Presentation and Status in Health Basket
Film Coated Tablets
90 X 801 mg
Adults: Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/day over a 14-day period as follows:
● Days 1 to 7: a dose of 267 mg administered three times a day (801 mg/day)
● Days 8 to 14: a dose of 534 mg administered three times a day (1602 mg/day)
● Day 15 onward: a dose of 801 mg administered three times a day (2403 mg/day)
The recommended maintenance daily dose of Esbriet is 801 mg three times a day with food for a total of 2403 mg/day.
Doses above 2403 mg/day are not recommended for any patient.
Patients who miss 14 consecutive days or more of Esbriet treatment should re-initiate therapy by undergoing the initial 2-week titration regimen up to the recommended daily dose.
For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.
Dose adjustments and other considerations for safe use:
Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal undesirable effects, patients should be reminded to take the medicinal product with food. If symptoms persist, the dose of pirfenidone may be reduced to 267 mg – 534 mg, two to three times a day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for one to two weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded to use a sunblock daily and avoid exposure to the sun. The dose of pirfenidone may be reduced to 801 mg each day (267 mg three times a day). If the rash persists after 7 days, Esbriet 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, Esbriet may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of pirfenidone should be adjusted or treatment discontinued according to the guidelines listed in section 4.4 at the attached doctor’s leaflet.
Elderly: No dose adjustment is necessary in patients 65 years and older.
Hepatic impairment: No dose adjustment is necessary in patients with mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B). However, since plasma levels of pirfenidone may be increased in some individuals with mild to moderate hepatic impairment, caution should be used with Esbriet treatment in this population. Esbriet therapy should not be used in patients with severe hepatic impairment or end stage liver disease.
Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Esbriet therapy should not be used in patients with severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Paediatric population: There is no relevant use of Esbriet in the paediatric population for the indication of IPF.
Method of administration: Esbriet is for oral use. The tablets are to be swallowed whole with water and taken with food to reduce the possibility of nausea and dizziness.
For the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in adults.
Hypersensitivity to the active substance or to any of the excipients.
History of angioedema with pirfenidone.
Concomitant use of fluvoxamine.
Severe hepatic impairment or end stage liver disease.
Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Esbriet. 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 Esbriet, 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 Esbriet 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.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 x ULN after starting Esbriet therapy,
confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Esbriet should be reduced or interrupted. Once liver function tests are within normal limits Esbriet 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, Esbriet should be discontinued and the patient should not be rechallenged.
If a patient exhibits an aminotransferase elevation to >5 x ULN, Esbriet should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Esbriet 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. Esbriet has not been studied in individuals with severe hepatic impairment and Esbriet must not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Esbriet. 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.
Angioedema: 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 Esbriet in the post-marketing setting. Therefore, patients who develop signs or symptoms of angioedema following administration of Esbriet should immediately discontinue treatment. Patients with angioedema should be managed according to standard of care. Esbriet must not be used in patients with a history of angioedema due to Esbriet.
Dizziness: Dizziness has been reported in patients taking Esbriet. 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 Esbriet may be warranted.
Fatigue: Fatigue has been reported in patients taking Esbriet. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Esbriet. Physicians should monitor patient’s weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance.
The most frequently reported adverse reactions during clinical study experience with Esbriet 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%).
See prescribing information for full details.
Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1.
Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Esbriet and fluvoxamine (a strong inhibitor of CYP1A2
with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers.
Esbriet is contraindicated in patients with concomitant use of fluvoxamine.
Fluvoxamine should be discontinued prior to the initiation of Esbriet therapy and avoided during Esbriet therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment.
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 Esbriet with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone should be reduced to 801 mg daily (267 mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Esbriet therapy. Discontinue Esbriet if necessary.
Co-administration of Esbriet 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 (534 mg, three times a day).
Esbriet should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or two times a day.
Esbriet 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).
Cigarette smoking and inducers of CYP1A2: 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.
Pregnancy and Lactation
Pregnancy: There are no data from the use of Esbriet in pregnant women. As a precautionary measure, it is preferable to avoid the use of Esbriet during pregnancy.
Breast-feeding: It is unknown whether pirfenidone or its metabolites are excreted in human milk. A risk to the breastfed infant cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue from Esbriet therapy, taking into account the benefit of breast-feeding for the child and the benefit of Esbriet therapy for the mother.
See prescribing information for full details.
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a total dose of 4,806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
In the event of a suspected overdose, supportive medical care should be provided including monitoring of vital signs and close observation of the clinical status of the patient.
Storage: Do not store above 30°C.
Shelf life after first opening: 3 months.