as wild-type or hereditary.

Posology

The recommended dose is one capsule of Vyndaqel 61 mg (tafamidis) orally once daily (see section 5.1).

Vyndaqel 61 mg (tafamidis) corresponds to 80 mg tafamidis meglumine. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis (see section 5.2).

Vyndaqel should be started as early as possible in the disease course when the clinical benefit on disease progression could be more evident. Conversely, when amyloid-related cardiac damage is more advanced, such as in NYHA Class III, the decision to start or maintain treatment should be taken at the discretion of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy (see section 5.1). There are limited clinical data in patients with NYHA Class IV.

If vomiting occurs after dosing, and the intact Vyndaqel capsule is identified, then an additional dose of Vyndaqel should be administered if possible. If no capsule is identified, then no additional dose is necessary, with resumption of dosing the next day as usual.

Special populations

Elderly

No dosage adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Hepatic and renal impairment

No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment. Limited data are available in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min). Tafamidis has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).

Paediatric population

There is no relevant use of tafamidis in the paediatric population.

Method of administration

Oral use.

The soft capsules should be swallowed whole and not crushed or cut. Vyndaqel may be taken with or without food.

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 Yellow Card Scheme at:www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

There is minimal clinical experience with overdose. During clinical trials, two patients diagnosed with ATTR-CM accidentally ingested a single tafamidis meglumine dose of 160 mg without the occurrence of any associated 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 treatment-related adverse event of mild hordeolum at this dose.

Management

In case of overdose, standard supportive measures should be instituted as required.