Chemical formula: C₁₂H₁₁NO Molecular mass: 185.222 g/mol PubChem compound: 40632
Pirfenidone interacts in the following cases:
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. 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. 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).
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).
Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal impairment.
In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor.
Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
If a patient exhibits an aminotransferase elevation to >3 to ≤5 x ULN after starting pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits pirfenidone may be re-escalated to the recommended daily dose if tolerated.
If a patient exhibits an aminotransferase elevation to ≤5 x ULN accompanied by symptoms or hyperbilirubinaemia, pirfenidone should be discontinued and the patient should not be rechallenged.
If a patient exhibits an aminotransferase elevation to >5 x ULN, pirfenidone should be discontinued and the patient should not be rechallenged.
Dizziness has been reported in patients taking pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of pirfenidone may be warranted.
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 Esbriet 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.
Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded to use a sunblock daily and to avoid exposure to the sun. The dose of pirfenidone may be reduced to 801 mg a day. If the rash persists after 7 days, pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period.
Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Fatigue has been reported in patients taking pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of pirfenidone in the post-marketing setting. Reports of anaphylactic reactions have also been received. Therefore, patients who develop signs or symptoms of angioedema or severe allergic reactions following administration of pirfenidone should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Pirfenidone must not be used in patients with a history of angioedema or hypersensitivity due to pirfenidone.
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.
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.
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%), anorexia (11.4% versus 3.5%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%).
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 following list 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 below. 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:
Common: Upper respiratory tract infection; urinary tract infection
Rare: Agranulocytosis1
Uncommon: Angioedema1
Not known: Anaphylaxis1
Very Common: Anorexia
Common: Weight decreased; decreased appetite
Common: Insomnia
Very Common: Headache
Common: Dizziness; somnolence; dysgeusia; lethargy
Common: Hot flush
Common: Dyspnoea; cough; productive cough
Very Common: Dyspepsia; nausea; diarrhoea
Common: Gastroesophageal reflux disease; vomiting; abdominal distension; abdominal discomfort; abdominal pain; abdominal pain upper; stomach discomfort; gastritis; constipation; flatulence
Common: ALT increased; AST increased; gamma glutamyl transferase increased
Rare: Total serum bilirubin increased in combination with increases of ALT and AST1
Very Common: Photosensitivity reaction; rash
Common: Pruritus; erythema; dry skin; rash erythematous; rash macular; rash pruritic
Common: Myalgia; arthralgia
Very Common: Fatigue
Common: Asthenia; non-cardiac chest pain
Common: Sunburn
1 Identified through post-marketing surveillance
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