Last Updated on eMC 04-05-2017 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:24-04-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

 

Pirfenidone
2,403 mg/day
(N = 174)

Placebo
(N = 174)

Decline of ≥10% or death or lung transplant

35 (20%)

60 (3534%)

Decline of less than 10%

97 (56%)

90 (52%)

No decline (FVC change >0%)

42 (24%)

24 (14%)

 

[ … ]

 

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

 

 

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:01-08-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Underlined text has been added:

3.       PHARMACEUTICAL form

 

Hard capsule (capsule).

 

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

10.       DATE OF REVISION OF THE TEXT

 

01 August 2016

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:08-09-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Underlined text has been added, text with strike-through deleted:

Minor editorial changes throughout and sections:

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

 

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:14-03-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): YES