MAH transfer to Roche Registration GmbH

Removal of Black Triangle:

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

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10.    Date of Revision of the Text

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08 February 2018

4.2       Posology and method of administration

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Renal impairment 

No dose adjustment is necessary in patients with mild to moderate renal impairment.  Esbriet should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal impairment.   Esbriet therapy should not be used in patients with severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (see sections 4.3 and 5.2). 

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4.3     Contraindications

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●          Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (see             sections 4.2 and 5.2 4.4).

4.8       Undesirable effects

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

5.2     Pharmacokinetic properties

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Biotransformation

Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro and in vivo studies to datae have not detected any indicate some pharmacologically relevant activity of the major metabolite (5‑carboxy-pirfenidone), even at concentrations or doses greatly above those associated with activity of pirfenidone itself in excess of peak plasma concentrations in IPF patients. This may become clinically relevant in patients with moderate renal impairment where plasma exposure to 5‑carboxy-pirfenidone is increased.

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Renal impairment

No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjects with mild to severe renal impairment compared with subjects with normal renal function. The parent substance 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) renal impairment groups than in the group with normal renal function, and the pharmacokinetics of this metabolite is altered in subjects with moderate to severe renal impairment. ; 100 (26.3) mg•h/L and 168 (67.4) mg•h/L compared to 28.7 (4.99) mg•h/L respectively.

AUC_0-∞  = 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) AUC0-∞ = area under the concentration-time curve from time zero to infinity

However, the predicted amount of metabolite accumulation at steady state is not pharmacodynamically important because the terminal elimination half‑life is only 1–2 hours in these subjectsExposure to 5-carboxy-pirfenidone increases 3.5 fold or more in patients with moderate renal impairment. Clinically relevant pharmacodynamic activity of the metabolite in patients with moderate renal impairment cannot be excluded. No dose adjustment is required in patients with mild to moderate renal impairment who are receiving pirfenidone.  Pirfenidone should be used with caution in patients with moderate renal impairment.  The use of pirfenidone is contraindicated in patients with severe renal impairment (CrCl <30ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 4.3).

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10.       DATE OF REVISION OF THE TEXT

08 December 2017

4.2       Posology and method of administration

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The recommended maintenance daily dose of Esbriet for patients with IPF is three 267 mg capsules three times a day with food for a total of 2403 mg/day.

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

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Dose adjustments and other considerations for safe use

Gastrointestinal events:  In patients who experience intolerance to therapy due to gastrointestinal sideundesirable effects, patients should be reminded to take the medicinal product with food. If symptoms persist Esbriet, the dose of pirfenidone may be reduced to 1‑2 capsules (267 mg – 534 mg) 2‑3two to three times/day with food with re‑escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1one to 2two weeks to allow symptoms to resolve.

Photosensitivity reaction or rash:  Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure to the sun (see section 4.4). The dose of Esbrietpirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Esbriet should be discontinued for 15 days, with re‑escalation to the recommended daily dose in the same manner as the dose escalation period.

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

Special populations

Elderly 

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

Hepatic impairment 

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 individuals with mild to moderate hepatic impairment, caution should be used with Esbriet treatment in this population. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2).  Esbriet hastherapy should not been studiedbe used in patients with severe hepatic impairment or end stage liver disease, and it should not be used in patients with these conditions (see sections (see section 4.3, 4.4 and 5.2). It is recommended to monitor liver function during treatment, and dose adjustments may be necessary in the event of elevations (see sections 4.4 and 5.2).

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Hepatic impairment

In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Esbrietpirfenidone exposure was increased by 60%. Esbriet should be used with caution in patients with pre‑existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Esbrietpirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not been studied in individuals with severe hepatic impairment and Esbriet shouldmust not be used in patients with severe hepatic impairment. (see section 4.3).

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Angioedema

Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of Esbriet in the post-marketing setting. Therefore, patients who develop signs or symptoms of angioedema following administration of Esbriet should immediately discontinue treatment. Patients with angioedema should be managed according to standard of care. Esbriet shouldmust not be used in patients with a history of angioedema due to Esbriet (see section 4.3).

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Weight loss

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

4.5     Interaction with other medicinal products and other forms of interaction

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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.  If concomitant use of Esbriet with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Esbrietpirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely 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) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice dailytwo times a day cannot be avoided, the dose of Esbrietpirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Esbriet should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily.two times a day.

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Cigarette smoking and inducers of CYP1A2

A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Esbrietpirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Esbriet therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone.

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4.6     Fertility, pregnancy and lactation

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Breast‑feeding

It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk (see section 5.3). A risk to the suckling childbreastfed infant cannot be excluded. 

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4.7     Effects on ability to drive and use machines

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

4.8       Undesirable effects

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 for up to 10 years.

Summary of the safety profile

The most commonlyfrequently reported adverse reactions during clinical study experience with Esbriet at a dose of 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%), anorexia (11.4% versus 3.5%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%).

Tabulated list of adverse reactions

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 for up to 10 years.

Serious adverse reactions were recorded at similar frequencies among patients treated with 2,403 mg/day of Esbriet and placebo in clinical studies.

Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving Esbriet at the recommended dose of 2,403 mg/day in three pooled pivotal Phase 3 studies. Adverse reactions from 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)] the adverse reactions are presented in order of decreasing seriousness.

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4.9     Overdose

There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a total dose of 4,806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12‑day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.

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

5.         PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

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5.2     Pharmacokinetic properties

Absorption

Administration of Esbriet capsules with food results in a large reduction in Cmax (by 50%) and a smaller effect on AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to healthy older adult volunteers (50‑66 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80‑85% of the AUC observed in the fasted state. Bioequivalence was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. In the fed state, the 801 mg tablet met bioequivalence criteria based on the 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 and capsule formulations. Compared to the fasted state, administration of either formulation with food reduced pirfenidone Cmax, with Esbriet tablet reducing the Cmax slightly less (by 40%) than Esbriet capsules (by 50%). A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when compared to the fasted group. Therefore, it is recommended that Esbriet be administered with food to reduce the incidence of nausea and dizziness.

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

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5.3     Preclinical safety data

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Environmental Risk Assessment (ERA)

Pirfenidone is not considered to present a potential risk to surface water, microorganisms and ground water or to sediment-dwelling invertebrates.

10.       DATE OF REVISION OF THE TEXT

24 April 2017

3.       PHARMACEUTICAL form

Hard capsule (capsule).

10.       DATE OF REVISION OF THE TEXT

01 August 2016

4.2         Posology and method of administration

[…]

Method of administration

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

4.7     Effects on ability to drive and use machines

No studies on the effects of the ability to drive and use machines have been performed. Esbriet may cause dizziness and fatigue, which could influence the ability to drive or use machines.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 February 2011

Date of latest renewal: 8 September 2015

10.     DATE OF REVISION OF THE TEXT

8 September 2015

3.         PHARMACEUTICAL FORM

Hard capsule (capsule).

Two piece capsules with a white opaque body and white opaque cap imprinted with “InterMune PFD 267 mg” in brown ink and containing a white to pale yellow powder.

10.     DATE OF REVISION OF THE TEXT

14 March 2015