Pirfenidone (pirfenidone)

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Pirfenidone is administered orally 3 times daily with food, at the same time every day.

If a dose of pirfenidone is missed, the next dose should be administered as soon as it is remembered; a double dose should not be administered to make up for a missed dose. No more than 3 doses should be taken per day.

Store capsules and tablets at 25degreesC; excursions permitted between 15-30degreesC.

Pirfenidone is metabolized principally by cytochrome P-450 (CYP) isoenzyme 1A2, and, to a lesser extent, by CYP isoenzymes 2C9, 2C19, 2D6, and 2E1.

In vitro studies indicate that pirfenidone has a weak inhibitory potential on P-glycoprotein (P-gp); effects of pirfenidone on P-gp substrates have not been studied to date.

Pirfenidone also demonstrated concentration-dependent inhibition of CYP2C9, 2C19, 1A2, 2D6, and 3A4 in vitro; effects of pirfenidone on drugs metabolized by these isoenzymes have not been studied to date.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Pirfenidone/Ciprofloxacin (>=750 Mg Bid)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1,2) Moderate inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1,2) Ciprofloxacin is a moderate inhibitor of CYP1A2.(3,4)

CLINICAL EFFECTS: Concurrent pirfenidone use with ciprofloxacin may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1,2)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine). The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The manufacturer of pirfenidone recommends avoiding concurrent use of ciprofloxacin at doses of 750 mg twice daily or higher. If concurrent use cannot be avoided, reduce pirfenidone dose to 534 mg three times daily (total daily dose of 1,602 mg/day). Monitor patients closely when ciprofloxacin is used at a daily dosage of 250 mg to 1,000 mg.(1,2) Combinations of ciprofloxacin with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and avoided during pirfenidone treatment.(2)

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(2)

Pirfenidone/Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1,2) Strong inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1,2) Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19, and a weak inhibitor of CYP2C9 and so inhibits both primary and secondary pirfenidone metabolic pathways.(3,4)

CLINICAL EFFECTS: Concurrent pirfenidone use with strong inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1,2)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with fluvoxamine, which also inhibits CYP2C19, or with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine). The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The US manufacturer of pirfenidone states that concurrent use with strong inhibitors of CYP1A2 is not recommended. Use of strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during treatment with pirfenidone. Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and avoided during pirfenidone treatment. If concurrent therapy of pirfenidone and strong CYP1A2 inhibitors cannot be avoided, reduce pirfenidone to one-267 mg capsule three times a day (total daily dose of 801 mg/day).(2) The Canadian(1) and Indian(5) manufacturers of pirfenidone states that fluvoxamine is contraindicated with pirfenidone and fluvoxamine should be discontinued prior to initiation of pirfenidone therapy. The concurrent use of pirfenidone and other strong or moderate CYP1A2 inhibitors should be used with caution.

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(2) Strong CYP1A2 inhibitors include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4)

Selected Cyp1a2 Substrates/Obeticholic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Although the mechanism is not clear, authors suspect obeticholic acid down-regulates CYP1A2 mRNA expression, resulting in lower systemic concentrations of the CYP1A2 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of obeticholic acid with narrow therapeutic index drugs which are primarily metabolized by CYP1A2 may lead to elevated levels and increased side effects of the CYP1A2 substrate. CYP1A2 substrates linked to this monograph include: agomelatine, pirfenidone, tacrine, theophylline, and tizanidine.

PREDISPOSING FACTORS: With tizanidine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5)

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window and are primarily metabolized by CYP1A2. If coadministration cannot be avoided, the manufacturer of obeticholic acid recommends close monitoring and possible dose reduction of the affected drug.(2) The US manufacturer of tizanidine recommends avoiding concurrent therapy with CYP1A2 inhibitors. If concurrent therapy is necessary, tizanidine should be initiated with a 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(4)

DISCUSSION: In an interaction study, multiple doses of obeticholic acid increased systemic exposure (AUC, area-under-curve) to caffeine (a sensitive CYP1A2 substrate) by 42%.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Pirfenidone/Ciprofloxacin (<750 Mg Bid)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1,2) Moderate inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1,2) Ciprofloxacin is a moderate inhibitor of CYP1A2.(3,4)

CLINICAL EFFECTS: Concurrent pirfenidone use with ciprofloxacin may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1,2)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine). The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The manufacturer of pirfenidone recommends avoiding concurrent use of ciprofloxacin at doses of 750 mg twice daily or higher. If concurrent use cannot be avoided, reduce pirfenidone dose to 534 mg three times daily (total daily dose of 1,602 mg/day). Monitor patients closely when ciprofloxacin is used at a daily dosage of 250 mg to 1,000 mg.(1,2) Combinations of ciprofloxacin with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and avoided during pirfenidone treatment.(2)

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(2)

Pirfenidone/Moderate Cyp1a2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1) Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1)

CLINICAL EFFECTS: Concurrent pirfenidone use with moderate inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1) The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The manufacturer of pirfenidone states that for concurrent use with moderate inhibitors of CYP1A2, dose reduction is recommended. Reduce the dose of pirfenidone to two-267 mg capsules three times a day (total daily dose of 1602 mg/day).(1) Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued prior to and avoided during pirfenidone treatment.(1)

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(1) In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)

*None.

There are no contraindication contraindications for this drug.

• Gastroesophageal reflux disease
• Tobacco smoker

• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Kidney disease with likely reduction in glomerular filtration rate (GFr)

Adverse effects reported in >=10% of patients receiving pirfenidone include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, decreased appetite, GERD, sinusitis, insomnia, decreased weight, and arthralgia.

Less Frequent

• Abnormal hepatic function tests
• Increased alanine transaminase
• Increased aspartate transaminase

Rare or Very Rare

• Agranulocytosis
• Angioedema
• DRESS syndrome
• Drug-induced hepatitis
• Hyperbilirubinemia
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Arthralgia
• Diarrhea
• Dizziness
• Dyspepsia
• Fatigue
• Gastroesophageal reflux disease
• Headache disorder
• Insomnia
• Nausea
• Sinusitis
• Skin rash
• Upper respiratory infection
• Vomiting
• Weight loss

Less Frequent

• Anorexia
• Dysgeusia
• Non-cardiac chest pain
• Pruritus of skin
• Skin photosensitivity

No enhanced messaging available.

Safety and efficacy of pirfenidone have not been established in pediatric patients.

Data on the use of pirfenidone in pregnant females are insufficient to determine the drug-associated risks of birth defects and miscarriage. In animal reproductive studies, pirfenidone was not teratogenic when administered at oral doses up to 2 and 3 times the maximum recommended adult dosage.

No data is available on the presence of pirfenidone or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. The known benefits of breastfeeding should be considered along with the mother's clinical need for pirfenidone and any potential adverse effects on the breast-fed infant from either the drug or the underlying maternal condition.

Pirfenidone or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk.

No dosage adjustment is required for geriatric patients.

In clinical studies of pirfenidone, 67% of patients were >=65 years of age and 22% were >=75 years of age. No overall differences in safety and efficacy were observed between geriatric patients and younger adults.