4.1. Therapeutic indications

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

4.2. Posology and method of administration

Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF.

Posology

Adults

Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/day over 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 Pirfenidone is 801 mg 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).

Patients who miss 14 consecutive days or more of Pirfenidone treatment should re-initiate therapy by undergoing 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 previous recommended daily dose without titration.

Dose adjustments and other considerations for safe use

Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal undesirable effects, patients should be reminded to take the medicinal product with food. If symptoms persist, the dose of pirfenidone may be reduced to 267 mg – 534 mg, two to three times a day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may 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 photosensitivity reaction or rash should be reminded to use a sunblock daily and avoid exposure to the sun (see section 4.4). The dose of pirfenidone may be reduced to 801 mg each day (267 mg three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period.

Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice (see section 4.4). Once the rash has resolved, Pirfenidone may be re-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 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 Pirfenidone treatment in this population. Pirfenidone therapy should not be used in patients with severe hepatic impairment or end stage liver disease (see section 4.3, 4.4 and 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild renal impairment. Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal impairment. Pirfenidone 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).

Paediatric population

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

Method of administration

Pirfenidone is for oral use. The tablets 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).

4.3. Contraindications

● 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 (see sections 4.2 and 5.2).

4.4. Special warnings and precautions for use

Hepatic function

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

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN without bilirubin elevation and without symptoms or signs of drug-induced liver injury after starting Pirfenidone therapy, other causes should be excluded, and the patient monitored closely. Discontinuation of other medicines associated with liver toxicity should be considered. If clinically appropriate, the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to 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 been reported post-marketing (see section 4.8).

In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

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

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

Hepatic impairment

In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Pirfenidone 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 pirfenidone 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). Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone must not be used in patients with severe hepatic impairment (see section 4.3).

Photosensitivity reaction and rash

Exposure to direct sunlight (including sunlamps) should be avoided or minimized during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may 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 with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with Pirfenidone treatment. If signs and symptoms suggestive of these reactions appear, Pirfenidone should be withdrawn immediately. If the patient has developed SJS, TEN or DRESS with the use of Pirfenidone, treatment with Esbriet must not be restarted and should be permanently discontinued.

Angioedema/Anaphylaxis

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 Pirfenidone in 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 following administration of Pirfenidone should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Pirfenidone must not be used in patients with a history of angioedema or hypersensitivity due to Pirfenidone (see section 4.3).

Dizziness

Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to 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, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.

Fatigue

Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see section 4.7).

Weight loss

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

Hyponatraemia

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

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

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

Fluvoxamine and inhibitors of CYP1A2

In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers.

Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine (see section 4.3). Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone 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. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone should be reduced to 801 mg daily (267 mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary (see sections 4.2 and 4.4).

Co-administration of Pirfenidone 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 two times a day cannot be avoided, the dose of pirfenidone should be reduced to 1602 mg daily (534 mg, three times a day).

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

Pirfenidone 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 potent inhibitors 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 the pharmacokinetics of pirfenidone. 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 Pirfenidone 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.

In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result 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 significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation 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 foetal viability.

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

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 breastfed infant cannot be excluded.

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

Fertility

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

4.7. Effects on ability to drive and use machines

Pirfenidone 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

Summary of the safety profile

The most frequently reported adverse reactions during clinical study experience with Pirfenidone 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%), decreased appetite (20.7%% versus 8.0%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%).

Tabulated list of adverse reactions

The safety of Pirfenidone 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.

Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving Pirfenidone 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), not known (cannot be estimated from the available data)] the adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions by SOC and MedDRA frequency

Infections and infestations

Very Common

Upper respiratory tract infection

Common

Urinary tract infection

Blood and lymphatic system disorders

Uncommon

Agranulocytosis1

Immune system disorders

Uncommon

Angioedema1

Not known

Anaphylaxis1

Metabolism and nutrition disorders

Very Common

Weight decreased; decreased appetite

Uncommon

Hyponatraemia1

Psychiatric disorders

Very Common

Insomnia

Nervous system disorders

Very Common

Headache; dizziness

Common

Somnolence; dysgeusia; lethargy

Vascular disorders

Common

Hot flush

Respiratory, thoracic and mediastinal disorders

Very Common

Dyspnoea; cough

Common

Productive cough

Gastrointestinal disorders

Very Common

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

Common

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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 with eosinophilia and systemic symptoms (DRESS)1

Musculoskeletal and connective tissue disorders

Very Common

Arthralgia

Common

Myalgia

General disorders and administration site conditions

Very Common

Fatigue

Common

Asthenia; non-cardiac chest pain

Injury poisoning and procedural complications

Common

Sunburn

1. Identified through post-marketing surveillance (see section 4.4)

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

Exposure-adjusted analyses of pooled clinical trials in IPF confirmed that the safety and tolerability profile of pirfenidone in IPF patients with advanced disease (n=366) is consistent with that established in IPF patients with non-advanced disease (n=942).

Description of selected adverse reactions

Decreased appetite

During the pivotal clinical trials, cases of decreased appetite were readily manageable and generally not associated with significant sequelae. Uncommonly, cases of decreased appetite were associated with significant weight loss and required medical intervention.

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 via the Yellow Card Scheme at www.mhra.gov.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.