Version May 2024
Idiopathic pulmonary fibrosis:
Days 1 to 7: Oral: 267 mg 3 times daily; total daily dose: 801 mg/day.
Days 8 to 14: Oral: 534 mg 3 times daily; total daily dose: 1,602 mg/day.
Day 15 and thereafter: Oral: 801 mg 3 times daily; maximum daily dose: 2,403 mg/day.
Reinitiation of therapy following interruption: If interruption <14 consecutive days, may reinitiate therapy at previous daily dose without retitration; if interruption ≥14 consecutive days, reinitiate therapy with the initial 2-week titration period up to recommended daily dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider dose modification or discontinuation as needed.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider dose modification or discontinuation as needed.
End-stage kidney disease requiring dialysis: Use is not recommended (has not been studied).
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider dose modification or discontinuation as needed.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Hepatotoxicity during treatment:
ALT/AST >3 to ≤5 × ULN without hyperbilirubinemia or symptoms: Rule out alternative causes and discontinue potentially confounding medications. As clinically appropriate, may continue current dose, may reduce dose (specific dosing reductions are not provided in manufacturer's labeling), or may temporarily discontinue therapy. Once aminotransferase elevations have resolved, may be re-titrated to the recommended daily dose. Monitor LFTs closely thereafter.
ALT/AST >3 to ≤5 × ULN with hyperbilirubinemia or symptoms: Discontinue therapy promptly and do not reinitiate.
ALT/AST >5 × ULN (regardless of serum bilirubin concentrations): Discontinue therapy promptly and do not reinitiate.
Gastrointestinal (eg, nausea, diarrhea, dyspepsia, vomiting): There are no specific dosage adjustments provided in the manufacturer's labeling; however, consider temporary dosage reduction and/or therapy interruption to allow for resolution of symptoms.
Photosensitivity reaction or rash: There is no specific dosage adjustment provided in the manufacturer's labeling; however, consider temporary dosage reduction and/or therapy interruption to allow for resolution of symptoms.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Skin rash (30%)
Gastrointestinal: Abdominal pain (24%), anorexia (13%), decreased appetite (21%), diarrhea (26%), dyspepsia (19%), gastroesophageal reflux disease (11%), nausea (36%), vomiting (13%)
Nervous system: Dizziness (18%), fatigue (26%), headache (22%)
Respiratory: Sinusitis (11%), upper respiratory tract infection (27%)
1% to 10%:
Dermatologic: Pruritus (8%), skin photosensitivity (9%)
Endocrine & metabolic: Weight loss (10%)
Gastrointestinal: Dysgeusia (6%)
Hepatic: Increased serum alanine aminotransferase (≤4%), increased serum aspartate aminotransferase (≥3 x ULN: ≤4%)
Nervous system: Insomnia (10%), noncardiac chest pain (5%)
Neuromuscular & skeletal: Arthralgia (10%), asthenia (6%)
Postmarketing:
Hematologic & oncologic: Agranulocytosis
Hepatic: Hepatoxicity
Hypersensitivity: Angioedema
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to pirfenidone or any component of the formulation; history of angioedema with pirfenidone; concomitant use of fluvoxamine; severe hepatic impairment or end-stage liver disease; severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease requiring dialysis.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• CNS effects: May cause dizziness and/or fatigue which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Incidence of dizziness may be reduced by administering with food. Dose reduction or discontinuation may be necessary if symptoms fail to improve or worsen.
• GI effects: Adverse effects including nausea/vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain have been reported; incidence may be reduced by administering with food. The incidence of gastrointestinal events was highest early in the course of treatment (initial 3 months) and decreased over time. Consider dose reduction or discontinuation of therapy if lack of improvement or worsening of symptoms.
• Hepatic effects: Serious and nonserious cases of drug-induced liver injury (including severe liver injury with fatal outcome) have been reported. Elevations of ALT and AST were reversible with dose modification or discontinuation of therapy. Obtain LFTs (ALT, AST, bilirubin) prior to initiation of treatment, monthly during the first 6 months, then every 3 months thereafter, and as clinically indicated. Dosage modification or interruption of therapy may be necessary for elevated LFTs.
• Photosensitivity: Photosensitivity reactions and rash have been reported with the majority of reactions occurring during the initial 6 months of therapy (severe reactions are uncommon); instruct patients to avoid or minimize exposure to the sun and/or sun lamps, to apply sunscreen (SPF ≥50 against UVA and UVB), wear protective clothing/hats, and to avoid concurrent use of other photosensitizing drugs. Patients should promptly report symptoms, reaction, or rash; dose reduction or therapy interruption may be necessary. If appropriate, may reinitiate therapy with re-escalation of dose as tolerated.
• Weight loss: Weight loss/anorexia have been reported with use; monitor weight during therapy.
Disease-related concerns:
• Hepatic impairment: Use with caution in mild to moderate impairment (Child-Pugh class A and B); pirfenidone systemic exposure increased by 60% in moderate impairment. Use in severe impairment (Child-Pugh class C) is not recommended (has not been studied).
• Kidney impairment: Use with caution in patients with kidney impairment; consider dose reduction and/or discontinuation as necessary; use in patients with end-stage kidney disease requiring dialysis is not recommended.
Special populations:
• Cigarette smokers: Clearance may be increased, and systemic exposure decreased in cigarette smokers due to hepatic enzyme (ie, CYP1A2) induction. Patients should be instructed to quit smoking prior to initiation of therapy; cigarette smoking should be avoided during therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Esbriet: 267 mg
Generic: 267 mg
Tablet, Oral:
Esbriet: 267 mg, 801 mg
Generic: 267 mg, 534 mg, 801 mg
Yes
Capsules (Esbriet Oral)
267 mg (per each): $41.26
Capsules (Pirfenidone Oral)
267 mg (per each): $23.09 - $44.12
Tablets (Esbriet Oral)
267 mg (per each): $46.44
801 mg (per each): $139.33
Tablets (Pirfenidone Oral)
267 mg (per each): $42.27 - $44.12
534 mg (per each): $132.36
801 mg (per each): $83.75 - $132.36
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Esbriet: 267 mg [DSC] [contains fd&c blue #2 (indigotine,indigo carmine)]
Generic: 267 mg
Tablet, Oral:
Esbriet: 267 mg, 801 mg
Generic: 267 mg, 801 mg
Oral: Administer with food at the same time each day.
Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis.
Substrate of CYP1A2 (major), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Pirfenidone. Management: Avoid this combination if possible. With ciprofloxacin doses of 1,500 mg/day, the pirfenidone dose should be reduced to 1,602 mg per (534 mg three times a day). With lower daily doses of ciprofloxacin, use pirfenidone with caution. Risk D: Consider therapy modification
CYP1A2 Inducers (Moderate): May decrease the serum concentration of Pirfenidone. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and moderate CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 1,602 mg per day (534 mg three times daily) and monitor for increased pirfenidone toxicities. Risk D: Consider therapy modification
CYP1A2 Inhibitors (Strong): May increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and strong CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 801 mg per day (267 mg three times daily) and monitor for increased pirfenidone toxicities. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Tobacco (Smoked): May decrease the serum concentration of Pirfenidone. Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Food decreased Cmax ~50% and AUC by ~15% to 20% compared to the fasted state. However, incidence of certain adverse events (eg, nausea, dizziness) was decreased when administered with food. Grapefruit products may inhibit the CYP-mediated metabolism of pirfenidone and increase its exposure. Management: Administer with food. Limit or avoid grapefruit products during therapy.
Adverse events have been observed in animal reproduction studies.
It is not known if pirfenidone is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Take with food to decrease frequency of dizziness or nausea. Limit or avoid grapefruit juice.
Hepatic function tests (ALT, AST, bilirubin; prior to initiation, monthly for first 6 months, then every 3 months thereafter and as clinically indicated based on symptoms of hepatic injury [eg, fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice]); signs of photosensitivity; GI symptoms (eg, diarrhea, nausea, vomiting); weight loss.
Precise mechanisms of action have not been fully elucidated; however, pirfenidone may exert antifibrotic properties by decreasing fibroblast proliferation and the production of fibrosis-associated proteins and cytokines; may decrease the formation and accumulation of extracellular matrix (ie, collagen) in response to transforming growth factor-beta and platelet derived growth factor. Pirfenidone is also believed to exert anti-inflammatory properties by decreasing the accumulation of inflammatory cells resulting from a variety of stimuli.
Distribution: ~59 to 71 L
Protein binding: Mean: 58% (primarily to albumin)
Metabolism: Hepatic primarily via CYP1A2 and to a lesser extent via CYP2C9, 2C19, 2D6, and 2E1; major metabolite (5-carboxy-pirfenidone) is inactive
Half-life elimination: ~3 hours
Time to peak, plasma: Median: 0.5 hours (fasting); 3 hours (with food)
Excretion: Urine (~80%; >99% as metabolite)
Altered kidney function: Systemic exposure (AUC0 to ∞) increased ~1.4, 1.5, and 1.2-fold in mild, moderate, and severe kidney impairment, respectively. The corresponding AUC0 to ∞ of 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold. The kidney clearance of 5-carboxy-pirfenidone decreased significantly in patients with moderate to severe impairment.
Hepatic function impairment: In patients with moderate impairment (Child Pugh class B), mean exposure, AUC0 to ∞ and Cmax increased ~1.6- and ~1.4-fold in moderate hepatic impairment, respectively.
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