Dosing and uses of Esbriet (pirfenidone)
Adult dosage forms and strengths
capsule
- 267mg
Idiopathic Pulmonary Fibrosis
Conduct liver function tests before initiating therapy (also see Dosage modifications and Cautions)
Initial dose titration
- Take with food
- Days 1-7: 267 mg (1 capsule) PO TID
- Days 8-14: 534 mg (2 capsules) PO TID
- Day 15 and thereafter: 801 mg (3 capsules) PO TID
Maintenance dose
- 801 mg (3 capsules) PO TID with food
- Not to exceed 2403 mg/day (9 capsules/day)
Dosage modifications
If patients experience significant adverse reactions (ie, gastrointestinal, photosensitivity reaction, rash), consider temporary dosage reductions or therapy interruptions of pirfenidone to allow for resolution of symptoms; discontinue if symptoms persist despite these interventions
CYP1A2 inhibitors
- Strong inhibitors (eg, fluvoxamine, enoxacin): Reduce maintenance dose to 267 mg (1 capsule) TID
- Moderate inhibitors (eg, ciprofloxacin): Reduce maintenance dose to 534 mg (2 capsules) TID (with ciprofloxacin 750 mg BID)
Elevated liver enzymes
- AST/ALT >3 to ≤5 x ULN (without symptoms): Discontinue confounding medications, exclude other causes, repeat liver function tests as needed; the full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (eg, until liver chemistry tests are within normal limits), with subsequent retitration to the full dosage as tolerated
- AST/ALT >5 x ULN or >3 times ULN with signs/symptoms of severe liver damage: Permanently discontinue; do not rechallenge
Hepatic impairment
- Mild-to-moderate (Child Pugh A or B): Use caution; monitor and consider dosage modification or discontinuation as needed
- Severe (Child Pugh C): Not recommended (not studied)
Renal impairment
- Mild, moderate, or severe: Use caution; monitor and consider dosage modification or discontinuation as needed
- ESRD requiring dialysis: No recommended (not studied)
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Esbriet (pirfenidone) adverse (side) effects
>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
Warnings
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 and lactation
Pregnancy category: C
Lactation: Unknown if distributed in human breast milk
Because of the potential for serious adverse effects in breastfed infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
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.
Pharmacology of Esbriet (pirfenidone)
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
