Esbriet

Avoid exposure to sunlight or tanning beds. Pirfenidone can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Avoid smoking while taking this medicine. Smoking could make pirfenidone less effective.

Other drugs may interact with pirfenidone, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using pirfenidone.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Pirfenidone should be taken with food to help decrease nausea or dizziness.

Pirfenidone is usually taken 3 times per day. Your dose needs will change over the first 15 days of your treatment.

• For the first week, you will take only 1 capsule at a time.
• During the second week, you will take 2 capsules at a time.
• From the third week on, you will take 3 capsules at a time.

You must follow this 2-week "dose escalation" schedule when you start taking pirfenidone, or if you start taking the medicine again after not taking it for 14 days or longer. Follow your doctor's dosing instructions very carefully.

If you do stop taking pirfenidone for any reason, talk with your doctor before restarting the medicine.

You may need frequent medical tests to be sure pirfenidone is not causing harmful effects on your liver. Your next few doses may be delayed or reduced based on the results of these tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Do not take more than 3 doses in one day.

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Kidney disease or
• Liver disease or
• Stomach or bowel problems—Use with caution. May make these conditions worse.

Idiopathic Pulmonary Fibrosis

Treatment of idiopathic pulmonary fibrosis (IPF) (designated an orphan drug by FDA for this use).1 4

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Diarrhea
• itching or skin rash
• nausea
• redness or other discoloration of the skin
• severe sunburn
• stomach discomfort, upset, or pain
• vomiting

• Cough or hoarseness
• fever with or without chills
• general feeling of tiredness or weakness
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lower back or side pain
• painful or difficult urination
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• unusual bleeding or bruising

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• body aches or pain
• change in taste
• dizziness
• ear congestion
• headache
• heartburn or indigestion
• increased sensitivity of the skin to sunlight
• joint or muscle pain
• lack or loss of strength
• loss of appetite
• pain or tenderness around the eyes and cheekbones
• sneezing
• stuffy or runny nose
• trouble sleeping
• unusual tiredness or weakness
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat idiopathic pulmonary fibrosis.

• If you have an allergy to pirfenidone or any other part of Esbriet (pirfenidone).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Kidney disease or liver disease.
• If you are taking any drugs that may make your skin more sensitive to light. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Esbriet with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Chest pain or pressure.
• Very loose stools (diarrhea).
• Very upset stomach or throwing up.
• Very bad belly pain.
• Sunburn.
• Any unexplained bruising or bleeding.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Dizziness.
• Upset stomach or throwing up.
• Belly pain or heartburn.
• Signs of a common cold.
• Headache.
• Joint pain.
• Not hungry.
• Change in taste.
• Feeling tired or weak.
• Not able to sleep.
• Weight loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

Esbriet belongs to the chemical class of pyridone. Esbriet is available as a white to off-white hard gelatin capsule containing 267 mg of pirfenidone for oral administration, or, as film-coated tablets containing 267 mg (yellow) and 801 mg (brown) pirfenidone.

Pirfenidone has a molecular formula of C12H11NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or 5-methyl-1-phenyl-2-(1H)-pyridone.

Pirfenidone is a white to pale yellow, non-hygroscopic powder. It is more soluble in methanol, ethyl alcohol, acetone and chloroform than in water and 1.0 N HCl. The melting point is approximately 109°C.

Esbriet capsule contains pirfenidone and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate.

In addition, the capsule shell contains gelatin and titanium dioxide. The capsule brown printing ink includes shellac, iron oxide black, iron oxide red, iron oxide yellow, propylene glycol, ammonium hydroxide.

Esbriet tablets contain pirfenidone and the following inactive ingredients: Microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, and iron oxide.

Mechanism of Action

The mechanism of action of pirfenidone in the treatment of IPF has not been established.

Pharmacodynamics

Cardiac Electrophysiology:

The effect of Esbriet on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received Esbriet 2403 mg/day (recommended dose) and 4005 mg/day (1.6 times recommended dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active control).

Relative to placebo, the maximum mean change from baseline in study-specific QT interval was 3.2 milliseconds (ms) and 2.2 ms for Esbriet 2403 mg/day and 4005 mg/day, respectively. No volunteer had a QTc interval greater than 480 ms or change from baseline greater than 60 ms. Although there was no evidence that Esbriet prolonged the QTc interval in this study, a definitive conclusion may not be drawn as the positive control (moxifloxacin) did not perform as expected in this study, and Esbriet at 4005 mg/day (1.7 times the maximum recommended dose) did not cover the maximum pirfenidone exposure increase with co-administration of fluvoxamine, a strong CYP1A2 inhibitor.

Pharmacokinetics

Absorption:

After single oral-dose administration of 801 mg Esbriet (three 267 mg capsules), the maximum observed plasma concentration (Cmax) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median Tmax increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations (Cmax) and AUC0-inf decreased by approximately 49% and 16% with food, respectively.

Bioequivalence was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. The effect of food on pirfenidone exposure was consistent between the tablet and capsule formulations.

A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, Esbriet was taken with food [see Dosage and Administration (2) and Clinical Studies (14)].

The absolute bioavailability of pirfenidone has not been determined in humans.

Distribution:

Esbriet binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 μg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.

Metabolism:

In vitro profiling studies in hepatocytes and liver microsomes have shown that Esbriet is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of Esbriet results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.

No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Elimination:

The mean terminal half-life is approximately 3 hours in healthy subjects. Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of Esbriet was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).

Specific Populations:

Hepatic Impairment

The pharmacokinetics of Esbriet and the 5-carboxy-pirfenidone metabolite were studied in 12 subjects with moderate hepatic impairment (Child Pugh Class B) and in 12 subjects with normal hepatic function. Results showed that the mean exposure, AUC0-inf and Cmax of pirfenidone increased approximately 1.6- and approximately 1.4-fold in subjects with moderate hepatic impairment, respectively. The exposure of 5-carboxy-pirfenidone did not change significantly in subjects with moderate hepatic impairment.

Renal Impairment

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were studied in 18 subjects with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to 50 mL/min), and severe (CLcr less than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CLcr (greater than or equal to 80 mL/min) renal function. Results showed that systemic exposure (AUC0-inf) to pirfenidone increased approximately 1.4, 1.5, and 1.2-fold in subjects with mild, moderate and severe renal impairment, respectively. The corresponding AUC0-inf of 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold, although the change in the patients with mild renal impairment was not statistically significant. The renal clearance of 5-carboxy-pirfenidone decreased significantly in patients with moderate to severe renal impairment.

The pharmacokinetics and safety of Esbriet has not been studied in subjects with end-stage renal disease requiring dialysis.

Geriatric

Results of population pharmacokinetic analysis suggest that no dosage adjustment is needed in geriatric patients.

Gender

Results of population pharmacokinetic analysis of Esbriet showed no significant differences in pharmacokinetics between males and females.

Obesity

Results of population pharmacokinetic analysis showed that obesity (Body Mass Index [BMI] greater than or equal to 30 kg/m2) has no significant effect on the pharmacokinetics of Esbriet.

Race

Population pharmacokinetic analysis showed that race has no significant effect on the pharmacokinetics of pirfenidone.

Drug Interaction Studies:

Cytochrome P450 1A2 Inhibitors

Pirfenidone is a substrate of cytochrome P450 1A2. In a single-dose drug interaction study in 25 healthy nonsmokers and 25 smokers, Esbriet was coadministered with fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days, and 50 mg in the morning and 100 mg at bedtime for 4 days). An approximately 4-fold increase in exposure to pirfenidone in nonsmokers and approximately 7-fold increase in exposure in smokers was observed.

In a single-dose drug interaction study in 27 healthy subjects, coadministration of 801 mg of Esbriet and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.

Cytochrome P450 1A2 Inducers

Following a single oral dose of 801 mg Esbriet in 25 smokers and 25 healthy nonsmokers, the systemic exposure in smokers was significantly lower compared to nonsmokers. AUC0-inf and Cmax of pirfenidone in smokers were 46% and 68% of those in nonsmokers, respectively.

Inhibitory Effect of Pirfenidone on P-glycoprotein (Pgp)

The potential for pirfenidone to inhibit Pgp mediated transport of digoxin (5.0 µM) was evaluated in the absence and presence of pirfenidone at concentrations ranging from 1 to 1000 µM in in vitro system. Pirfenidone showed weak inhibition (10 to 30%) of Pgp facilitated digoxin B-A efflux at concentrations of 100 µM and above. Effect of pirfenidone upon Pgp substrate pharmacokinetics and safety has not been evaluated in humans.

Inhibitory Effect of Pirfenidone on CYP2C9, 2C19 or 1A2, 2D6, 3A4

The potential for pirfenidone to inhibit CYP2C9, 2C19 or 1A2 was evaluated in vitro at concentrations up to 1000 µM (approximately 10-fold the mean human Cmax). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1000 µM, pirfenidone inhibits the activity of these enzymes by 30.4%, 27.5%, 34.1%, 21%, and 9.6%, respectively. Effect of pirfenidone upon pharmacokinetics and safety of CYP2C9, 2C19, 1A2, 2D6, and 3A4 substrates has not been evaluated in humans.

NDC 50242-123-01

Esbriet®
(pirfenidone)
tablets

801 mg

Keep out of reach of children.

Rx only
90 tablets

Genentech

10181492

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: The effects in the nursing infant are unknown.