Pirfenidone Drug Information

Pirfenidone capsules are indicated for the treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone is a pyridone indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Testing Prior to Pirfenidone Capsules Administration

Conduct liver function tests prior to initiating treatment with pirfenidone capsules.

Recommended Dosage

The recommended daily maintenance dosage of pirfenidone capsule is 801 mg three times daily for a total of 2,403 mg/day. Doses should be taken with food at the same time each day. Upon initiation of treatment, titrate to the full dosage of 2,403 mg/day over a 14-day period as follows: Table 1: Dosage Titration for Pirfenidone Capsules in Patients with IPF s above 2,403 mg/day are not recommended for any patient.

Patients should not take 2 doses at the same time to make up for a missed dose. Patients should not take more than 3 doses per day.

Dosage

Modifications due to Adverse Reactions Patients who miss 14 or more days of pirfenidone capsules should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage. For treatment interruption of less than 14 days, the dosage prior to the interruption can be resumed. If patients experience significant adverse reactions (i.e. gastrointestinal, photosensitivity reaction or rash, severe cutaneous adverse reactions (SCAR)), consider temporary dosage reductions or interruptions of pirfenidone capsules to allow for resolution of symptoms.

If a SCAR is confirmed, permanently discontinue pirfenidone capsules. Dosage Modification due to Elevated Liver Enzymes Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows: If a patient exhibits >3 but ≤5 × the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting pirfenidone capsules therapy: Discontinue confounding medications, exclude other causes, and monitor the patient closely.

Repeat liver chemistry tests as clinically indicated. The full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent re-titration to the full dosage as tolerated. If a patient exhibits >3 but ≤5 × ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia: Permanently discontinue pirfenidone capsules.

Do not rechallenge patient with pirfenidone capsules.

Dosage

Modifications due to Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce pirfenidone capsules to 267 mg three times a day (801 mg/day). Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 750 mg twice daily, reduce pirfenidone capsules to 534 mg three times a day (1,602 mg/day).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of pirfenidone has been evaluated in more than 1,400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials. Subjects ages ranged from 40 to 80 years (mean age of 67 years).

Most patients were male (74%) and Caucasian (95%). At the recommended dosage of 2,403 mg/day, 14.6% of patients on pirfenidone compared to 9.6% on placebo permanently discontinued treatment 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. The most common adverse reactions with an incidence of ≥ 10% and more frequent in the pirfenidone than placebo treatment group are listed in Table 2. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and Lymphatic System Disorders: Agranulocytosis Hepatobiliary Disorders: Drug-induced liver injury Immune System Disorders: Angioedema Skin and Subcutaneous Tissue Disorders: Severe Cutaneous Adverse Reactions (SCAR)

CYP1A2 Inhibitors Pirfenidone is metabolized primarily (70% to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Strong CYP1A2 Inhibitors The concomitant administration of pirfenidone and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to pirfenidone. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during pirfenidone treatment.

In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of pirfenidone as needed. Moderate CYP1A2 Inhibitors Concomitant administration of pirfenidone and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to pirfenidone.

If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily. Concomitant CYP1A2 and other CYP Inhibitors Agents or combinations of agents that are moderate or 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 discontinued prior to and avoided during pirfenidone treatment.

CYP1A2 Inducers

The concomitant use of pirfenidone and a CYP1A2 inducer may decrease the exposure of pirfenidone and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to pirfenidone treatment and avoid the concomitant use of pirfenidone and a strong CYP1A2 inducer.

Pregnancy Risk Summary The data with pirfenidone use in pregnant women are insufficient to inform on drug associated risks for major birth defects and miscarriage. In animal reproduction studies, pirfenidone was not teratogenic in rats and rabbits at oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Animal Data Animal reproductive studies were conducted in rats and rabbits. In a combined fertility and embryofetal development study, female rats received pirfenidone at oral doses of mg/kg/day from 2 weeks prior to mating, during the mating phase, and throughout the periods of early embryonic development from gestation days (GD) 0 to 5 and organogenesis from GD 6 to 17. In an embryofetal development study, pregnant rabbits received pirfenidone at oral doses of mg/kg/day throughout the period of organogenesis from GD 6 to 18.

In these studies, pirfenidone at doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m 2 basis at maternal oral doses up to 1,000 mg/kg/day in rats and 300 mg/kg/day in rabbits, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles (e.g., prolonged estrous cycle) were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/m 2 basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, female rats received pirfenidone at oral doses of mg/kg/day from GD 7 to lactation day 20.

Prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/m 2 basis at a maternal oral dose of 1,000 mg/kg/day).

Pediatric Use Safety and effectiveness of pirfenidone in pediatric patients have not been established.

There is limited clinical experience with overdosage. Multiple-dosages of pirfenidone up to a maximum tolerated dose of 4,005 mg per day were administered as five 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation. In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.