This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Health care professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 20 mg of tafamidis (as meglumine). Excipients: Each soft capsule contains 77.2 mg of sorbitol (E420). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Soft capsule. Off-white to light yellow, opaque, oblong (approximately 21.5 mm) capsule imprinted with "FX 6A" in black ink.

CLINICAL PARTICULARS

Posology and method of administration

Treatment should be initiated by and remain under the supervision of a physician knowledgeable in the management of patients with transthyretin amyloid polyneuropathy.

The recommended dose of Vyndaqel is 20 mg orally once daily. Vyndaqel should be added to the standard of care for the treatment of the transthyretin familial amyloid polyneuropathy (TTR-FAP) patient. 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 Vyndaqel post-liver transplantation, Vyndaqel should be discontinued in patients who undergo liver transplantation.

Data in the elderly patients are very limited. No dosage adjustment is required for elderly patients (>= 65 years).

No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment Tafamidis has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).

The soft capsules should be swallowed whole, not crushed or cut, and taken with or without food. If vomiting occurs shortly after dosing, and 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 Vyndaqel dosing the next day as usual.

Contraindications

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

Special warnings and precautions for use

Women of childbearing potential should use appropriate contraception when taking Vyndaqel (see section 4.6). Vyndaqel contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Interaction with other medicinal products and other forms of interaction

In a clinical study in healthy volunteers, tafamidis did not induce or inhibit CYP3A4 enzyme.

data also indicated that tafamidis does not significantly inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

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

Fertility, pregnancy and lactation

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

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

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

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

Effects on ability to drive and use machines

No studies on the effects of tafamidis on the ability to drive or use machines have been performed.

Undesirable effects

TTR amyloid polyneuropathy is a rare disorder. The overall clinical data reflect exposure of 127 TTR amyloid polyneuropathy patients to 20 mg of tafamidis administered daily for an average of 538 days (ranging from 15 to 994 days). The adverse reactions were generally mild or moderate in severity. 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
	Vaginal infection
Gastrointestinal disorders	Diarrhoea
	Upper abdominal pain

Reportingofsuspectedadversereactions

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

thenationalreportingsystem

listed in Appendix V.

Overdose

No cases of acute overdose have been reported. In clinical trials of healthy volunteers, the highest dose of tafamidis given was 120 mg in a single dose and 60 mg once daily for two weeks. Four treatment- related adverse events were reported at these doses levels in healthy volunteers: headache (mild), somnolence (mild), myalgia (moderate), and insomnia (mild).

PHARMACOLOGIC PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code N07XX08 Mechanismofaction Tafamidis is a novel specific stabilizer of transthyretin.

TTR amyloid polyneuropathy is a multi-faceted, progressive, axonal degenerative neuropathy characterized by sensory, motor and autonomic impairment. The dissociation of the transthyretin tetramer to monomers is the rate limiting step in the pathogenesis of TTR amyloid polyneuropathy, also known as TTR familial amyloid polyneuropathy (TTR-FAP). The folded monomers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates. These intermediates then misassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of transthyretin tetramer dissociation forms the rationale for the use of tafamidis to slow disease progression.

The pivotal study of Vyndaqel was an 18-month, multicenter, randomized, double-blind, placebo- controlled study that evaluated the safety and efficacy of once-daily 20 mg tafamidis in 128 patients with TTR amyloid polyneuropathy with the V30M mutation and primarily stage 1 disease (do not routinely require assistance with ambulation). The primary outcome measures were the Neuropathy Impairment Score of the Lower Limb (NIS-LL - a physician assessment of the neurologic exam of the lower limbs) and the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN - a patient reported outcome, total quality of life score [TQOL]). Other outcome measures included composite scores of large nerve fiber (nerve conduction, vibration threshold and heart rate response to deep breathing - HRDB) and small nerve fiber function (heat pain and cooling threshold and HRDB) and nutritional assessments utilizing the modified body mass index (mBMI - BMI multiplied by serum albumin in g/L). Eighty-six of the 91 patients completing the 18 month treatment period subsequently enrolled in an open label extension study, where they all received once daily 20 mg tafamidis for an additional 12 months. Following 18 months of treatment, more Vyndaqel-treated patients were NIS-LL Responders (change of less than 2 points on NIS-LL) Outcomes for the pre-specified analyses of the primary endpoints are provided in the following table:

The secondary endpoints demonstrated that Vyndaqel treatment resulted in less deterioration of neurologic function and improved nutritional status (mBMI) compared with placebo, as shown in the following table.

In the open-label extension study, the rate of change in the NIS-LL during the 12 months of treatment was similar to that observed in those patients randomised and treated with tafamidis in the previous double blind 18 month period. Although data are limited, (one open label study in 21 patients), taking into account the mechanism of action of tafamidis and the results on TTR stabilisation, Vyndaqel is expected to be beneficial in patients with stage 1 TTR amyloid polyneuropathy due to mutations other than V30M. The effects of tafamidis on cardiac disease progression have not yet been adequately characterised. The European Medicines Agency has waived the obligation to submit the results of studies with Vyndaqel in all subsets of paediatric population in neuropathic heredofamilial amyloid polyneuropathy (see section 4.2 for information on paediatric use). This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Pharmacokinetic properties

After oral administration of the soft capsule, the maximum plasma concentration (Cmax) is achieved at a median time (tmax) of 1.75 hours after dosing in the fasted state. Concomitant administration of food decreased the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.

Tafamidis is highly protein bound (99.9%) in plasma. The apparent steady state volume of distribution is 25.7 liters.

There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Following daily administration of a 20 mg dose of tafamidis for 14 days in healthy subjects, mean steady-state half-life was 59 h and mean total clearance was 0.42 l/h.

Results from once-daily dosing with tafamidis 15, 30, or 60 mg for 14 days demonstrated dose- dependent increases in Cmax and AUC between doses of 15 mg and 30 mg and less than dose proportional between 30 and 60 mg, indicating saturation of absorption process beyond 30 mg. Pharmacokinetic parameters were similar after single and repeated administration of 20 mg dose, indicating a lack of induction or inhibition of tafamidis metabolism. Results of once-daily dosing with tafamidis 20 mg for 14 days demonstrated that steady-state was achieved by Day 14. Cmax(ss) and Cmin(ss) was 2.7 and 1.6 ug/ml, respectively.

Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and increased total clearance (0.52 l/h vs. 0.31l/h) of tafamidis in patients with moderate hepatic impairment (Child-Pugh Score of 7-9 inclusive) compared to healthy subjects due to a higher unbound fraction of tafamidis. As patients with moderate hepatic impairment have lower TTR levels than healthy subjects, dosage adjustment is not necessary as the stoichiometry of tafamidis with its target protein TTR would be sufficient for stabilization of the TTR tetramer. Tafamidis has not specifically been evaluated in patients with renal impairment, but a dosage adjustment in patients with renal impairment is considered not necessary. Based on population PK results, subjects older than 60 years old had an average 19% lower estimate of clearance at steady-state compared to subjects less than 60 years old. However, the difference in clearance would not be clinically significant and would not result in clinically relevant different steady-state levels compared to younger subjects.

Preclinical safety data

Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity. In repeated dose toxicity studies the liver appeared as a target organ for toxicity in the different species tested. Liver effects were seen at doses above (>3) human exposure and have generally been shown to be reversible. There was no evidence of adverse reactions of tafamidis on fertility, reproductive performance or mating behaviour in the rat at any dose level. In a developmental toxicity study in rabbits, a slight increase in skeletal malformations and variations, abortions in few females, and reduction in foetal weights were observed at an AUC0-24 ratio of 3.2-fold, based on the human AUC at steady state. In the rat peri- and post-natal development study with tafamidis, decreased pup survival and reduced pup weights were noted following maternal treatment during pregnancy and lactation at doses of 15 and 30 mg/kg. Decreased foetal weights in males were associated with delayed sexual maturation (preputial separation) and impaired performance in a water-maze test for learning and memory. The NOAEL for viability and growth in the F1 generation offspring following maternal treatment during pregnancy and lactation with tafamidis was 5 mg/kg (HED=0.8 mg/kg), a dose approximately 4.6- times the anticipated clinical human dose.

PHARMACEUTICAL PARTICULARS

List of excipients

Shellac glaze 45% (20% esterified) in ethanol Isopropyl alcohol Iron oxide black (E172) Propylene glycol Ammonium hydroxide 28%

Incompatibilities

Shelf life

Special precautions for storage

Do not store above 25degC. Store in the original container in order to protect from light.

Nature and contents of container

Two polyvinyl chloride/aluminum blisters each containing 15 soft capsules, in a box, giving a total of 30 soft capsules per box.

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

Vyndaqel versus Placebo: NIS-LL and TQOL at Month 18 (Study Fx-005)
	Placebo	Vyndaqel
Pre-specified ITT Analysis	N=61	N=64
NIS-LL Responders (% Patients) Difference (Vyndaqel minus Placebo) 95% CI of Difference (p-value)	29.5%	45.3%
	15.8% -0.9%, 32.5% (0.068)
TQOL Change from Baseline LSMean (SE) Difference in LSMeans (SE) 95% CI of Difference (p-value)	7.2 (2.36)	2.0 (2.31)
	-5.2 (3.31) -11.8, 1.3 (0.116)
Pre-specified Efficacy Evaluable Analysis	N=42		N=45
NIS-LL Responders (% Patients) Difference (Vyndaqel minus Placebo) 95% CI of Difference (p-value)	38.1%		60.0%
	21.9% 1.4%, 42.4% (0.041)
TQOL Change from Baseline LSMean (SE) Difference in LSMeans (SE) 95% CI of Difference (p-value)	8.9 (3.08)		0.1 (2.98)
	-8.8 (4.32) -17.4, -0.2 (0.045)
In the pre-specified ITT NIS-LL Responder analysis, patients who discontinued prior to the 18-month time point due to liver transplantation were categorized as non-responders. The pre-specified Efficacy Evaluable analysis used observed data for those patients who completed the 18 month treatment per protocol.

Secondary Endpoints Changes from Baseline to Month 18 LSMean (Standard Errors) (Observed Cases) (Study Fx-005)
	Placebo	Vyndaqel	P-value	Vyndaqel % change relative to Placebo
NIS-LL change from BL LSMean (SE)	5.8 (0.96)	2.8 (0.95)	0.027	-51%
Large Fiber change from BL LSMean (SE)	3.2 (0.63)	1.5 (0.62)	0.066	-53%
Small Fiber change from BL	1.6 (0.32)	0.3 (0.31)	0.005	-81%
LSMean (SE)
mBMI change from BL LSMean (SE)	-33.8 (11.8)	39.3 (11.5)	<0.001	NA
mBMI was derived as the product of serum albumin and Body Mass Index. NA=Not applicable

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS