VYNDAQEL 61mg capsule me medication leaflet

Vyndaqel 61 mg soft capsules

Each soft capsule contains 61 mg of micronized 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.

Reddish brown, opaque, oblong (approximately 21 mm) capsule printed with “VYN 61” in white.

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

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

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

The recommended dose is one capsule of Vyndaqel 61 mg (tafamidis) orally once daily (see section5.1).

Vyndaqel 61 mg (tafamidis) corresponds to 80 mg tafamidis meglumine. Tafamidis and tafamidismeglumine 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 ondisease progression could be more evident. Conversely, when amyloid-related cardiac damage is moreadvanced, such as in NYHA Class III, the decision to start or maintain treatment should be taken at thediscretion of a physician knowledgeable in the management of patients with amyloidosis orcardiomyopathy (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 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 has not been studied in patients with severe hepatic impairment andcaution 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 tafamidis andcontinue to use appropriate contraception for 1-month after stopping treatment with tafamidis (seesection 4.6).

Tafamidis should be added to the standard of care for the treatment of patients with transthyretinamyloidosis. 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 dataavailable regarding the use of tafamidis in organ transplantation, tafamidis should be discontinued inpatients 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 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 (breast cancer resistant protein) at the61 mg/day tafamidis dose with IC50=1.16 µM and may cause drug-drug interactions at clinicallyrelevant concentrations with substrates of this transporter (e.g. methotrexate, rosuvastatin, imatinib). Ina clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increasedapproximately 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 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 61 mgdose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to result inclinically significant interactions.

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

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 TTR due to the highbinding affinity tafamidis has to the TTR thyroxine receptor. No corresponding clinical findingsconsistent with thyroid dysfunction have been observed.

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

There are no data on the use of tafamidis in pregnant women. Studies in animals have showndevelopmental toxicity (see section 5.3). Tafamidis is not recommended during pregnancy and inwomen 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 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 is believed to have no ornegligible influence on the ability to drive or use machines.

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 patientsdiagnosed with ATTR-CM (see section 5.1).

The frequency of adverse events in patients treated with 80 mg tafamidis meglumine was generallysimilar and comparable to placebo.

The following adverse events were reported more often in patients treated with tafamidis meglumine80 mg compared to placebo: flatulence [8 patients (4.5%) versus 3 patients (1.7%)] and liver functiontest increased [6 patients (3.4%) versus 2 patients (1.1%)]. A causal relationship has not beenestablished.

Safety data for tafamidis 61 mg are available from its open-label long-term extension study.

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 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 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 with

ATTR-CM accidentally ingested a single tafamidis meglumine dose of 160 mg without the occurrenceof any associated adverse events. The highest dose of tafamidis meglumine given to healthy volunteersin a clinical trial was 480 mg as a single dose. There was one reported treatment-related adverse eventof 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 in ATTR-CM 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.

In a multicentre, international, double-blind, placebo-controlled, randomised study (see Clinicalefficacy and safety section), TTR stabilisation was observed at Month 1 and was maintained through

Month 30.

Biomarkers associated with heart failure (NT-proBNP and Troponin I) favoured Vyndaqel overplacebo.

Efficacy was demonstrated in a multicentre, international, double-blind, placebo-controlled,randomised 3-arm study in 441 patients with wild-type or hereditary ATTR-CM.

Patients were randomised to either tafamidis meglumine 20 mg (n=88) or 80 mg [administered asfour 20 mg tafamidis meglumine capsules] (n=176) or matching placebo (n=177) once daily, inaddition to standard of care (e.g. diuretics) for 30 months. Treatment assignment was stratified by thepresence or absence of a variant TTR genotype as well as by baseline severity of disease (NYHA

Class). Table 1 describes the patient demographics and baseline characteristics.

Table 1: Patient demographics and baseline characteristics

Characteristic Pooled Tafamidis Placebo

N=264 N=177

Age — year

Mean (standard deviation) 74.5 (7.2) 74.1 (6.7)

Median (minimum, maximum) 75 (46, 88) 74 (51, 89)

Sex — number (%)

Male 241 (91.3) 157 (88.7)

Female 23 (8.7) 20 (11.3)

TTR genotype — number (%)

ATTRm 63 (23.9) 43 (24.3)

ATTRwt 201 (76.1) 134 (75.7)

NYHA Class — number (%)

NYHA Class I 24 (9.1) 13 (7.3)

NYHA Class II 162 (61.4) 101 (57.1)

NYHA Class III 78 (29.5) 63 (35.6)

Abbreviations: ATTRm=variant transthyretin amyloid, ATTRwt=wild-type transthyretin amyloid, NYHA=New York Heart Association.

The primary analysis used a hierarchical combination applying the method of Finkelstein-Schoenfeld(F-S) to all-cause mortality and frequency of cardiovascular-related hospitalisations, which is definedas the number of times a subject is hospitalised (i.e., admitted to a hospital) for cardiovascular-relatedmorbidity. The method compared each patient to every other patient within each stratum in a pair-wisemanner that proceeds in a hierarchical fashion using all-cause mortality followed by frequency ofcardiovascular-related hospitalisations when patients cannot be differentiated based on mortality.

This analysis demonstrated a significant reduction (p=0.0006) in all-cause mortality and frequency ofcardiovascular-related hospitalisations in the pooled tafamidis 20 mg and 80 mg dose group versusplacebo (Table 2).

Table 2: Primary analysis using Finkelstein-Schoenfeld (F-S) Method of all-cause mortality andfrequency of cardiovascular-related hospitalisations

Primary analysis Pooled Tafamidis Placebo

N=264 N=177

Number (%) of subjects alive* at month 30 186 (70.5) 101 (57.1)

Average cardiovascular-related hospitalisations during 0.297 0.45530 months (per patient per year) among those alive atmonth 30†p-value from F-S Method 0.0006

* Heart transplantation and cardiac mechanical assist device implantation are considered indicators of approaching end stage. As such, thesesubjects are treated in the analysis as equivalent to death. Therefore, such subjects are not included in the count of “Number of Subjects Aliveat Month 30” even if such subjects are alive based on 30 month vital status follow-up assessment.† Descriptive mean among those who survived the 30 months.

Analysis of the individual components of the primary analysis (all-cause mortality andcardiovascular-related hospitalisation) also demonstrated significant reductions for tafamidis versusplacebo.

The hazard ratio from the all-cause mortality Cox-proportional hazard model for pooled tafamidis was0.698 (95% CI 0.508, 0.958), indicating a 30.2% reduction in the risk of death relative to the placebogroup (p=0.0259). A Kaplan-Meier plot of time to event all-cause mortality is presented in Figure 1.

Figure 1: All-cause mortality*

* Heart transplants and cardiac mechanical assist devices treated as death. Hazard ratio from Cox-proportional hazards model with treatment,

TTR genotype (variant and wild-type), and New York Heart Association (NYHA) Baseline classification (NYHA Classes I and II combinedand NYHA Class III) as factors.

There were significantly fewer cardiovascular-related hospitalisations with tafamidis compared withplacebo with a reduction in risk of 32.4% (Table 3).

Table 3: Cardiovascular-related hospitalisation frequency

Pooled Tafamidis Placebo

N=264 N=177

Total (%) number of subjects with 138 (52.3) 107 (60.5)

Cardiovascular-related hospitalisations

Cardiovascular-related hospitalisations per year* 0.4750 0.7025

Pooled tafamidis versus placebo treatment 0.6761difference (relative risk ratio)*p-value* < 0.0001

Abbreviation: NYHA=New York Heart Association.

* This analysis was based on a Poisson regression model with treatment, TTR genotype (variant and wild-type), New York Heart Association(NYHA) Baseline classification (NYHA Classes I and II combined and NYHA Class III), treatment-by-TTR genotype interaction, andtreatment-by-NYHA Baseline classification interaction terms as factors.

The treatment effect of tafamidis on functional capacity and health status was assessed by the6-Minute Walk Test (6MWT) and the Kansas City Cardiomyopathy Questionnaire-Overall Summary(KCCQ-OS) score (composed of the Total Symptom, Physical Limitation, Quality of Life, and Social

Limitation domains), respectively. A significant treatment effect favouring tafamidis was firstobserved at Month 6 and remained consistent through Month 30 on both the 6MWT distance and

KCCQ-OS score (Table 4).

Table 4: 6MWT and KCCQ-OS and component domain scores

Endpoints Baseline Mean (SD) Change from Baseline to Treatment p-value

Month 30, LS mean (SE) difference

Pooled Placebo Pooled Placebo from placebo

Tafamidis N=177 Tafamidis LS mean

N=264 (95% CI)6MWT* 350.55 353.26 -54.87 -130.55 75.68 p< 0.0001(metres) (121.30) (125.98) (5.07) (9.80) (57.56, 93.80)

KCCQ-OS* 67.27 65.90 -7.16 -20.81 13.65 p< 0.0001(21.36) (21.74) (1.42) (1.97) (9.48, 17.83)

* Higher values indicate better health status.

Abbreviations: 6MWT=6-Minute Walk Test; KCCQ-OS=Kansas City Cardiomyopathy Questionnaire-Overall Summary; LS=least squares;

CI=confidence interval.

Results from F-S method represented by win ratio for the combined endpoint and its components(all-cause mortality and frequency of cardiovascular-related hospitalisation) consistently favouredtafamidis versus placebo by dose and across all subgroups (wild-type, variant and NYHA Class I & II,and III) except for cardiovascular-related hospitalisation frequency in NYHA Class III (Figure 2)which is higher in the tafamidis treated group compared to placebo (see section 4.2). Analyses of6MWT and KCCQ-OS also favoured tafamidis relative to placebo within each subgroup.

Figure 2: Results from F-S Method and components by subgroup and dose

Abbreviations: ATTRm=variant transthyretin amyloid, ATTRwt=wild type transthyretin amyloid, F-S=Finkelstein-Schoenfeld,

CI=Confidence Interval.

* F-S results presented using win ratio (based on all-cause mortality and frequency of cardiovascular hospitalisation). The Win ratio is thenumber of pairs of treated-patient “wins” divided by number of pairs of placebo patient “wins.”

Heart transplants and cardiac mechanical assist devices treated as death.

In applying the F-S method to each dose group individually, tafamidis reduced the combination ofall-cause mortality and frequency of cardiovascular-related hospitalisations for both the 80 mg and20 mg doses compared to placebo (p=0.0030 and p=0.0048, respectively). Results of the primaryanalysis, 6MWT at Month 30 and KCCQ-OS at Month 30 were statistically significant for both thetafamidis meglumine 80 mg and 20 mg doses versus placebo, with similar results for both doses.

Efficacy data for tafamidis 61 mg are not available as this formulation was not evaluated in thedouble-blind, placebo-controlled, randomised phase 3 study. The relative bioavailability of tafamidis61 mg is similar to tafamidis meglumine 80 mg at steady-state (see section 5.2).

A supra-therapeutic, single, 400 mg oral dose of tafamidis meglumine solution in healthy volunteersdemonstrated no 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).

After oral administration of the soft capsule once daily, the maximum peak concentration (Cmax) isachieved within a median time (tmax) of 4 hours for tafamidis 61 mg and 2 hours for tafamidismeglumine 80 mg (4 x 20 mg) after dosing in the fasted state. Concomitant administration of a highfat, high calorie meal altered the rate of absorption, but not the extent of absorption. These resultssupport the administration of tafamidis with or without food.

Tafamidis is highly protein bound (> 99%) in plasma. The apparent steady-state volume of distributionis 18.5 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 is 0.263 L/h and the population mean half-life isapproximately 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.

The relative bioavailability of tafamidis 61 mg is similar to tafamidis meglumine 80 mg atsteady-state. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis.

Pharmacokinetic parameters were similar after single and repeated administration of 20 mg dose oftafamidis meglumine, 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 equal to the human

AUC at steady-state at the clinical dose of 61 mg tafamidis.

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 ≥ 2.1 times the human AUC at steady-state at the clinical dose of61 mg tafamidis.

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 of tafamidis = 0.8 mg/kg/day), a doseapproximately equal to the clinical dose of 61 mg tafamidis.

Gelatine (E 441)

Glycerine (E 422)

Red iron oxide (E 172)

Sorbitan

Mannitol (E 421)

Purified water

Macrogol 400 (E 1521)

Polysorbate 20 (E 432)

Povidone (K-value 90)

Butylated hydroxytoluene (E 321)

Printing ink (Opacode white)

Ethyl alcohol

Isopropyl alcohol

Purified water

Macrogol 400 (E 1521)

Polyvinyl acetate phthalate

Propylene glycol (E 1520)

Titanium dioxide (E 171)

Ammonium hydroxide (E 527) 28%

Not applicable.

2 years

None.

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/1/11/717/003

EU/1/11/717/004

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: http://www.ema.europa.eu.