ESBRIET Film-coated tablet Ref.[9677] Active ingredients: Pirfenidone

Hepatic function

Elevated transaminases have been commonly reported in patients treated with Esbriet. Liver function tests (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 (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 Esbriet 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 Esbriet should be reduced or interrupted. Once liver function tests are within normal limits Esbriet 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, Esbriet should be permanently discontinued and the patient should not be rechallenged.

If a patient exhibits an aminotransferase elevation to ≥5 x ULN, Esbriet 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%. 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 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). Esbriet has not been studied in individuals with severe hepatic impairment and Esbriet 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 minimised during treatment with Esbriet. 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 Esbriet treatment. If signs and symptoms suggestive of these 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 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 Esbriet 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 Esbriet should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Esbriet must not be used in patients 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 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 Esbriet may be warranted.

Fatigue

Fatigue has been reported in patients taking Esbriet. 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 Esbriet (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 Esbriet (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

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 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 Esbriet 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.

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. If concomitant use of Esbriet 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 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 two times a day cannot be avoided, 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 or two 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 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 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.

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.

Pregnancy

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 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 Esbriet 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 Esbriet therapy, taking into account the benefit of breast-feeding for the child and the benefit of Esbriet therapy for the mother.

Fertility

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 drive or use machines, therefore patients should exercise caution when driving or operating machinery if they experience these symptoms.

Summary of the safety profile

The most frequently 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%), 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 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.

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), 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:

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 Esbriet 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 national reporting system listed in Appendix V.

Not applicable.