VYNDAQEL 20mg soft capsules medication leaflet

Vyndaqel 20 mg soft capsules

Each soft capsule contains 20 mg of micronized tafamidis meglumine equivalent to 12.2 mg tafamidis.

Each soft capsule contains no more than 44 mg of sorbitol (E 420).

For the full list of excipients, see section 6.1.

Soft capsule.

Yellow, opaque, oblong (approximately 21 mm) capsule imprinted with “VYN 20” in red.

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

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

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 doseof Vyndaqel should be administered if possible. If no capsule is identified, then no additional dose isnecessary, with resumption of dosing the next day as usual.

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

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 orequal to 30 mL/min). Tafamidis meglumine has not been studied in patients with severe hepaticimpairment and caution is recommended (see section 5.2).

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

Oral use.

The soft capsules should be swallowed whole and not crushed or cut. Vyndaqel may be taken with orwithout food.

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

Women of childbearing potential should use appropriate contraception when taking tafamidismeglumine and continue to use appropriate contraception for 1-month after stopping treatment withtafamidis 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 dataavailable regarding the use of tafamidis meglumine post-liver transplantation, tafamidis meglumineshould 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 bemonitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substratemay be considered (see section 4.5).

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

The additive effect of concomitantly administered products containing sorbitol (or fructose) anddietary 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 othermedicinal products for oral use administered concomitantly.

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

In vitro tafamidis inhibits the efflux transporter BCRP with IC50=1.16 µM and may cause drug-druginteractions 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 multipledaily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate relatedadverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substratemay 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 clinicallyrelevant concentrations with substrates of these transporters (e.g. non-steroidal anti-inflammatorydrugs, 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 meglumine20 mg dose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to resultin clinically significant interactions.

No interaction studies have been performed evaluating the effect of other medicinal products ontafamidis meglumine.

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

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

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

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

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

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

The overall clinical data reflect exposure of 127 patients with ATTR-PN to 20 mg of tafamidismeglumine administered daily for an average of 538 days (ranging from 15 to 994 days). The adversereactions were generally mild or moderate in severity.

Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categoriesusing 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 ofdecreasing seriousness. Adverse reactions reported from the clinical programme in the tabular listingbelow 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is minimal clinical experience with overdose. During clinical trials, two patients diagnosed withtransthyretin amyloid cardiomyopathy (ATTR-CM) accidentally ingested a single tafamidismeglumine dose of 160 mg without the occurrence of any associated adverse events. The highest doseof 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.

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

5. PHARMACOLOGIC PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs, ATC code N07XX08

Tafamidis is a selective stabiliser of TTR. Tafamidis binds to TTR at the thyroxine binding sites,stabilising the tetramer and slowing dissociation into monomers, the rate-limiting step in theamyloidogenic process.

Transthyretin amyloidosis is a severely debilitating condition induced by the accumulation of variousinsoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair normalfunction. The dissociation of the transthyretin tetramer to monomers is the rate-limiting step in thepathogenesis of transthyretin amyloidosis. The folded monomers undergo partial denaturation toproduce alternatively folded monomeric amyloidogenic intermediates. These intermediates thenmisassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds withnegative cooperativity to the two thyroxine binding sites on the native tetrameric form of transthyretinpreventing dissociation into monomers. The inhibition of TTR tetramer dissociation forms therationale for the use of tafamidis to slow disease progression in stage 1 ATTR-PN patients.

A TTR stabilisation assay was utilised as a pharmacodynamic marker and assessed the stability of the

TTR tetramer.

Tafamidis stabilised both the wild-type TTR tetramer and the tetramers of 14 TTR variants testedclinically after once-daily dosing with tafamidis. Tafamidis also stabilised the TTR tetramer for25 variants tested ex vivo, thus demonstrating TTR stabilisation of 40 amyloidogenic TTR genotypes.

The pivotal study of tafamidis meglumine in stage 1 ATTR-PN patients was an 18-month, multicentre,randomised, double-blind, placebo-controlled study. The study evaluated the safety and efficacy ofonce-daily 20 mg tafamidis meglumine in 128 patients with ATTR-PN with the Val30Met mutationand primarily stage 1 disease; 126 of the 128 patients did not routinely require assistance withambulation. 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 oflife score [TQOL]). Other outcome measures included composite scores of large nerve fibre (nerveconduction, vibration threshold and heart rate response to deep breathing - HRDB) and small nervefibre function (heat pain and cooling threshold and HRDB) and nutritional assessments utilizing themodified body mass index (mBMI - BMI multiplied by serum albumin in g/L). Eighty-six of the91 patients completing the 18 month treatment period subsequently enrolled in an open-label extensionstudy, where they all received once daily 20 mg tafamidis meglumine for an additional 12 months.

Following 18 months of treatment, more tafamidis meglumine-treated patients were NIS-LL

Responders (change of less than 2 points on NIS-LL) Outcomes for the pre-specified analyses of theprimary endpoints are provided in the following table:

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) 29.5% 45.3%

Difference (Vyndaqel minus Placebo) 15.8%95% CI of Difference (p-value) -0.9%, 32.5% (0.068)

TQOL Change from Baseline LSMean (SE) 7.2 (2.36) 2.0 (2.31)

Difference in LSMeans (SE) -5.2 (3.31)95% CI of Difference (p-value) -11.8, 1.3 (0.116)

Pre-specified Efficacy Evaluable Analysis N=42 N=45

NIS-LL Responders (% Patients) 38.1% 60.0%

Difference (Vyndaqel minus Placebo) 21.9%95% CI of Difference (p-value) 1.4%, 42.4% (0.041)

TQOL Change from Baseline LSMean (SE) 8.9 (3.08) 0.1 (2.98)

Difference in LSMeans (SE) -8.8 (4.32)95% CI of Difference (p-value) -17.4, -0.2 (0.045)

Vyndaqel versus Placebo: NIS-LL and TQOL at Month 18 (Study Fx-005)

Placebo Vyndaqel

Pre-specified ITT Analysis N=61 N=64

In the pre-specified ITT NIS-LL Responder analysis, patients who discontinued prior to the 18-month time point due to livertransplantation were categorized as non-responders. The pre-specified Efficacy Evaluable analysis used observed data for those patientswho completed the 18 month treatment per protocol.

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

Secondary Endpoints Changes from Baseline to Month 18 LSMean (Standard Error)(Intent-to-Treat Population) (Study Fx-005)

Placebo Vyndaqel P-value Vyndaqel % change

N=61 N=64 relative to Placebo

NIS-LL change from BL 5.8 (0.96) 2.8 (0.95) 0.027 -52%

LSMean (SE)

Large Fibre change from BL 3.2 (0.63) 1.5 (0.62) 0.066 -53%

LSMean (SE)

Small Fibre change from BL 1.6 (0.32) 0.3 (0.31) 0.005 -81%

LSMean (SE)mBMI change from BL -33.8 39.3 (11.5) < 0.0001 NA

LSMean (SE) (11.8)mBMI was derived as the product of serum albumin and Body Mass Index.

Based on repeated measures analysis of variance with change from baseline as the dependent variable, an unstructured covariance matrix,treatment, month and treatment-by-month as fixed effects, and subject as a random effect in the model.

NA=not applicable.

In the open-label extension study, the rate of change in the NIS-LL during the 12 months of treatmentwas similar to that observed in those patients randomised and treated with tafamidis in the previousdouble blind 18 month period.

The effects of tafamidis have been assessed in patients with non-Val30Met ATTR-PN in a supportiveopen-label study in 21 patients and a post-marketing observational study in 39 patients. Based on theresults of these studies, the mechanism of action of tafamidis and the results on TTR stabilisation,tafamidis meglumine is expected to be beneficial in patients with stage 1 ATTR-PN due to mutationsother than Val30Met.

The effects of tafamidis have been assessed in a double-blind, placebo-controlled, randomised 3-armstudy in 441 patients with wild-type or hereditary transthyretin amyloid cardiomyopathy (ATTR-CM).

The primary analysis of pooled tafamidis meglumine (20 mg and 80 mg) versus placebo demonstrateda significant reduction (p=0.0006) in all-cause mortality and frequency of cardiovascular-relatedhospitalisations.

A supra-therapeutic, single, 400 mg oral dose of tafamidis solution in healthy volunteers demonstratedno prolongation of the QTc interval.

The European Medicines Agency has waived the obligation to submit the results of studies withtafamidis in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 forinformation on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

After oral administration of the soft capsule once daily, the maximum peak concentration (Cmax) isachieved within a median time (tmax) of 4 hours after dosing in the fasted state. Concomitantadministration of a high fat, high calorie meal altered the rate of absorption, but not the extent ofabsorption. These results support the administration of tafamidis with or without food.

Tafamidis is highly protein bound (> 99%) in plasma. The apparent steady-state volume of distributionis 16 litres.

The extent of tafamidis binding to plasma proteins has been evaluated using animal and humanplasma. The affinity of tafamidis for TTR is greater than that for albumin. Therefore, in plasma,tafamidis is likely to bind preferentially to TTR despite the significantly higher concentration ofalbumin (600 μM) relative to TTR (3.6 μM).

There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, itis suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route ofbiotransformation is plausible in humans, as approximately 59% of the total administered dose isrecovered in faeces, and approximately 22% recovered in urine. Based on population pharmacokineticresults, the apparent oral clearance of tafamidis meglumine is 0.228 L/h and the population meanhalf-life is approximately 49 hours.

Exposure from once-daily dosing with tafamidis meglumine increased with increasing dose up to480 mg single dose and multiple doses up to 80 mg/day. In general, increases were proportional ornear proportional to dose and tafamidis clearance was stationary over time.

Pharmacokinetic parameters were similar after single and repeated administration of 20 mg tafamidismeglumine, indicating a lack of induction or inhibition of tafamidis metabolism.

Results of once-daily dosing with 15 mg to 60 mg oral solution tafamidis meglumine for 14 daysdemonstrated that steady-state was achieved by Day 14.

Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and increased totalclearance (0.52 L/h versus 0.31 L/h) of tafamidis meglumine in patients with moderate hepaticimpairment (Child-Pugh Score of 7-9 inclusive) compared to healthy subjects due to a higher unboundfraction of tafamidis. As patients with moderate hepatic impairment have lower TTR levels thanhealthy subjects, dosage adjustment is not necessary as the stoichiometry of tafamidis with its targetprotein TTR would be sufficient for stabilisation of the TTR tetramer. The exposure to tafamidis inpatients with severe hepatic impairment is unknown.

Tafamidis has not specifically been evaluated in a dedicated study of patients with renal impairment.

The influence of creatinine clearance on tafamidis pharmacokinetics was evaluated in a populationpharmacokinetic analysis in patients with creatinine clearance greater than 18 mL/min.

Pharmacokinetic estimates indicated no difference in apparent oral clearance of tafamidis in patientswith creatinine clearance less than 80 mL/min compared to those with creatinine clearance greater thanor equal to 80 mL/min. Dosage adjustment in patients with renal impairment is considered notnecessary.

Based on population pharmacokinetic results, subjects ≥ 65 years had an average 15% lower estimateof apparent oral clearance at steady-state compared to subjects less than 65 years old. However, thedifference in clearance results in < 20% increases in mean Cmax and AUC compared to youngersubjects and is not clinically significant.

In vitro data indicated that tafamidis does not significantly inhibit cytochrome P450 enzymes

CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Tafamidis isnot expected to cause clinically relevant drug interaction due to induction of CYP1A2, CYP2B6 or

In vitro studies suggest that it is unlikely tafamidis will cause drug interactions at clinically relevantconcentrations with substrates of UDP glucuronosyltransferase (UGT) systemically. Tafamidis mayinhibit intestinal activities of UGT1A1.

Tafamidis showed a low potential to inhibit Multi-Drug Resistant Protein (MDR1) (also known as

P-glycoprotein; P-gp) systemically and in the gastrointestinal (GI) tract, organic cation transporter 2(OCT2), multidrug and toxin extrusion transporter 1 (MATE1) and MATE2K, organic aniontransporting polypeptide 1B1 (OATP1B1) and OATP1B3 at clinically relevant concentrations.

Nonclinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, fertility and early embryonic development, genotoxicity and carcinogenic potential. Inrepeat-dose toxicity and the carcinogenicity studies, the liver appeared as a target organ for toxicity inthe different species tested. Liver effects were seen at exposures approximately ≥ 2.5-times the human

AUC at steady-state at the clinical dose of 20 mg tafamidis meglumine.

In a developmental toxicity study in rabbits, a slight increase in skeletal malformations and variations,abortions in few females, reduced embryo-foetal survival, and reduction in foetal weights wereobserved at exposures approximately ≥ 7.2 times the human AUC at steady-state at the clinical dose of20 mg tafamidis meglumine.

In the rat pre- and postnatal development study with tafamidis, decreased pup survival and reducedpup weights were noted following maternal dose administration during pregnancy and lactation atdoses of 15 and 30 mg/kg/day. Decreased pup weights in males were associated with delayed sexualmaturation (preputial separation) at 15 mg/kg/day. Impaired performance in a water-maze test forlearning and memory was observed at 15 mg/kg/day. The NOAEL for viability and growth in the F1generation offspring following maternal dose administration during pregnancy and lactation withtafamidis was 5 mg/kg/day (human equivalent dose = 0.8 mg/kg/day), a dose approximately 4.6 timesthe clinical dose of 20 mg tafamidis meglumine.

Gelatine (E 441)

Glycerine (E 422)

Yellow iron oxide (E 172)

Sorbitan

Mannitol (E 421)

Titanium dioxide (E 171)

Purified water

Macrogol 400 (E 1521)

Sorbitan monooleate (E 494)

Polysorbate 80 (E 433)

Ethyl alcohol

Isopropyl alcohol

Purified water

Macrogol 400 (E 1521)

Polyvinyl acetate phthalate

Propylene glycol (E 1520)

Carmine (E 120)

Brilliant Blue FCF (E 133)

Ammonium hydroxide (E 527) 28%

Not applicable.

2 years

Do not store above 25°C.

PVC/PA/alu/PVC-alu perforated unit dose blisters.

Pack sizes: a pack of 30 x 1 soft capsules and a multipack containing 90 (3 packs of 30 x 1) softcapsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/11/717/001

EU/1/11/717/002

Date of first authorisation: 16 November 2011

Date of latest renewal: 22 July 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: https://www.ema.europa.eu.