Pirfenidone

PIRFENIDONE- pirfenidone tablet, film coated
Teva Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Pirfenidone tablets are indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Pirfenidone Tablets Administration

Conduct liver function tests prior to initiating treatment with pirfenidone tablets [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

The recommended daily maintenance dosage of pirfenidone tablets 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 Tablets in Patients with IPF

Treatment days

Dosage

Days 1 through 7

267 mg three times daily (801 mg/day)

Days 8 through 14

534 mg three times daily (1,602 mg/day)

Days 15 onward

801 mg three times daily (2,403 mg/day)

Dosages 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.

2.3 Dosage Modifications due to Adverse Reactions

Patients who miss 14 or more days of pirfenidone tablets should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage [see Dosage and Administration (2.2)]. 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), consider temporary dosage reductions or interruptions of pirfenidone tablets to allow for resolution of symptoms [see Warnings and Precautions (5.1, 5.2, 5.3)].

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 tablets 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 tablets.
  • Do not rechallenge patient with pirfenidone tablets.

If a patient exhibits >5 × ULN ALT and/or AST:

  • Permanently discontinue pirfenidone tablets.
  • Do not rechallenge patient with pirfenidone tablets.

2.4 Dosage Modifications due to Drug Interactions

Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin)

Reduce pirfenidone tablets 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 tablets to 534 mg three times a day (1,602 mg/day).

3 DOSAGE FORMS AND STRENGTHS

Film-coated tablets:

  • 267 mg yellow, biconvex, oval shaped, debossed with “3610” on one side and “TEVA” on the other side.
  • 801 mg purple, biconvex, oval shaped, debossed with “3611” on one side and “TEVA” on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Elevated Liver Enzymes and Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with pirfenidone. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with pirfenidone 2,403 mg/day in three Phase 3 trials 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 pirfenidone 2,403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3× ULN were reversible with dose modification or treatment discontinuation.

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with pirfenidone, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage modification or interruption may be necessary for liver enzyme elevations [see Dosage and Administration ( 2.1, 2.3)].

5.2 Photosensitivity Reaction or Rash

Patients treated with pirfenidone 2,403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash [see Dosage and Administration (2.3)].

5.3 Gastrointestinal Disorders

In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain were more frequently reported by patients in the pirfenidone treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2,403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the pirfenidone 2,403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions [see Dosage and Administration (2.3)].

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