Pirfenidone

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).

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.

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).

Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal 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.

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.

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.

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. 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.

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.

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.

The table below 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 the table. 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.

Adverse reactions by SOC and MedDRA frequency:

¹ Identified through post-marketing surveillance.
² Cases of severe drug-induced liver injury, including reports with fatal outcome have been identified through post-marketing surveillance.

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.