4.1. Therapeutic indications

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

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a physician knowledgeable in the management of patients with transthyretin amyloid polyneuropathy (ATTR-PN).

Posology

The recommended dose of tafamidis meglumine is 20 mg orally once daily.

Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis.

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 meglumine 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 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.

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) 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 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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 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 transthyretin amyloid cardiomyopathy (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.