Esbriet: Indications, Dosage, Precautions, Adverse Effects
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Esbriet - Product Information

Manufacture: Roche
Country: Canada
Condition: Idiopathic Pulmonary Fibrosis
Class: Miscellaneous uncategorized agents
Form: Capsules
Ingredients: Pirfenidone, Microcrystalline cellulose, Croscarmellose sodium, Povidone, Magnesium stearate, Titanium dioxide, Gelatin, Shellac

Summary Product Information

Route of Administration Dosage Form / Strength Nonmedicinal Ingredients
Oral Capsules, 267 mg Capsule content:
Microcrystalline cellulose
Croscarmellose sodium
Povidone
Magnesium stearate
Capsule shell: body
Titanium dioxide
Gelatin
Capsule shell: cap
Titanium dioxide
Gelatin
Imprinting Inks
Brown S-1-16530 or 03A2 inks containing:
Shellac
Iron oxide black
Iron oxide red
Iron oxide yellow
Propylene glycol
Ammonium hydroxide

Indications and Clinical Use

ESBRIET (pirfenidone) is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) in adults.

Geriatrics (≥65 years of age)

No dose adjustment is necessary in patients 65 years and older (see ACTION AND CLINICAL PHARMACOLOGY).

Pediatrics (<18 years of age)

The safety and effectiveness of ESBRIET in paediatric patients have not been established.

Contraindications

  • Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
  • History of angioedema with pirfenidone (see WARNINGS AND PRECAUTIONS).
  • Concomitant use of fluvoxamine (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).
  • Severe hepatic impairment or end-stage liver disease (see WARNINGS AND PRECAUTIONS).
  • Severe renal impairment (CrCl <30 mL/min) or end stage renal disease requiring dialysis (see WARNINGS AND PRECAUTIONS).

Warnings and Precautions

General

Drug-Interactions with Inhibitors of CYP1A2 and Other CYP Isoenzymes

Fluvoxamine

ESBRIET is contraindicated in patients with concomitant use of fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on CYP2C9, 2C19, and 2D6). Fluvoxamine should be discontinued prior to the initiation of treatment with ESBRIET and avoided during ESBRIET therapy due to the potential for reduced clearance of pirfenidone (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Ciprofloxacin

Co-administration of ESBRIET and 750 mg of ciprofloxacin (a moderate and selective inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily (a total daily dose of 1500 mg) cannot be avoided, the dose of ESBRIET should be reduced to 1602 mg daily (two capsules, three times a day). ESBRIET should be used with caution when ciprofloxacin is used at a total daily dose of 250 to 1000 mg (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

Strong and Selective Inhibitors of CYP1A2

In vitro-in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 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 ESBRIET should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with ESBRIET therapy. Discontinue ESBRIET if necessary (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

Other CYP1A2 Inhibitors

Agents or combinations of agents that are moderate to strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be avoided during ESBRIET treatment. ESBRIET should be used with caution in patients treated with moderate inhibitors of CYP1A2 that do not inhibit other CYP isoenzymes (see DRUG INTERACTIONS).

Treatment with ESBRIET should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF.

ESBRIET should be taken with food to reduce the incidence of dizziness or nausea.

Physicians should monitor patients as frequently as clinically indicated for toxicities and according to the instructions of “DOSAGE AND ADMINISTRATION” and “DRUG INTERACTIONS” in the product monograph for any additional medication used to treat the patient. For significant side effects, the treatment of symptoms and dose reduction or discontinuation of ESBRIET should be considered.

Fatigue

Fatigue has been reported in patients treated with ESBRIET. Therefore, patients should know how they react to ESBRIET before they engage in activities requiring mental alertness or coordination (e.g., driving or using machinery). If fatigue does not improve or if it worsens in severity, dose reduction or discontinuation of pirfenidone may be warranted.

Endocrine and Metabolism

Weight Loss

Anorexia and weight loss have been reported in patients treated with ESBRIET. Physicians should monitor patients’ weight, and when appropriate, encourage increased caloric intake if weight loss is considered to be of clinical significance.

Gastrointestinal

Gastrointestinal events (e.g., nausea, diarrhoea, dyspepsia, vomiting) have been reported in patients treated with ESBRIET. Patients who experience gastrointestinal side effects should be reminded to take ESBRIET with food. If gastrointestinal events do not improve or worsen in severity, dose reduction or discontinuation of ESBRIET may be warranted.

Hepatic/Biliary/Pancreatic

Elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) have been reported in patients treated with ESBRIET. In some cases, these have been associated with concomitant elevations in bilirubin. Liver chemistry 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 elevations of ALT and/ or AST the dose of ESBRIET may need to be reduced or treatment discontinued (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

In patients with moderate hepatic impairment (i.e., Child-Pugh Class B), ESBRIET 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 ESBRIET exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY). ESBRIET has not been studied in individuals with severe hepatic impairment. ESBRIET should not be used in patients with severe hepatic impairment or end-stage liver disease (see CONTRAINDICATIONS).

Immune System

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 should not be used in patients with a history of angioedema due to ESBRIET (see CONTRAINDICATIONS).

Neurologic

Dizziness

Dizziness has been reported in patients treated with ESBRIET. Therefore, patients should know how they react to ESBRIET before they engage in activities requiring mental alertness or coordination (e.g., driving or using machinery). Patients who experience intolerance to therapy due to dizziness should be reminded to take ESBRIET with food to reduce dizziness. If dizziness does not improve or worsens in severity, dose adjustment or discontinuation of ESBRIET may be warranted.

Renal

ESBRIET should not be used in patients with severe renal impairment, or end-stage renal disease requiring dialysis (CrCl <30 mL/min, per Cockcroft-Gault equation) (see CONTRAINDICATIONS). No dose adjustment is necessary in patients with mild to moderate renal impairment.

Skin

Photosensitivity Reaction and Rash

Photosensitivity reaction and rash have been reported in patients treated with ESBRIET. Patients treated with ESBRIET should be advised to avoid or minimize exposure to direct and indirect sunlight, including through windows and from sunlamps, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to use daily an effective sun block (at least SPF 50 against UVA and UVB), and to wear clothing that protects against sun exposure such as wide-brimmed hats and long sleeves. Patients should be instructed to report promptly to their physician symptoms of photosensitivity reaction or rash. Severe photosensitivity reactions are uncommon. Dose reduction and temporary treatment discontinuation may be necessary in the event of photosensitivity reaction or rash. ESBRIET may be reintroduced with re-escalation to the tolerated dose in the same manner as the dose-escalation period (see DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women

ESBRIET has not been studied in pregnant women. In animals, placental transfer of pirfenidone and/or its metabolites to the foetus occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid.

At high doses (≥1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in foetal viability.

The use of ESBRIET should be avoided during pregnancy.

Nursing Women

It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown rapid excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk (see TOXICOLOGY). A risk to the breast-fed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue ESBRIET therapy, taking into account the benefits of breast-feeding for the child and of ESBRIET therapy for the mother.

Fertility

No adverse effects on fertility were observed in preclinical studies (see TOXICOLOGY).

Paediatrics (<18 years of age)

The safety and effectiveness of ESBRIET in paediatric patients have not been established.

Geriatrics (≥65 years of age)

No dose adjustment is necessary in patients 65 years and older (see ACTION AND CLINICAL PHARMACOLOGY).

Monitoring and Laboratory Tests

Liver chemistry 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 elevation in ALT, AST and/or bilirubin, the dose of ESBRIET may need to be reduced or treatment discontinued (see DOSAGE AND ADMINISTRATION: Recommendations in case of elevations in ALT, AST, bilirubin).

If a patient exhibits any ALT and/or AST elevation accompanied by symptoms (e.g. jaundice) or accompanied by hyperbilirubinaemia, ESBRIET should be discontinued promptly. The patient should be monitored closely until resolution of elevated ALT, AST and bilirubin and symptoms. The patient should NOT be re-challenged with ESBRIET.

If a patient exhibits ALT and/or AST elevation to >5 × ULN regardless of the level of serum bilirubin, ESBRIET should be discontinued promptly and the patient monitored closely until resolution of ALT and AST. The patient should NOT be re-challenged with ESBRIET.

Adverse Reactions

Adverse Drug Reaction

The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.

The most common adverse reactions (≥10%) are nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastro-esophageal reflux disease, sinusitis, insomnia, weight decreased, and arthralgia.

At the recommended dosage of 2403 mg/day, 14.6% of patients on ESBRIET compared to 9.6% on placebo permanently discontinued treatment because of an adverse event and 42.7% of patients on ESBRIET compared to 16.2% on placebo had a dose interruption or reduction because of an adverse event. The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

ESBRIET was studied in 3 randomized, double-blind, placebo-controlled trials (Studies PIPF-016, PIPF-004 and PIPF-006) in which a total of 623 patients received 2403 mg/day of ESBRIET and 624 patients received placebo. Subjects ages ranged from 40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). The mean duration of exposure to ESBRIET was 62 weeks (range: 2 to 118 weeks) in these 3 trials. Patients in these studies could elect to participate in an open-label extension study to examine the long-term safety of ESBRIET (Study PIPF 012).

Table 1 Adverse Drug Reactions Occurring in ≥3% Patients on ESBRIET and >with Greater Frequency than Placebo in Studies PIPF-004, and PIPF-006, and PIPF-016
Adverse Drug Reactions Number of Patients, n (%)
Randomized Patient Subset Updated
Pirfenidone
(N = 623)
Placebo
(N = 624)
Gastrointestinal Disorders
Nausea 225 (36.1) 97 (15.5)
Abdominal paina 165 (26.5) 103 (16.5)
Diarrhoea 161 (25.8) 127 (20.4)
Dyspepsia 115 (18.5) 43 (6.9)
Vomiting 83 (13.3) 39 (6.3)
Gastro-oesophageal reflux disease 69 (11.1) 44 (7.1)
Dry mouth 19 (3.0) 17 (2.7)
General Disorders and Administration Site Conditions
Fatigue 162 (26.0) 119 (19.1)
Asthenia 40 (6.4) 24 (3.8)
Non-cardiac chest pain 32 (5.1) 25 (4.0)
Infections and Infestations
Upper respiratory tract infection 167 (26.8) 158 (25.3)
Sinusitis 68 (10.9) 64 (10.3)
Influenza 41 (6.6) 38 (6.1)
Gastroenteritis viral 29 (4.7) 17 (2.7)
Rhinitis 20 (3.2) 19 (3.0)
Injury, Poisoning And Procedural Complications
Sunburn 23 (3.7) 11 (1.8)
Investigations
Weight decreased 63 (10.1) 34 (5.4)
Gamma-Glutamyltransferase increased 24 (3.9) 11 (1.8)
Alanine Aminotransferase increased 20 (3.2) 9 (1.4)
Metabolism and Nutrition Disorders
Anorexia 81 (13.0) 31 (5.0)
Decreased appetite 50 (8.0) 20 (3.2)
Musculoskeletal and Connective Tissue Disorders
Arthralgia 62 (10.0) 44 (7.1)
Musculoskeletal Pain 24 (3.9) 22 (3.5)
Musculoskeletal Chest Pain 19 (3.0) 7 (1.1)
Nervous System Disorders
Headache 137 (22.0) 120 (19.2)
Dizziness 112 (18.0) 71 (11.4)
Dysgeusia 36 (5.8) 14 (2.2)
Somnolence 22 (3.5) 18 (2.9)
Psychiatric Disorders
Insomnia 65 (10.4) 41 (6.6)
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal Pain 38 (6.1) 36 (5.8)
Epistaxis 22 (3.5) 21 (3.4)
Respiratory Tract Congestion 21 (3.4) 12 (1.9)
Skin and Subcutaneous Tissue Disorders
Rash 189 (30.3) 64 (10.3)
Photosensitivity Reaction 58 (9.3) 7 (1.1)
Pruritus 49 (7.9) 33 (5.3)
Erythema 25 (4.0) 16 (2.6)
Dry Skin 21 (3.4) 11 (1.8)
Vascular Disorders
Hot Flush 25 (4.0) 14 (2.2)
Hypertension 20 (3.2) 17 (2.7)
Includes abdominal pain, upper abdominal pain, abdominal distension, abdominal discomfort, and stomach discomfort.

Abnormal Haematological and Clinical Chemistry Findings

In studies PIPF 004 and PIPF 006, haematology and urinalysis parameters were similar between patients taking ESBRIET and placebo. Serum chemistry parameters were also similar across the groups with the exception of gamma glutamyl transferase (GGT) and creatinine. A mean increase at 72 weeks from Baseline in GGT level of 7.6 U/L was observed in the ESBRIET group while no change was seen in the placebo group. A mean decrease at 72 weeks from Baseline of 5.6 µmol/L in serum creatinine was observed in the ESBRIET group, compared with a mean decrease of 1.1 µmol/L in the placebo group. Few patients experienced shifts from Grade 0, 1, or 2 to Grade 3 or 4 in laboratory tests in the studies and across treatment groups. There was an imbalance between ESBRIET and placebo groups for shifts in hyponatraemia, hypophosphataemia and lymphopaenia, which were more frequent in the ESBRIET group. Marked laboratory abnormalities in pooled data from studies PIPF-004, PIPF-006, and PIPF-016 occurred infrequently (≤1% per treatment group) and with no greater frequency in the ESBRIET group than in the placebo group, with the following exceptions in liver tests, lymphocytes, and hyponatremia. Patients treated with ESBRIET 2403 mg/day had a higher incidence of elevations in ALT or AST ≥3 × ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥10 × ULN in ALT or AST occurred in 0.3% of patients in the ESBRIET 2403 mg/day group and in 0.2% of patients in the placebo group. Grade 0 to 3 reductions in lymphocyte count were seen in 6 ESBRIET patients (1.0%) and in 1 placebo patient (0.2%). One ESBRIET patient (0.2%) had a post-Baseline Grade 4 lymphocyte abnormality at Week 4, which was resolved at Week 6, Grade 2 at Weeks 12, 24, and 36, and resolved thereafter. Lymphocyte abnormalities were not associated with AEs. Grade 0 to 3 sodium (hyponatremia) abnormalities were reported in 9 ESBRIET patients (1.5%) and 1 placebo patient (0.2%).

Demographic Factors

No effect was seen between adverse events and sex (male versus female), age (<65 versus ≥65 years), or Baseline IPF severity (FVC <70% predicted versus FVC 70% to 80% predicted versus FVC ≥80% predicted) within the ESBRIET group. No effect also was seen for race (white versus non-white); however, there were only 65 non-white patients in the three predominantly North American Phase III studies combined

Dose-Response Relationship (PIPF-004 and PIPF-006)

Study PIPF-004 included a group receiving a lower dose of ESBRIET (1197 mg/day) than the marketed dose of 2403 mg/day. Adverse drug reaction rates in the lower dose ESBRIET group were intermediate to the ESBRIET 2403 mg/day and placebo groups for a number of the more frequently occurring adverse drug reactions including nausea, dyspepsia, abdominal pain, decreased appetite, dizziness, headache, photosensitivity reaction and rash.

Adverse Drug Reactions in SP3

The safety analysis in the randomized, double-blind Phase III study (SP3) conducted in Japan included 109 patients who were treated with 1800 mg/day pirfenidone. This dose is comparable to the 2403 mg/day dose administered in studies PIPF-004 and PIPF-006 on a weight-normalized basis to account for the heavier body weight of the mostly North American patients in PIPF-004 and PIPF-006. In study SP3, 107 patients received placebo, and 55 patients received pirfenidone 1200 mg/day, for approximately 52 weeks. The adverse drug reaction profile for pirfenidone in the Japanese study, SP3, was generally similar to that observed with ESBRIET in studies PIPF-004 and PIPF-006 (primarily North American patients), with the exception of a higher incidence of photosensitivity reaction (51.4%) and a lower incidence of rash (9.2%) in patients on 1800 mg/day in the Japanese study. However, no photosensitivity reaction or rash was serious, severe, or life-threatening. The incidence of serious adverse drug reactions was 9.2% in the pirfenidone 1800 mg/day group and 5.6% in the placebo group.

Adverse Drug Reactions in Long-Term Studies

Study PIPF-012 was an uncontrolled, open-label extension, long-term, safety study which allowed patients who completed PIPF-004 and PIPF-006 to continue on pirfenidone treatment at 2403 mg/day or switch to pirfenidone 2403 mg/day from placebo treatment. A total of 603 patients were enrolled in Study PIPF-012. The mean duration of pirfenidone 2403 mg/day treatment in Study PIPF-012 was 27.5 weeks. The adverse drug reaction profile resulting from an interim analysis was similar to that observed in the Phase III trials and previous trials. No new safety signals or trends were observed.

Post-Market Adverse Drug Reactions

Because post-marketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In post-marketing experience in Japan many of the adverse reactions reported during post-approval use of pirfenidone (marketed as Pirespa) are consistent with the clinical trial experience with ESBRIET. These events include: abdominal discomfort, constipation, diarrhoea, dyspepsia, nausea, vomiting, ALT increased, AST increased, GGT increased, decreased appetite, dizziness, dysgeusia, somnolence, photosensitivity reaction, pruritus, rash.

The serious and unexpected adverse drug reactions include, but are not limited to, the following:

Blood and Lymphatic Disorders: Agranulocytosis, febrile neutropaenia, anaemia

Cardiac Disorders: Atrial fibrillation, palpitations, angina pectoris, ventricular tachycardia

Gastrointestinal Disorders: Gastric ulcer haemorrhage, gastritis, ileus

Metabolism and Nutrition Disorders: Dehydration, hyperkalaemia

General Disorders and Administration Site Condition: Pyrexia

Hepatobiliary Disorders: Bilirubin increased in combination with increases of ALT and AST, hepatic function abnormal, liver disorder

Immune System: Angioedema

Infections and Infestations: Bronchopulmonary aspergillosis, pneumonia, pneumonia bacterial, urinary tract infection

Investigations: C-reactive protein increased, hepatic enzyme increased, platelet count decreased, blood urea increased, renal impairment

Respiratory, Thoracic and Mediastinal Disorders: Lung disorder, pneumonitis, pneumothorax

Drug Interactions

Overview

Drug-Interactions with Inhibitors of CYP1A2 and Other CYP Isoenzymes

Fluvoxamine

ESBRIET is contraindicated in patients with concomitant use of fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on CYP2C9, 2C19, and 2D6). Fluvoxamine should be discontinued prior to the initiation of treatment with ESBRIET and avoided during ESBRIET therapy due to the potential for reduced clearance of pirfenidone (see CONTRAINDICATIONS).

Ciprofloxacin

Co-administration of ESBRIET and 750 mg of ciprofloxacin (a moderate and selective inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily (a total daily dose of 1500 mg) cannot be avoided, the dose of ESBRIET should be reduced to 1602 mg daily (two capsules, three times a day). ESBRIET should be used with caution when ciprofloxacin is used at a total daily dose of 250 to 1000 mg (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Strong and Selective Inhibitors of CYP1A2

In vitro-in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 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 ESBRIET should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with ESBRIET therapy. Discontinue ESBRIET if necessary (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Other CYP1A2 Inhibitors

Agents or combinations of agents that are moderate to strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be avoided during ESBRIET treatment. ESBRIET should be used with caution in patients treated with moderate inhibitors of CYP1A2 that do not inhibit other CYP isoenzymes.

Pirfenidone is primarily metabolized via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1.

Patients should discontinue and avoid use of strong inhibitors of CYP1A2 due to the potential for reduced clearance of pirfenidone (see Table 2).

Patients should discontinue and avoid use of strong inducers of CYP1A2 to avoid reduced exposure to pirfenidone (see Table 2).

Drug-Drug Interactions

In a Phase I 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 an approximately 4-fold increase in exposure to pirfenidone in non-smokers.

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated)

Table 2 Established or Potential Drug-Drug Interactions
Ref. Effect Clinical Comment
CYP1A2 Inhibitors
CYP1A2, 2C9, 2C19, 2D6:
Fluvoxamine
CT ↑4× AUC0-∞, ↑2× Cmax
Increased exposure (and reduced
clearance)
Concomitant therapy is
contraindicated (see
WARNINGS AND
PRECAUTIONS).
CYP1A2:
Ciprofloxacin
CT ↑81% AUC0-∞, ↑23% Cmax
Increased exposure (and reduced
clearance)
Concomitant therapy should be
used with caution. Dose
reductions may be needed (see
WARNINGS AND
PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
CYP1A2:
Methoxsalen
Mexiletine
Oral contraceptives
T ↑AUC0-∞, ↑Cmax
Potential for increased exposure
(and reduced clearance)
Concomitant therapy should be
used with caution.
Inhibitors of Other CYPs when Administered with CYP1A2 Inhibitors
CYP2C9:
Amiodarone
Miconazole
T ↑AUC0-∞, ↑Cmax
Potential for increased exposure
(and reduced clearance)
Concomitant therapy with these
agents and moderate-strong
CYP1A2 inhibitors (listed above)
should be discontinued and
avoided.
CYP2C19:
Fluconazole
Esomeprazole
Moclobemide
Omeprazole
Voriconazole
T ↑AUC0-∞, ↑Cmax
Potential for increased exposure
(and reduced clearance)
Concomitant therapy with these
agents and moderate-strong
CYP1A2 inhibitors (listed above)
should be discontinued and
avoided.
CYP2D6:
Bupropion
Fluoxetine
Paroxetine
Quinidine
Cinacalcet
Duloxetine
Terbinafine
T ↑AUC0-∞, ↑Cmax
Potential for increased exposure
(and reduced clearance)
Concomitant therapy with these
agents and moderate-strong
CYP1A2 inhibitors (listed above)
should be discontinued and
avoided.
CYP Inducers
CYP1A2:
Phenytoin
T ↓AUC0-∞, ↓Cmax
Potential for reduced exposure
Concomitant therapy should be
discontinued and avoided.
CYP2C9:
Carbamazepine
Rifampin
T ↓AUC0-∞, ↓Cmax
Potential for reduced exposure
Concomitant therapy should be
discontinued and avoided.
CYP2C9, 2C19:
Rifampin
T ↓AUC0-∞, ↓Cmax
Potential for reduced exposure
Concomitant therapy should be
discontinued and avoided.
Legend: CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

Administration of ESBRIET with food results in a large reduction in Cmax (by approximately 50%) and a smaller reduction in AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to healthy older adult volunteers (50–66 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80 to 85% of the AUC observed in the fasted state. Less nausea and dizziness were observed in fed when compared with fasted subjects. Therefore, ESBRIET should be administered with food to reduce the incidence of dizziness or nausea (see DOSAGE AND ADMINISTRATION: Dosing Considerations).

Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with ESBRIET to prevent increased exposure to ESBRIET.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Cigarette Smoking and Inducers of CYP1A2

Cigarette smoking induces hepatic enzyme production, including CYP1A2, and thus may increase clearance of ESBRIET leading to reduced exposure. Patients should stop smoking before, and not smoke during ESBRIET therapy to avoid reduced exposure to pirfenidone. In a Phase I study the exposure to pirfenidone insmokers was significantly less than in non-smokers. Cigarette smoking should be avoided during ESBRIET therapy to prevent reduced exposure to pirfenidone.

Effects on Ability to Drive and Use Machines:

No studies on the effects on the ability to drive and use machines have been performed. ESBRIET may cause dizziness and fatigue, which could influence the ability to drive or use machines. Patients should be reminded to takeESBRIET with food to reduce the incidence of dizziness.

Dosage and Administration

Dosing Considerations

  • Treatment with ESBRIET should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF.
  • ESBRIET should be taken with food (see DRUG INTERACTIONS).
  • ESBRIET should not be taken concomitantly with fluvoxamine (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).
  • Reduction of the ESBRIET dose may be required for ciprofloxacin and strong but selective inhibitors of CYP1A2 (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).

Recommended Dose and Dosage Adjustment

Adults

Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine capsules per day over a 14-day period to improve tolerability as follows:

Days 1 to 7: one capsule, three times a day (801 mg/day) with food
Days 8 to 14: two capsules, three times a day (1602 mg/day) with food
Day 15 onward: three capsules, three times a day (2403 mg/day) with food

The recommended daily dose of ESBRIET for patients with IPF is three 267 mg capsules three times a day with food for a total of 2403 mg/day.

Doses above 2403 mg/day are not recommended for any patient.

Dose Adjustments

Gastrointestinal Events

In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take ESBRIET with food. If gastrointestinal events do not improve, or worsen in severity, dose reduction or discontinuation of ESBRIET may be warranted.

Photosensitivity Reaction or Rash

Patients who experience severe photosensitivity reaction or rash should be instructed to discontinue ESBRIET promptly and to seek medical advice without delay (see WARNINGS AND PRECAUTIONS). Once the rash has resolved, ESBRIET may bere-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.

Ciprofloxacin

Co-administration of ESBRIET and 750 mg of ciprofloxacin (a moderate and selective inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily (a total daily dose of 1500 mg) cannot be avoided, the dose ofESBRIET should be reduced to 1602 mg daily (two capsules, three times a day). ESBRIET should be used with caution when ciprofloxacin is used at a total daily dose of 250 to 1000 mg (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).

Elderly

No dose adjustment is necessary in patients 65 years and older.

Paediatric

ESBRIET has not been studied in paediatric patients, and is not recommended for use in this patient population.

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 individuals with moderate hepatic impairment (around 60% increase in Child-Pugh Class B), patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see DRUG INTERACTIONS). ESBRIET should not be used in patients with severe hepatic impairment or end-stage liver disease (see CONTRAINDICATIONS). Liver chemistry tests (ALT, AST, bilirubin) should be monitored before and during treatment with ESBRIET. Dose adjustments, including discontinuation, may be necessary in the event of elevations in ALT, AST, and/or bilirubin (see WARNINGS AND PRECAUTIONS, and see below for dose adjustments).

Recommendations in Case of ALT, AST, Bilirubin Elevations

For patients with confirmed elevations in ALT, AST or bilirubin during treatment, dose adjustments, including discontinuation, may be necessary. Confounding medicinal products should be discontinued promptly, other causes excluded and close monitoring of the patient is advised.

If a patient exhibits a Grade 2 ALT and/or AST elevation to >3 to ≤5 × ULN without hyperbilirubinaemia after starting treatment with ESBRIET at the recommended dose of 2403 mg/day, or any time after starting therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. As clinically appropriate, ESBRIET can be continued at the recommended dose of 2403 mg/day, reduced or temporarily discontinued. Once ALT and AST levels have resolved, ESBRIET may be re-escalated to the recommended daily dose and continued, if tolerated and the patient should be monitored closely.

If a patient exhibits any ALT and/or AST elevation accompanied by symptoms or accompanied by hyperbilirubinaemia (excluding patients with known predominantly unconjugated hyperbilirubinaemia, e.g., Gilbert’s syndrome), ESBRIET should be discontinued promptly. The patient should be monitored closely until resolution of elevated ALT, AST, bilirubin, and symptoms. The patient should NOT be re-challenged with ESBRIET.

If a patient exhibits ALT and/or AST elevation to >5 × ULN regardless of the level of serum bilirubin, ESBRIET should be discontinued promptly and the patient monitored closely until resolution of elevated ALT, AST, and bilirubin. The patient should NOT be re-challenged with ESBRIET.

Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment. ESBRIET should not be used in patients with severe renal impairment or end-stage renal disease requiring dialysis (CrCl <30mL/min, per Cockcroft-Gault equation) (see CONTRAINDICATIONS).

Missed Dose

If a dose is missed, the next capsule(s) should be taken as originally planned. Double doses should not be taken to make up for forgotten capsules or doses.

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.

If treatment is missed for less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

Administration

ESBRIET is to be swallowed whole with water and taken with food to reduce the possibility of nausea or dizziness.

Overdosage

In studies PIPF-004 and PIPF-006, an overdose was defined as any study drug exposure of greater than 15 capsules (>4005 mg) in any given day or greater than 5 capsules (>1335 mg) in any single dose. No patients met the definition of overdose in these studies. There is therefore, limited clinical experience with overdose. Multiple doses of pirfenidone up to 4806 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 generally consistent with the most frequently reported adverse reactions for pirfenidone.

There is no specific antidote. 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

The mechanisms of action of pirfenidone have not been fully established. However, existing data suggest that pirfenidone exerts anti-fibrotic and anti-inflammatory properties in a variety of in vitro systems and animal models of pulmonary fibrosis (e.g., bleomycin- and transplant-induced fibrosis).

IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β). Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). Pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli.

Pharmacodynamics

An observed dose-response relationship favouring a dose of 2403 mg/day pirfenidone compared with 1197 mg/day pirfenidone was observed in a Phase III randomized, double-blind, placebo-controlled study (PIPF-004). A PK-PD evaluation of a subset of these patients showed a weak positive relationship between pirfenidone plasma exposure and the primary endpoint of FVC change.

A double-blind, randomized, placebo- and active-controlled parallel arm study was performed to determine the impact of two doses of pirfenidone (2403 mg/day & 4005 mg/day) on QT interval in healthy human volunteers (40/treatment arm). ECG assessments were performed at baseline and on day 10 of treatment. There was no evidence of a treatment-related effect on the QTc interval at either of the tested doses. Statistically significant increases in heart rate were observed, with maximum increases of 3.8 bpm (90% CI 1.7, 5.9) in the pirfenidone 2403 mg/day group and 4.9 bpm (90% CI 2.5, 7.4) in the pirfenidone 4005 mg/day group.

Pharmacokinetics

Table 3 Arithmetic Mean (Range) Pirfenidone Pharmacokinetic Parameters in Patients with IPF
N Cmax
(µg/mL)
AUCa
(mg•h/L)
Tmax
(h)
IPF patients
(PIPF-004)
57 14.7
(6.48–33.6)
180
(85.6–544)
not measured

a: AUC0–24 estimates reflect three doses of 801 mg administered over the 24 hour period at steady-state

Absorption

The bioavailability of pirfenidone has not been determined in humans.

Administration of pirfenidone with food results in a large reduction in Cmax (by around 50%) and a smaller reduction of AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to healthy older adult volunteers (50 to 66 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80 to 85% of the AUC observed in the fasted state. Reduced incidences of adverse events (in particular nausea and dizziness) were observed in fed subjects when compared to the fasted group. Therefore, ESBRIET should be administered with food to reduce the incidence of dizziness or nausea.

Distribution

Pirfenidone binds to human plasma proteins, primarily to albumin. The overall mean binding ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 µg/mL). Mean apparent oral steady-state volume of distribution is approximately 70 L, indicating that pirfenidone distribution to tissues is modest.

Metabolism

Pirfenidone is primarily metabolized via CYP1A2 (approximately 70–80%) with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro and in vivo studies to date have not detected any activity of the major metabolite, 5-carboxy-pirfenidone.

The clearance of oral pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging study in healthy older adults administered doses ranging from 267 mg to 1335 mg three times a day, the mean clearance decreased by approximately 25% above a dose of 801 mg three times a day. The concentration-dependence of pirfenidone clearance did not appear to translate into a lack of dose proportionality in the Phase III trial and is not likely to be clinically relevant.

Excretion

Following single dose administration of pirfenidone in healthy older adults, the mean apparent terminal elimination half-life was approximately 2.4 hours. Approximately 80% of an orally administered dose of pirfenidone is cleared in the urine within 24 hours of dosing. The majority of pirfenidone is excreted as the 5-carboxy-pirfenidone metabolite (>95% of that recovered), with less than 1% of pirfenidone excreted unchanged in urine.

Special Populations and Conditions

Population pharmacokinetic analyses were conducted, using data collected from four studies in healthy subjects or patients with renal impairment and one study in patients with IPF. Results showed no clinically relevant effects of age, gender or body size on the pharmacokinetics of pirfenidone.

Paediatrics

The safety and effectiveness of ESBRIET in paediatric patients have not been established.

Geriatrics

The independent effect of patient age on the PK of pirfenidone is relatively small (the predicted AUC for pirfenidone was approximately 23% higher in 80 year old compared to 50 year old patients) and unlikely to be clinically significant.

Gender

No clinically relevant effect of gender on the pharmacokinetics of pirfenidone has been observed. The Cmax of pirfenidone in females was approximately 10% higher than in males.

Race

No clinically relevant effect of race on the pharmacokinetics of pirfenidone has been observed. The predicted AUC0-24 of pirfenidone was found to be 21% lower in Caucasian compared with African-American subjects. However, there were only a small number of non-Caucasian patients included in controlled clinical trials.

Body Size

No clinically relevant effect of body size on the pharmacokinetics of pirfenidone has been observed. Obese subjects were observed to have higher exposure than either normal or overweight subjects but the former were older and had worse renal function.

Hepatic Insufficiency

The pharmacokinetics of pirfenidone were compared in subjects with moderate hepatic impairment (Child-Pugh Class B) and normal hepatic function. Results showed that there was a mean increase of 60% in pirfenidone exposure after a single dose of 801 mg pirfenidone (3 × 267 mg capsule) in patients with moderate hepatic impairment. Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment and patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP enzyme inhibitor (in particular a CYP1A2 inhibitor). ESBRIET is contraindicated in severe hepatic impairment and end stage liver disease (see CONTRAINDICATIONS).

Renal Insufficiency

No significant differences in the pharmacokinetics of pirfenidone were observed in subjects with mild renal impairment (CrCl of 51–80 mL/min; Cockcroft-Gault equation) to severe renal impairment (CrCl <30 mL/min) compared with subjects with normal renal function (CrCl >80 mL/min). However, the parent drug is predominantly metabolized to 5-carboxy-pirfenidone, and the pharmacokinetics of this metabolite are altered in subjects with moderate to severe renal impairment. The AUC0-∞ of 5-carboxy-pirfenidone was significantly higher in the moderate (p = 0.009) and severe (p < 0.0001) renal impairment groups than in the group with normal renal function; 100 (26.3) and 168 (67.4) mg•h/L compared to 28.7 (4.99) mg•h/L respectively. However, the predicted amount of metabolite accumulation at steady state is minimal as the terminal elimination half-life is only 1–2 hours in these subjects. No dose adjustment is required in patients with mild to moderate renal impairment who are receiving pirfenidone. ESBRIET is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end stage renal disease requiring dialysis (see CONTRAINDICATIONS).

Japanese Patients

Study SP3: a phase III study conducted in Japanese patients, compared pirfenidone 1800 mg/day (tablets, a comparable dose to 2403 mg/day in the North American and European populations of PIPF-004/006 on a weight-normalized basis) with placebo (N = 110, N = 109, respectively). Treatment with pirfenidone 1800 mg/day statistically significantly reduced mean decline in vital capacity (VC) at Week 52 (the primary endpoint) compared with placebo (-0.09 ± 0.02 L versus -0.16 ± 0.02 L respectively, relative difference 43.8%, p = 0.042). There was also a statistically significant prolongation in progression free survival compared with placebo (HR: 0.64 [0.43–0.96], p = 0.028).

Storage and Stability

Store at room temperature (15 - 30°C).

Special Handling Instructions

There are no special handling instructions for ESBRIET.

Dosage Forms, Composition and Packaging

ESBRIET is supplied as hard gelatin two-piece capsule, with a white opaque body and white opaque cap imprinted with “PFD 267 mg” in brown ink and containing a white to pale yellow powder.

Each capsule contains 267 mg pirfenidone.

In addition, each capsule contains the following nonmedicinal ingredients:

Capsule content:

Microcrystalline cellulose
Croscarmellose sodium
Povidone
Magnesium stearate

Capsule shell: body

Titanium dioxide
Gelatin

Capsule shell: cap

Titanium dioxide
Gelatin

Imprinting Inks

Brown S-1-16530 or 03A2 inks containing:

Shellac
Iron oxide black
Iron oxide red
Iron oxide yellow
Propylene glycol
Ammonium hydroxide

ESBRIET is supplied in 250 mL white HDPE bottle with child-resistant closure containing 270 capsules, or in treatment packs as follows:

2-week treatment initiation pack

7 x PVC/PE/PCTFE aluminium foil blister strips, each containing 3 capsules (for the Week 1 dosing), packaged together with 7 x PVC/PE/PCTFE aluminium foil blister strips, each containing 6 capsules (for the Week 2 dosing), for a total of 63 capsules per pack.