pirfenidone (Rx)

>10%

Nausea (36%)

Rash (30%)

Upper respiratory tract infection (27%)

Diarrhea (26%)

Abdominal pain (24%)

Headache (22%)

Dyspepsia (19%)

Dizziness (18%)

Vomiting (13%)

GERD (11%)

Sinusitis (11%)

1-10%

Insomnia (10%)

Weight decreased (10%)

Arthralgia (10%)

Photosensitivity (9%)

Decreased appetite (8%)

Pruritus (8%)

Asthenia (6%)

Dysgeusia (6%)

Noncardiac chest pain (5%)

AST/ALT ≥3 x ULN (3.7%)

<1%

AST/ALT ≥10 x ULN (0.3%)

Postmarketing Reports

Blood and lymphatic system disorders: Agranulocytosis

Immune system disorders: Angioedema

Hepatobiliary disorders: Bilirubin increased in combination with increases of ALT and AST

Contraindications

None

Cautions

Conduct liver function tests (ALT, AST, and bilirubin) before initiating, monthly for 6 months, and then q3months thereafter and,as clinically indicated; dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevation (see Dosage Modifications)

Photosensitivity and rash reported; avoid exposure to sunlight and sunlamps and wear protective clothing daily; temporary dosage reductions or discontinuations may be required

Nausea, vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain reported; temporary dosage reductions or discontinuations may be required

Pirfenidone is a CYP1A2 substrate; discontinue moderate or strong CYP1A inhibitors before initiating pirfenidone and avoid use during therapy; if unable to avoid, pirfenidone dose reduction required

Discontinue strong CYP1A2 inducers before initiating pirfenidone and avoid use during therapy; likely to decrease exposure and lead to loss of pirfenidone efficacy

Smoking associated with decreased systemic exposure; encourage patient to quit smoking

Pregnancy: Data in pregnant women are insufficient to inform on drug associated risks for major birth defects and miscarriage

Lactation: No information is available on presence of pirfenidone in human milk, effects of drug on breastfed infant, or effects of drug on milk production; lack of clinical data during lactation precludes clear determination of risk of pirfenidone to infant during lactation; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and potential adverse effects on breastfed child from pirfenidone or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established

Inhibits transforming growth factor (TGF)-beta, a chemical mediator that controls many cell functions including proliferation and differentiation

Also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation

Absorption

Peak plasma time: 0.5-4 hr

Food decreased the rate and extent of absorption; Cmax and AUC decreased by ~49% and 16% with food, respectively

A reduced incidence of adverse reactions was observed in the fed group when compared with the fasted group; administered with food in clinical trials

Distribution

Protein bound: 58%

Vd: 59-71 L

Metabolism

Metabolized in the liver by CYP1A2 to inactive metabolites

Elimination

Half-life: 3 hr

Majority of dose excreted as 5-carboxy-pirfenidone metabolite (99.6%)

Excretion: 80% urine

Oral Administration

Take with food

Take doses at same time each day

Missed doses

• If ≥14 days: Reinitiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage
• If <14 days: Resume the dosage prior to the interruption