Side Effects of Esbriet (pirfenidone)

Esbriet (pirfenidone) is an anti-inflammatory drug used to prevent and improve lung function in idiopathic pulmonary fibrosis, a type of serious lung disease in which the lung progressively develops scar tissue. 

Scientists believe Esbriet prevents lung damage by inhibiting the production of tissue-destructive chemicals such as

• reactive oxygen species,
• inflammatory chemicals like tumor necrosis factor-alpha (TNF-alpha), and
• pro-inflammatory growth factor-beta (TGF-beta). 

In clinical studies Esbriet was better than placebo in improving lung function; however, it did not improve survival in people with idiopathic pulmonary fibrosis. 

Common side effects of Esbriet include

• rash,
• headache,
• upper respiratory infections,
• diarrhea,
• nausea,
• vomiting,
• indigestion,
• heartburn, and
• stomach pain.

Serious side effects of Esbriet include

• liver problems and
• sensitivity to sunlight.

Drug interactions of Esbriet include strong CYP1A2 enzyme inhibitors such as the following because they may cause significant increases in blood levels of Esbriet:

• fluvoxamine,
• enoxacin, and
• ciprofloxacin. 

Similarly, use of Esbriet should be avoided with strong CYP1A2 inducers, which may decrease blood levels of Esbriet and consequently decrease the effectiveness of treatment. 

No adequate studies of Esbriet in pregnant women exist. Due to the lack of conclusive safety data, Esbriet should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. 

It is unknown if Esbriet is excreted in human milk. As many drugs can enter breast milk and have the potential of causing harm to the nursing infant, Esbriet should be used cautiously while breastfeeding.

Common side effects of pirfenidone include:

• rash,
• headache,
• upper respiratory infections,
• diarrhea,
• nausea,
• vomiting,
• indigestion,
• heartburn, and
• stomach pain.

Pirfenidone may cause liver problems and sensitivity to sunlight.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Liver Enzyme Elevations and Drug-Induced Liver Injury
• Photosensitivity Reaction or Rash
• Gastrointestinal Disorders

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.

• Esbriet was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2403 mg/day of Esbriet and 624 patients received placebo.
• Subjects ages ranged from 40 to 80 years (mean age of 67 years).
• Most patients were male (74%) and Caucasian (95%).
• The mean duration of exposure to Esbriet was 62 weeks (range: 2 to 118 weeks) in these 3 trials.
• At the recommended dosage of 2403 mg/day, 14.6% of patients on Esbriet compared to 9.6% on placebo permanently discontinued treatment because of an adverse event.
• The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.

The most common adverse reactions with an incidence of ≥10% and more frequent in the Esbriet than placebo treatment group are listed in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Esbriet-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3

Adverse reactions occurring in ≥5 to <10% of Esbriet-treated patients and more commonly than placebo are

• photosensitivity reaction (9% vs. 1%),
• decreased appetite (8% vs. 3%),
• pruritus (8% vs. 5%),
• asthenia (6% vs. 4%),
• dysgeusia (6% vs. 2%), and
• non-cardiac chest pain (5% vs. 4%).

Postmarketing Experience

In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post-approval use of pirfenidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and Lymphatic System Disorders

Agranulocytosis

Immune System Disorders

Angioedema

Hepatobiliary Disorders

Drug-induced liver injury

CYP1A2 Inhibitors

Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.

Strong CYP1A2 Inhibitors

The concomitant administration of Esbriet and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to Esbriet.

Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of Esbriet and avoided during Esbriet treatment. In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of Esbriet as needed.

Moderate CYP1A2 Inhibitors

Concomitant administration of Esbriet and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to Esbriet.

If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily.

Concomitant CYP1A2 And Other CYP Inhibitors

Agents or combinations of agents that are moderate or strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of Esbriet (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during Esbriet treatment.

CYP1A2 Inducers

The concomitant use of Esbriet and a CYP1A2 inducer may decrease the exposure of Esbriet and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to Esbriet treatment and avoid the concomitant use of Esbriet and a strong CYP1A2 inducer .