Esbriet^® (Tablets, Capsules) Instructions for Use

ATC Code

L04AX05 (Pirfenidone)

Active Substance

Pirfenidone

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Immunosuppressive agent. The mechanism of action of pirfenidone has not been fully established. However, existing data indicate that Pirfenidone exhibits antifibrotic and anti-inflammatory properties in a variety of in vitro systems and in animal models of pulmonary fibrosis (bleomycin-induced fibrosis and transplantation).

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing and inflammatory lung disease caused by the synthesis and release of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL-1β). Pirfenidone is able to reduce the accumulation of inflammatory cells in response to various stimuli.

It reduces fibroblast proliferation, the production of fibrosis-related proteins and cytokines, and increases the biosynthesis and accumulation of interstitial matrix in response to cytokine growth factors such as transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF).

Pharmacokinetics

The absorption processes, plasma concentrations and AUC values depend on the dosage form of the drug used.

Pirfenidone binds to human plasma proteins, predominantly to serum albumin. The overall mean binding level ranged from 50% to 58% at concentrations observed in clinical studies (1-100 µg/ml). The mean apparent V_d at steady state after oral administration was approximately 70 L, indicating moderate distribution of pirfenidone in tissues.

In an in vitro metabolism study with hepatic microsomes, it was found that Pirfenidone is metabolized primarily via the CYP1A2 isoenzyme with lesser involvement of other CYP isoenzymes, including CYP2C9, 2C19, 2D6 and 2E1 isoenzymes. In vitro and in vivo studies to date have not revealed any activity of the main metabolite (5-carboxy-Pirfenidone) even at doses and concentrations exceeding those associated with the activity of pirfenidone itself.

The clearance of pirfenidone after oral administration is moderately saturable.

After a single dose of pirfenidone was administered to healthy elderly volunteers, the mean apparent terminal T_1/2 was approximately 2.4 hours. Approximately 80% of orally administered pirfenidone is excreted by the kidneys within 24 hours. The largest amount of pirfenidone is excreted as the metabolite 5-carboxy-pirfenidone (>95% of the excreted amount), less than 1% of pirfenidone is excreted by the kidneys unchanged.

In a study of the pharmacokinetics of pirfenidone and the metabolite 5-carboxy-pirfenidone in patients with moderate hepatic impairment (Child-Pugh class B) and without hepatic impairment, a mean 60% increase in pirfenidone exposure was noted after a single 801 mg dose of pirfenidone in patients with moderate hepatic impairment.

No clinically significant differences in the pharmacokinetics of pirfenidone were found in patients with mild to severe renal impairment (compared to patients with normal renal function). The parent drug was predominantly metabolized to 5-carboxy-pirfenidone. The AUCo-∞ of 5-carboxy-pirfenidone was significantly higher in patients with moderate renal impairment (p=0.009) and severe renal impairment (p<0.0001) compared to patients with normal renal function. However, the estimated amount of accumulated metabolite at steady state did not affect pharmacodynamics because the terminal T_1/2 in these patients is only 1-2 hours.

Indications

Idiopathic pulmonary fibrosis in adults.

ICD codes

Dosage Regimen

Administer orally with food to reduce nausea and dizziness.

Initiate treatment using a three-week titration schedule to reach the full maintenance dose.

For Week 1, administer one 267 mg capsule or tablet three times daily for a total daily dose of 801 mg.

For Week 2, administer one 534 mg capsule or tablet three times daily for a total daily dose of 1602 mg.

From Week 3 onward, administer one 801 mg capsule or tablet three times daily for the full maintenance dose of 2403 mg per day.

Do not exceed the maximum recommended daily dose of 2403 mg.

For dose adjustment due to adverse reactions, reduce the daily dose to 1602 mg (534 mg three times daily) or 801 mg (267 mg three times daily) as tolerated.

In cases of significant liver enzyme elevation, interrupt treatment until values return to baseline, then re-initiate or adjust the dose.

For patients with moderate hepatic impairment (Child-Pugh B), the maximum dose is 534 mg three times daily (1602 mg/day).

For patients taking moderate CYP1A2 inhibitors (e.g., ciprofloxacin), the maximum dose is 534 mg three times daily (1602 mg/day).

Discontinue treatment if the patient starts smoking, as this reduces pirfenidone exposure.

Adverse Reactions

Hematopoietic system: rarely – agranulocytosis.

Immune system: infrequently – angioedema.

Metabolism: very often – anorexia, weight loss; often – decreased appetite.

Nervous system and psyche: very often – headache, dizziness, insomnia; often – drowsiness; dysgeusia (taste disturbance), apathy.

Cardiovascular system: often – flushing.

Respiratory system: often – upper respiratory tract infections, dyspnea, cough, productive cough.

Digestive system: very often – dyspepsia, nausea, diarrhea, vomiting, GERD; often – abdominal pain (including upper abdominal pain), abdominal pains, abdominal distension, flatulence, discomfort sensation, gastritis, constipation.

Liver and biliary tract: often – increased activity of AST, ALT, gamma-glutamyltransferase; rarely – increased serum bilirubin concentration together with increased ALT and AST activity.

Skin and subcutaneous tissues: very often – rash; often – photosensitivity reactions, erythema, pruritus, dry skin, erythematous rash, macular rash, pruritic rash.

Musculoskeletal system: very often – arthralgia; often – myalgia.

General reactions: very often – fatigue; often – asthenia, extracardiac chest pain.

Other: often – urinary tract infections; sunburn.

Contraindications

Hypersensitivity to pirfenidone, concurrent use of fluvoxamine, severe (CrCl <30 ml/min) renal failure, end-stage renal disease requiring dialysis, severe hepatic impairment, end-stage liver disease, smoking, concurrent use of potent inducers of the CYP1A2 isoenzyme, pregnancy, breastfeeding period, age under 18 years.

With caution: mild or moderate hepatic impairment (Child-Pugh class A and B); concurrent use of ciprofloxacin at a dose of 250 mg or 500 mg 1-2 times/day; concurrent use of moderate inhibitors of the CYP1A2 isoenzyme; moderate (CrCl 30-50 ml/min) renal failure.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

In patients receiving Pirfenidone, increased ALT and AST activity >3×ULN was observed, rarely accompanied by an increase in bilirubin concentration. Liver function tests (ALT, AST and bilirubin) should be performed before starting therapy with pirfenidone, then at monthly intervals for the first 6 months and thereafter at three-month intervals. In case of a significant increase in liver transaminase activity, the dose of pirfenidone should be adjusted or treatment discontinued. In patients with confirmed increased ALT, AST or bilirubin during treatment, a dose adjustment may be required.

Exposure to direct sunlight (including sunlamps) should be avoided or minimized during therapy with pirfenidone. Patients should be informed about the need to use effective sunscreens during the day, to wear protective clothing, and to avoid other drugs that cause photosensitivity. Patients should be informed to report symptoms of photosensitivity reactions or rash to their doctor. If photosensitivity reactions or rash occur, dose adjustment or temporary discontinuation of therapy may be required.

Effect on ability to drive vehicles and operate machinery

The use of pirfenidone may cause dizziness and fatigue, which may affect the ability to drive vehicles and operate machinery.

Drug Interactions

Concomitant use of pirfenidone and fluvoxamine (a potent inhibitor of the CYP1A2 isoenzyme with inhibitory effects on CYP2C9, CYP2C19 and CYP2D6 isoenzymes) resulted in a 4-fold increase in pirfenidone exposure in non-smoking patients. This combination is contraindicated. Treatment with fluvoxamine must be discontinued before starting therapy with pirfenidone and fluvoxamine should not be taken during therapy with pirfenidone due to reduced clearance of pirfenidone. Potent and selective inhibitors of the CYP1A2 isoenzyme can increase pirfenidone exposure by approximately 2-4 times (data obtained by extrapolating in vitro study results to in vivo conditions). If concomitant use of pirfenidone with potent and selective inhibitors of the CYP1A2 isoenzyme cannot be avoided, adjustment of the pirfenidone dose is required. If necessary, Pirfenidone should be discontinued.

Concomitant use of pirfenidone and ciprofloxacin (a moderate and selective inhibitor of the CYP1A2 isoenzyme) at a dose of 750 mg led to an 81% increase in pirfenidone exposure. If the use of ciprofloxacin at a dose of 750 mg twice daily cannot be avoided, the dose of pirfenidone should be adjusted. Caution should be exercised when using pirfenidone concomitantly with ciprofloxacin at a dose of 250 mg or 500 mg 1-2 times/day, as well as when using pirfenidone concomitantly with moderate inhibitors of the CYP1A2 isoenzyme.

Pirfenidone should not be used with drugs/drug combinations that are moderate or potent inhibitors of both the CYP1A2 isoenzyme and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (i.e., CYP2C9, CYP2C19, CYP2D6 and CYP2E1).

The exposure of pirfenidone in smoking patients (inducer of the CYP1A2 isoenzyme) was 50% of that in non-smoking patients.

Smoking can enhance the production of liver enzymes, thereby increasing clearance and reducing pirfenidone exposure. Concomitant use of potent inducers of the CYP1A2 isoenzyme, including smoking, should be avoided during therapy with pirfenidone, based on the reported interaction with smoking and its potential to induce the CYP1A2 isoenzyme. Patients should be advised to discontinue potent inducers of the CYP1A2 isoenzyme and to stop smoking before and during treatment with pirfenidone.

Concomitant therapy with moderate inducers of the CYP1A2 isoenzyme (e.g., omeprazole) may theoretically lead to a decrease in pirfenidone plasma concentration.

Concomitant use of potent inducers of the CYP1A2 isoenzyme and other CYP isoenzymes involved in the metabolism of pirfenidone (e.g., rifampicin) may lead to a significant decrease in pirfenidone plasma concentration. Concomitant use of these combinations should be avoided.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.