ESBRIET 267mg tablets medication leaflet

Esbriet 267 mg film-coated tablets

Esbriet 534 mg film-coated tablets

Esbriet 801 mg film-coated tablets

Each film-coated tablet contains 267 mg pirfenidone.

Each film-coated tablet contains 534 mg pirfenidone.

Each film-coated tablet contains 801 mg pirfenidone.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Esbriet 267 mg film-coated tablets are yellow, oval, approximately 1.3 x 0.6. cm biconvex film-coatedtablets, debossed with “PFD”.

Esbriet 534 mg film-coated tablets are orange, oval, approximately 1.6 x 0.8 cm biconvex film-coatedtablets, debossed with “PFD”.

Esbriet 801 mg film-coated tablets are brown, oval, approximately 2 x 0.9 cm biconvex film-coatedtablets, debossed with “PFD”.

Esbriet is indicated in adults for the treatment of idiopathic pulmonary fibrosis (IPF).

Treatment with Esbriet should be initiated and supervised by specialist physicians experienced in thediagnosis and treatment of IPF.

Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/dayover a 14-day period as follows:

● Days 1 to 7: a dose of 267 mg administered three times a day (801 mg/day)● Days 8 to 14: a dose of 534 mg administered three times a day (1602 mg/day)● Day 15 onward: a dose of 801 mg administered three times a day (2403 mg/day)

The recommended maintenance daily dose of Esbriet is 801 mg three times a day with food for a totalof 2403 mg/day.

Doses above 2403 mg/day are not recommended for any patient (see section 4.9).

Patients who miss 14 consecutive days or more of Esbriet treatment should re-initiate therapy byundergoing the initial 2-week titration regimen up to the recommended daily dose.

For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previousrecommended daily dose without titration.

Dose adjustments and other considerations for safe use

Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinalundesirable effects, patients should be reminded to take the medicinal product with food. If symptomspersist, the dose of pirfenidone may be reduced to 267 mg - 534 mg, two to three times a day withfood with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patientsmay be instructed to interrupt treatment for one to two weeks to allow symptoms to resolve.

Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivityreaction or rash should be reminded to use a sunblock daily and avoid exposure to the sun (see section4.4). The dose of pirfenidone may be reduced to 801 mg each day (267 mg three times a day). If therash persists after 7 days, Esbriet should be discontinued for 15 days, with re-escalation to therecommended daily dose in the same manner as the dose escalation period.

Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt thedose and to seek medical advice (see section 4.4). Once the rash has resolved, Esbriet may bere-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.

Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases(ALT/AST) with or without bilirubin elevation, the dose of pirfenidone should be adjusted ortreatment discontinued according to the guidelines listed in section 4.4.

No dose adjustment is necessary in patients 65 years and older (see section 5.2).

No dose adjustment is necessary in patients with mild to moderate hepatic impairment (i.e. Child-Pugh

Class A and B). However, since plasma levels of pirfenidone may be increased in some individualswith mild to moderate hepatic impairment, caution should be used with Esbriet treatment in thispopulation. Esbriet therapy should not be used in patients with severe hepatic impairment or end stageliver disease (see section pct. 4.3, pct. 4.4 and 5.2).

No dose adjustment is necessary in patients with mild renal impairment. Esbriet should be used withcaution in patients with moderate (CrCl 30-50 ml/min) renal impairment. Esbriet therapy should notbe used in patients with severe renal impairment (CrCl <30 ml/min) or end stage renal diseaserequiring dialysis (see sections 4.3 and 5.2).

There is no relevant use of Esbriet in the paediatric population for the indication of IPF.

Esbriet is for oral use. The tablets are to be swallowed whole with water and taken with food to reducethe possibility of nausea and dizziness (see sections 4.8 and 5.2).

● Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.● History of angioedema with pirfenidone (see section 4.4).● Concomitant use of fluvoxamine (see section 4.5).● Severe hepatic impairment or end stage liver disease (see sections 4.2 and 4.4).● Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (seesections 4.2 and 5.2).

Hepatic function

Elevated transaminases have been commonly reported in patients treated with Esbriet. Liver functiontests (ALT, AST and bilirubin) should be performed prior to the initiation of treatment with Esbriet,and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter (seesection 4.8).

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN without bilirubin elevation andwithout symptoms or signs of drug-induced liver injury after starting Esbriet therapy, other causesshould be excluded, and the patient monitored closely. Discontinuation of other medicines associatedwith liver toxicity should be considered. If clinically appropriate, the dose of Esbriet should bereduced or interrupted. Once liver function tests are within normal limits Esbriet may be re-escalatedto the recommended daily dose if tolerated.

Drug-induced liver injury

Uncommonly, elevations in AST and ALT were associated with concomitant bilirubin increases.

Cases of severe drug-induced liver injury, including isolated cases with fatal outcome, have beenreported post-marketing (see section 4.8).

In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluationand measurement of liver function tests should be performed in patients who report symptoms thatmay indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, orjaundice.

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN accompanied byhyperbilirubinaemia or clinical signs or symptoms indicative of liver injury, Esbriet should bepermanently discontinued and the patient should not be rechallenged.

If a patient exhibits an aminotransferase elevation to ≥5 x ULN, Esbriet should be permanentlydiscontinued and the patient should not be rechallenged.

In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure wasincreased by 60%. Esbriet should be used with caution in patients with pre-existing mild to moderatehepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased pirfenidoneexposure. Patients should be monitored closely for signs of toxicity especially if they areconcomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not beenstudied in individuals with severe hepatic impairment and Esbriet must not be used in patients withsevere hepatic impairment (see section 4.3).

Photosensitivity reaction and rash

Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatmentwith Esbriet. Patients should be instructed to use a sunblock daily, to wear clothing that protectsagainst sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patientsshould be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severephotosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuationmay be necessary in mild to severe cases of photosensitivity reaction or rash (see section 4.2).

Severe skin reactions

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction witheosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have beenreported post-marketing in association with Esbriet treatment. If signs and symptoms suggestive ofthese reactions appear, Esbriet should be withdrawn immediately. If the patient has developed SJS,

TEN or DRESS with the use of Esbriet, treatment with Esbriet must not be restarted and should bepermanently discontinued.

Angioedema/Anaphylaxis

Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may beassociated with difficulty breathing or wheezing have been received in association with use of Esbrietin the post-marketing setting. Reports of anaphylactic reactions have also been received. Therefore,patients who develop signs or symptoms of angioedema or severe allergic reactions followingadministration of Esbriet should immediately discontinue treatment. Patients with angioedema orsevere allergic reactions should be managed according to standard of care. Esbriet must not be used inpatients with a history of angioedema or hypersensitivity due to Esbriet (see section 4.3).

Dizziness

Dizziness has been reported in patients taking Esbriet. Therefore, patients should know how they reactto this medicinal product before they engage in activities requiring mental alertness or coordination(see section 4.7). In clinical studies, most patients who experienced dizziness had a single event, andmost events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsensin severity, dose adjustment or even discontinuation of Esbriet may be warranted.

Fatigue has been reported in patients taking Esbriet. Therefore, patients should know how they react tothis medicinal product before they engage in activities requiring mental alertness or coordination (seesection 4.7).

Weight loss

Weight loss has been reported in patients treated with Esbriet (see section 4.8). Physicians shouldmonitor patient’s weight, and when appropriate encourage increased caloric intake if weight loss isconsidered to be of clinical significance.

Hyponatraemia

Hyponatraemia has been reported in patients treated with Esbriet (see section 4.8). As the symptomsof hyponatraemia may be subtle and masked by the presence of concomitant morbidities, regularmonitoring of the relevant laboratory parameters is recommended, especially in the presence ofevocative signs and symptoms such as nausea, headache or dizziness.

Esbriet contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions fromother CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1.

Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoidedduring treatment with pirfenidone.

Fluvoxamine and inhibitors of CYP1A2

In a Phase 1 study, the co-administration of Esbriet and fluvoxamine (a strong inhibitor of CYP1A2with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-foldincrease in exposure to pirfenidone in non-smokers.

Esbriet is contraindicated in patients with concomitant use of fluvoxamine (see section 4.3).

Fluvoxamine should be discontinued prior to the initiation of Esbriet therapy and avoided during

Esbriet therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both

CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone(e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment.

In vitro and in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g.enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. Ifconcomitant use of Esbriet with a strong and selective inhibitor of CYP1A2 cannot be avoided, thedose of pirfenidone should be reduced to 801 mg daily (267 mg, three times a day). Patients should beclosely monitored for emergence of adverse reactions associated with Esbriet therapy. Discontinue

Esbriet if necessary (see sections 4.2 and 4.4).

Co-administration of Esbriet and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increasedthe exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg two times a day cannot beavoided, the dose of pirfenidone should be reduced to 1602 mg daily (534 mg, three times a day).

Esbriet should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once ortwo times a day.

Esbriet should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g.amiodarone, propafenone).

Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potentinhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as

CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine,paroxetine).

Cigarette smoking and inducers of CYP1A2

A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on thepharmacokinetics of pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed innon-smokers. Smoking has the potential to induce hepatic enzyme production and thus increasemedicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2including smoking should be avoided during Esbriet therapy based on the observed relationshipbetween cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged todiscontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment withpirfenidone.

In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoreticallyresult in a lowering of pirfenidone plasma levels.

Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other

CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significantlowering of pirfenidone plasma levels. These medicinal products should be avoided wheneverpossible.

There are no data from the use of Esbriet in pregnant women.

In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential foraccumulation of pirfenidone and/or its metabolites in amniotic fluid.

At high doses (≥1,000 mg/kg/day) rats exhibited prolongation of gestation and reduction in foetalviability.

As a precautionary measure, it is preferable to avoid the use of Esbriet during pregnancy.

It is unknown whether pirfenidone or its metabolites are excreted in human milk. Availablepharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milkwith the potential for accumulation of pirfenidone and/or its metabolites in milk (see section 5.3). Arisk to the breastfed infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from Esbriet therapy,taking into account the benefit of breast-feeding for the child and the benefit of Esbriet therapy for themother.

No adverse effects on fertility were observed in preclinical studies (see section 5.3).

Esbriet may cause dizziness and fatigue, which could have a moderate influence on the ability to driveor use machines, therefore patients should exercise caution when driving or operating machinery ifthey experience these symptoms.

The most frequently reported adverse reactions during clinical study experience with Esbriet at a doseof 2,403 mg/day compared to placebo, respectively, were nausea (32.4% versus 12.2%), rash (26.2%versus 7.7%), diarrhoea (18.8% versus 14.4%), fatigue (18.5% versus 10.4%), dyspepsia (16.1%versus 5.0%), decreased appetite (20.7%% versus 8.0%), headache (10.1% versus 7.7%), andphotosensitivity reaction (9.3% versus 1.1%).

The safety of Esbriet has been evaluated in clinical studies including 1,650 volunteers and patients.

More than 170 patients have been investigated in open studies for more than five years and some forup to 10 years.

Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving Esbrietat the recommended dose of 2,403 mg/day in three pooled pivotal Phase 3 studies. Adverse reactionsfrom post-marketing experience are also listed in Table 1. Adverse reactions are listed by System

Organ Class (SOC) and within each frequency grouping [Very common (≥1/10), common (≥1/100 to<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot beestimated from the available data)] the adverse reactions are presented in order of decreasingseriousness.

Table 1 Adverse reactions by SOC and MedDRA frequency

Very Common Upper respiratory tract infection

Common Urinary tract infection

Uncommon Agranulocytosis1

Uncommon Angioedema1

Not known Anaphylaxis1

Very Common Weight decreased; decreased appetite

Uncommon Hyponatraemia1

Very Common Insomnia

Table 1 Adverse reactions by SOC and MedDRA frequency

Very Common Headache; dizziness

Common Somnolence; dysgeusia; lethargy

Common Hot flush

Very Common Dyspnoea; cough

Common Productive cough

Very Common Dyspepsia; nausea; diarrhoea; gastroesophageal reflux disease; vomiting;constipation

Common Abdominal distension; abdominal discomfort; abdominal pain; abdominalpain upper; stomach discomfort; gastritis; flatulence

Common ALT increased; AST increased; gamma glutamyl transferase increased

Uncommon Total serum bilirubin increased in combination with increases of ALT and

AST1; Drug-induced liver injury2

Very Common Rash

Common Photosensitivity reaction; pruritus; erythema; dry skin; rash erythematous;rash macular; rash pruritic

Not Known Stevens-Johnson syndrome1; toxic epidermal necrolysis1; drug reaction witheosinophilia and systemic symptoms (DRESS)1

Very Common Arthralgia

Common Myalgia

Very Common Fatigue

Common Asthenia; non-cardiac chest pain

Injury poisoning and procedural complications

Common Sunburn1. Identified through post-marketing surveillance (see section 4.4)2. Cases of severe drug-induced liver injury, including reports with fatal outcome have been identifiedthrough post-marketing surveillance (see section pct. 4.3, pct. 4.4).

Exposure-adjusted analyses of pooled clinical trials in IPF confirmed that the safety and tolerabilityprofile of Esbriet in IPF patients with advanced disease (n=366) is consistent with that established in

IPF patients with non-advanced disease (n=942).

Decreased appetite

During the pivotal clinical trials, cases of decreased appetite were readily manageable and generallynot associated with significant sequelae. Uncommonly, cases of decreased appetite were associatedwith significant weight loss and required medical intervention.

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 limited clinical experience with overdose. Multiple doses of pirfenidone up to a total dose of4,806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteersover a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with themost frequently reported adverse reactions for pirfenidone.

In the event of a suspected overdose, supportive medical care should be provided including monitoringof vital signs and close observation of the clinical status of the patient.

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX05

The mechanism of action of pirfenidone has not been fully established. However, existing data suggestthat pirfenidone exerts both antifibrotic and anti-inflammatory properties in a variety of in vitrosystems and animal models of pulmonary fibrosis (bleomycin- and transplant-induced fibrosis).

IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release ofpro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta(IL-1β) and pirfenidone has been shown to reduce the accumulation of inflammatory cells in responseto various stimuli.

Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins andcytokines, and the increased biosynthesis and accumulation of extracellular matrix in response tocytokine growth factors such as, transforming growth factor-beta (TGF-β) and platelet-derived growthfactor (PDGF).

The clinical efficacy of Esbriet has been studied in four Phase 3, multicentre, randomised,double-blind, placebo-controlled studies in patients with IPF. Three of the Phase 3 studies (PIPF-004,

PIPF-006, and PIPF-016) were multinational, and one (SP3) was conducted in Japan.

PIPF-004 and PIPF-006 compared treatment with Esbriet 2403 mg/day to placebo. The studies werenearly identical in design, with few exceptions including an intermediate dose group (1,197 mg/day) in

PIPF-004. In both studies, treatment was administered three times daily for a minimum of 72 weeks.

The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted

Forced Vital Capacity (FVC). In the combined PIPF-004 and PIPF-006 population treated with thedose of 2,403 mg/d comprising in total 692 patients, the median baseline percent predicted FVCvalues were 73.9% in the Esbriet group and 72.0% in the placebo group (range: 50-123% and 48-138%, respectively), and the median baseline percent predicted Carbon Monoxide Diffusing Capacity(DLco) 45.1% in the Esbriet group and 45.6% in the placebo group (range: 25-81% and 21-94%,respectively). In PIPF-004, 2.4% in the Esbriet group and 2.1% in the placebo group had percentpredicted FVC below 50% and/or percent predicted DLco below 35% at Baseline. In PIPF-006, 1.0%in the Esbriet group and 1.4% in the placebo group had percent predicted FVC below 50% and/orpercent predicted DLco below 35% at Baseline.

In study PIPF-004, the decline of percent predicted FVC from Baseline at Week 72 of treatment wassignificantly reduced in patients receiving Esbriet (N=174) compared with patients receiving placebo(N=174; p=0.001, rank ANCOVA). Treatment with Esbriet also significantly reduced the decline ofpercent predicted FVC from Baseline at Weeks 24 (p=0.014), 36 (p<0.001), 48 (p<0.001), and60 (p<0.001). At Week 72, a decline from baseline in percent predicted FVC of ≥10% (a thresholdindicative of the risk of mortality in IPF) was seen in 20% of patients receiving Esbriet compared to35% receiving placebo (Table 2).

Table 2 Categorical assessment of change from Baseline to Week 72in percent predicted FVC in study PIPF-004

Pirfenidone2,403 mg/day Placebo(N = 174) (N = 174)

Decline of ≥10% or death or lung transplant 35 (20%) 60 (34%)

Decline of less than 10% 97 (56%) 90 (52%)

No decline (FVC change >0%) 42 (24%) 24 (14%)

Although there was no difference between patients receiving Esbriet compared to placebo in changefrom Baseline to Week 72 of distance walked during a six minute walk test (6MWT) by theprespecified rank ANCOVA, in an ad hoc analysis, 37% of patients receiving Esbriet showed adecline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-004.

In study PIPF-006, treatment with Esbriet (N=171) did not reduce the decline of percent predicted

FVC from Baseline at Week 72 compared with placebo (N=173; p=0.501). However, treatment with

Esbriet reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p<0.001),36 (p=0.011), and 48 (p=0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patientsreceiving Esbriet and 27% receiving placebo (Table 3).

Table 3 Categorical assessment of change from Baseline to Week 72in percent predicted FVC in study PIPF-006

Pirfenidone2,403 mg/day Placebo(N = 171) (N = 173)

Decline of ≥10% or death or lung transplant 39 (23%) 46 (27%)

Decline of less than 10% 88 (52%) 89 (51%)

No decline (FVC change >0%) 44 (26%) 38 (22%)

The decline in 6MWT distance from Baseline to Week 72 was significantly reduced compared withplacebo in study PIPF-006 (p<0.001, rank ANCOVA). Additionally, in an ad hoc analysis, 33% ofpatients receiving Esbriet showed a decline of ≥50 m in 6MWT distance, compared to 47% of patientsreceiving placebo in PIPF-006.

In a pooled analysis of survival in PIPF-004 and PIPF-006 the mortality rate with Esbriet 2403 mg/daygroup was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47-1.28]).

PIPF-016 compared treatment with Esbriet 2,403 mg/day to placebo. Treatment was administeredthree times daily for 52 weeks. The primary endpoint was the change from Baseline to Week 52 inpercent predicted FVC. In a total of 555 patients, the median baseline percent predicted FVC and%DLCO were 68% (range: 48-91%) and 42% (range: 27-170%), respectively. Two percent of patientshad percent predicted FVC below 50% and 21% of patients had a percent predicted DLCO below 35%at Baseline.

In study PIPF-016, the decline of percent predicted FVC from Baseline at Week 52 of treatment wassignificantly reduced in patients receiving Esbriet (N=278) compared with patients receiving placebo(N=277; p<0.000001, rank ANCOVA). Treatment with Esbriet also significantly reduced the declineof percent predicted FVC from Baseline at Weeks 13 (p<0.000001), 26 (p<0.000001), and 39(p=0.000002). At Week 52, a decline from Baseline in percent predicted FVC of ≥10% or death wasseen in 17% of patients receiving Esbriet compared to 32% receiving placebo (Table 4).

Table 4 Categorical assessment of change from Baseline to Week 52in percent predicted FVC in study PIPF-016

Pirfenidone2,403 mg/day Placebo(N = 278) (N = 277)

Decline of ≥10% or death 46 (17%) 88 (32%)

Decline of less than 10% 169 (61%) 162 (58%)

No decline (FVC change >0%) 63 (23%) 27 (10%)

The decline in distance walked during a 6MWT from Baseline to Week 52 was significantly reducedin patients receiving Esbriet compared with patients receiving placebo in PIPF-016 (p=0.036, rank

ANCOVA); 26% of patients receiving Esbriet showed a decline of ≥50 m in 6MWT distancecompared to 36% of patients receiving placebo.

In a pre-specified pooled analysis of studies PIPF-016, PIPF-004, and PIPF-006 at Month 12, all-causemortality was significantly lower in Esbriet 2403 mg/day group (3.5%, 22 of 623 patients) comparedwith placebo (6.7%, 42 of 624 patients), resulting in a 48% reduction in the risk of all-cause mortalitywithin the first 12 months (HR 0.52 [95% CI, 0.31-0.87], p=0.0107, log-rank test).

The study (SP3) in Japanese patients compared pirfenidone 1800 mg/day (comparable to 2403 mg/dayin the US and European populations of PIPF-004/006 on a weight-normalised basis) with placebo(N=110, N=109, respectively). Treatment with pirfenidone significantly reduced mean decline in vitalcapacity (VC) at Week 52 (the primary endpoint) compared with placebo (-0.09±0.02 lversus -0.16±0.02 l respectively, p=0.042).

IPF patients with advanced lung function impairment

In pooled post-hoc analyses of studies PIPF-004, PIPF-006 and PIPF-016, in the population ofadvanced IPF (n = 170) with FVC < 50% at baseline and/or DLco < 35% at baseline, the annualdecline of FVC in patients receiving Esbriet (n=90) compared with patients receiving placebo (n=80)was -150.9 mL and -277.6 mL, respectively.

In MA29957, a supportive 52-week Phase IIb, multicentre, randomised, double-blind, placebo-controlled clinical trial in IPF patients with advanced lung function impairment (DLco < 40% ofpredicted) and at high risk of grade 3 pulmonary hypertension, 89 patients treated with Esbrietmonotherapy had a similar decline in FVC as Esbriet-treated patients in the post-hoc analysis of thepooled phase 3 trials PIPF-004, PIPF-006, and PIPF-016.

The European Medicines Agency has waived the obligation to submit the results of studies with

Esbriet in all subsets of the paediatric population in IPF (see section 4.2 for information on paediatricuse).

Administration of Esbriet capsules with food results in a large reduction in Cmax (by 50%) and asmaller effect on AUC, compared to the fasted state. Following oral administration of a single dose of801 mg to healthy older adult volunteers (50-66 years of age) in the fed state, the rate of pirfenidoneabsorption slowed, while the AUC in the fed state was approximately 80-85% of the AUC observed inthe fasted state. Bioequivalence was demonstrated in the fasted state when comparing the 801 mgtablet to three 267 mg capsules. In the fed state, the 801 mg tablet met bioequivalence criteria based onthe AUC measurements compared to the capsules, while the 90% confidence intervals for Cmax(108.26% - 125.60%) slightly exceeded the upper bound of standard bioequivalence limit (90% CI:80.00% - 125.00%). The effect of food on pirfenidone oral AUC was consistent between the tablet andcapsule formulations. Compared to the fasted state, administration of either formulation with foodreduced pirfenidone Cmax, with Esbriet tablet reducing the Cmax slightly less (by 40%) than Esbrietcapsules (by 50%). A reduced incidence of adverse events (nausea and dizziness) was observed in fedsubjects when compared to the fasted group. Therefore, it is recommended that Esbriet beadministered with food to reduce the incidence of nausea and dizziness.

The absolute bioavailability of pirfenidone has not been determined in humans.

Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean bindingranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 μg/ml). Meanapparent oral steady-state volume of distribution is approximately 70 l, indicating that pirfenidonedistribution to tissues is modest.

Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions fromother CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro data indicate somepharmacologically relevant activity of the major metabolite (5-carboxy-pirfenidone) at concentrationsin excess of peak plasma concentrations in IPF patients. This may become clinically relevant inpatients with moderate renal impairment where plasma exposure to 5-carboxy-pirfenidone is increased

The oral clearance of pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging studyin healthy older adults administered doses ranging from 267 mg to 1,335 mg three times a day, themean clearance decreased by approximately 25% above a dose of 801 mg three times a day. Followingsingle dose administration of pirfenidone in healthy older adults, the mean apparent terminalelimination half-life was approximately 2.4 hours. Approximately 80% of an orally administered doseof pirfenidone is cleared in the urine within 24 hours of dosing. The majority of pirfenidone isexcreted as the 5-carboxy-pirfenidone metabolite (>95% of that recovered), with less than 1% ofpirfenidone excreted unchanged in urine.

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were compared insubjects with moderate hepatic impairment (Child-Pugh Class B) and in subjects with normal hepaticfunction. Results showed that there was a mean increase of 60% in pirfenidone exposure after a singledose of 801 mg pirfenidone (3 x 267 mg capsule) in patients with moderate hepatic impairment.

Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment andpatients should be monitored closely for signs of toxicity especially if they are concomitantly taking aknown CYP1A2 inhibitor (see sections 4.2 and 4.4). Esbriet is contraindicated in severe hepaticimpairment and end stage liver disease (see sections 4.2 and 4.3).

No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjectswith mild to severe renal impairment compared with subjects with normal renal function. The parentsubstance is predominantly metabolised to 5-carboxy-pirfenidone. The mean (SD) AUC0-∞ of 5-carboxy-pirfenidone was significantly higher in the moderate (p = 0.009) and severe (p < 0.0001) renalimpairment groups than in the group with normal renal function; 100 (26.3) mg*h/L and 168(67.4) mg*h/L compared to 28.7 (4.99) mg*h/L respectively.

Renal AUC0-∞ (mg*hr/L)

Impairment Statistics Pirfenidone 5-Carboxy-Pirfenidone

Group

Normal Mean (SD) 42.6 (17.9) 28.7 (4.99)n = 6 Median (25th-75th) 42.0 (33.1-55.6) 30.8 (24.1-32.1)a

Mild Mean (SD) 59.1 (21.5) 49.3 (14.6)n=6 Median (25th-75th) 51.6 (43.7-80.3) 43.0 (38.8-56.8)b

Moderate Mean (SD) 63.5 (19.5) 100 (26.3)n = 6 Median (25th-75th) 66.7 (47.7-76.7) 96.3 (75.2-123)c

Severe Mean (SD) 46.7 (10.9) 168 (67.4)n = 6 Median (25th-75th) 49.4 (40.7-55.8) 150 (123-248)

AUC0-∞ = area under the concentration-time curve from time zero to infinity.a p-value versus Normal = 1.00 (pair-wise comparison with Bonferroni)b p-value versus Normal = 0.009 (pair-wise comparison with Bonferroni)c p-value versus Normal < 0.0001 (pair-wise comparison with Bonferroni)

Exposure to 5-carboxy-pirfenidone increases 3.5-fold or more in patients with moderate renalimpairment. Clinically relevant pharmacodynamic activity of the metabolite in patients with moderaterenal impairment cannot be excluded. No dose adjustment is required in patients with mild renalimpairment who are receiving pirfenidone. Pirfenidone should be used with caution in patients withmoderate renal impairment. The use of pirfenidone is contraindicated in patients with severe renalimpairment (CrCl <30ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 4.3).

Population pharmacokinetic analyses from 4 studies in healthy subjects or subjects with renalimpairment and one study in patients with IPF showed no clinically relevant effect of age, gender orbody size on the pharmacokinetics of pirfenidone.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In repeated dose toxicity studies increases in liver weight were observed in mice, rats and dogs; thiswas often accompanied by hepatic centrilobular hypertrophy. Reversibility was observed aftercessation of treatment. An increased incidence of liver tumours was observed in carcinogenicitystudies conducted in rats and mice. These hepatic findings are consistent with an induction of hepaticmicrosomal enzymes, an effect which has not been observed in patients receiving Esbriet. Thesefindings are not considered relevant to humans.

A statistically significant increase in uterine tumours was observed in female rats administered1,500 mg/kg/day, 37 times the human dose of 2,403 mg/day. The results of mechanistic studiesindicate that the occurrence of uterine tumours is probably related to a chronic dopamine-mediated sexhormone imbalance involving a species-specific endocrine mechanism in the rat which is not presentin humans.

Reproductive toxicology studies demonstrated no adverse effects on male and female fertility orpostnatal development of offspring in rats and there was no evidence of teratogenicity in rats(1,000 mg/kg/day) or rabbits (300 mg/kg/day). In animals placental transfer of pirfenidone and/or itsmetabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites inamniotic fluid. At high doses (≥450 mg/kg/day) rats exhibited a prolongation of oestrous cycle and ahigh incidence of irregular cycles. At high doses (≥1,000 mg/kg/day) rats exhibited a prolongation ofgestation and reduction in fetal viability. Studies in lactating rats indicate that pirfenidone and/or itsmetabolites are excreted in milk with the potential for accumulation of pirfenidone and/or itsmetabolites in milk.

Pirfenidone showed no indication of mutagenic or genotoxic activity in a standard battery of tests andwhen tested under UV exposure was not mutagenic. When tested under UV exposure pirfenidone waspositive in a photoclastogenic assay in Chinese hamster lung cells.

Phototoxicity and irritation were noted in guinea pigs after oral administration of pirfenidone and withexposure to UVA/UVB light. The severity of phototoxic lesions was minimised by application ofsunscreen.

Microcrystalline cellulose

Croscarmellose sodium

Povidone K30

Colloidal anhydrous silica

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc267 mg tablet

Iron oxide yellow (E172)534 mg tablet

Iron oxide yellow (E172)

Iron oxide red (E172)801 mg tablet

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

267 mg tablet and 801 mg tablet3 years for blisters.4 years for bottles.

534 mg tablet2 years.

This medicinal product does not require any special storage conditions.

High-Density Polyethylene (HDPE) bottle with a child-resistant and tamper-evident screw cap

Pack sizes267 mg film-coated tablets1 bottle containing 90 film-coated tablets2 bottles each containing 90 film-coated tablets (180 film-coated tablets in total)534 mg film-coated tablets1 bottle containing 21 film-coated tablets1 bottle containing 90 film-coated tablets801 mg film-coated tablets1 bottle containing 90 film-coated tablets

PVC/Aclar (PCTFE) aluminium foil blister

Pack sizes267 mg film-coated tablets1 blister containing 21 film-coated tablets (21 in total)2 blisters each containing 21 film-coated tablets (42 in total)4 blisters each containing 21 film-coated tablets (84 in total)8 blisters each containing 21 Film-coated tablets (168 in total)2-week treatment initiation pack: multipack containing 63 (1 pack containing 1 blister of 21 and 1pack containing 2 blisters of 21) film-coated tablets

Continuation pack: multipack containing 252 (3 packs each containing 4 blisters of 21) film-coatedtablets801 mg film-coated tablets4 blisters each containing 21 film-coated tablets (84 in total)

Continuation pack: multipack containing 252 (3 packs each containing 4 blisters of 21) film-coatedtablets

Not all pack sizes may be marketed.

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/11/667/007

EU/1/11/667/008

EU/1/11/667/009

EU/1/11/667/010

EU/1/11/667/011

EU/1/11/667/012

EU/1/11/667/013

EU/1/11/667/014

EU/1/11/667/015

EU/1/11/667/016

EU/1/11/667/017

EU/1/11/667/018

EU/1/11/667/019

Date of first authorisation: 28 February 2011

Date of latest renewal: 08 September 2015

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

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