Consumer medicine information

Pirfenidone Dr.Reddy's

Pirfenidone

BRAND INFORMATION

Brand name

Pirfenidone Dr. Reddy's

Active ingredient

Pirfenidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pirfenidone Dr.Reddy's.

SUMMARY CMI

Pirfenidone Dr.Reddy's

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Pirfenidone Dr.Reddy's?

Pirfenidone Dr.Reddy's contains the active ingredient Pirfenidone. Pirfenidone Dr.Reddy's is used to treat Idiopathic Pulmonary Fibrosis (IPF).

For more information, see Section 1. Why am I using Pirfenidone Dr.Reddy's? in the full CMI.

2. What should I know before I use Pirfenidone Dr.Reddy's?

Do not use if you have ever had an allergic reaction to Pirfenidone or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Pirfenidone Dr.Reddy's? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Pirfenidone Dr.Reddy's and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Pirfenidone Dr.Reddy's?

  • Follow all directions given to you by your doctor or pharmacist carefully.

More instructions can be found in Section 4. How do I use Pirfenidone Dr.Reddy's? in the full CMI.

5. What should I know while using Pirfenidone Dr.Reddy's?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using pirfenidone.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine
Things you should not do
  • Do not this medicine to treat any other complaints unless your doctor tells you to.
    Do not stop taking your medicine or lower the dosage without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how medicine affects you.
Smoking
  • You should stop smoking before and during treatment with Pirfenidone Dr.Reddy's.
  • Cigarette smoking can reduce the effect of Pirfenidone Dr.Reddy's
Looking after your medicine
  • Keep your tablets in the bottle until it is time to take them.
  • If you take the tablets out of the bottle they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using Pirfenidone? in the full CMI.

6. Are there any side effects?

Some common side effects include skin reactions after going out in the sun or using sunlamps or tanning beds, rash or itching, feeling sick (nausea) and tiredness.

There are also serious side effects such as infection of the throat or of the airways going into the lungs or/or sinusitis, weight loss, difficulty in sleeping, dizziness serious and yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Pirfenidone Dr.Reddy's

Active ingredient(s): Pifenidone

Consumer Medicine Information (CMI)

This leaflet provides important information about using Pirfenidone Dr.Reddy's. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Pirfenidone Dr.Reddy's.

Where to find information in this leaflet:

1. Why am I using Pirfenidone Dr.Reddy's?
2. What should I know before I use Pirfenidone Dr.Reddy's?
3. What if I am taking other medicines?
4. How do I use Pirfenidone Dr.Reddy's?
5. What should I know while using Pirfenidone Dr.Reddy's?
6. Are there any side effects?
7. Product details

1. Why am I using Pirfenidone Dr.Reddy's?

Pirfenidone Dr.Reddy's contains the active ingredient pirfenidone.

Pirfenidone Dr.Reddy's is used to treat idiopathic Pulmonary Fibrosis (IPF).

IPF is a condition in which the tissues in your lungs become swollen and as a result makes it hard for your lungs to work property.

Pirfenidone Dr.Reddy's helps to reduce the scarring and swelling in the lungs, and helps you breathe better.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children.

2. What should I know before I use Pirfenidone Dr.Reddy's?

Warnings

Do not use Pirfenidone Dr.Reddy's if:

  • you are allergic to Pirfenidone, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant.

It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine.

It is not known if pirfenidone passes into breast milk. Talk to your doctor or pharmacist before taking Pirfenidone Dr.Reddy's, your doctor will discuss the risks and benefits of taking this medicine while breast feeding..

Do not give this medicine to a child or adolescents under the age of 18 years.

Safety and effectiveness in children and adolescents younger than 18 years have not been established.

Do not take Pirfenidone Dr.Reddy's if you are taking a medicine called fluvoxamine (used to treat depression and obsessive compulsive disorder (OCD).

Do not take Pirfenidone Dr.Reddy's if you have experienced an allergic reaction when previously taking Pirfenidone Dr.Reddy's.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not take Pirfenidone Dr.Reddy's if you have or have had any of the following:

  • severe liver problems
  • severe kidney problems including dialysis

Do not take Pirfenidone Dr.Reddy's after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • liver problems
  • are a smoker

Avoid the sun, including sunlamps or tanning beds, while taking Pirfenidone Dr.Reddy's.

You may become more sensitive to sunlight while taking Pirfenidone Dr.Reddy's.

It is important to wear sunblock daily and cover your arms legs and head to reduce exposure to sunlight.

You should stop smoking before and during treatment with Pirfenidone Dr.Reddy's.

Cigarette smoking can reduce the effect of Pirfenidone Dr.Reddy's.

Pirfenidone Dr.Reddy's may cause dizziness and tiredness.

Be careful if you have to take part in activities where you have to be alert and co-ordinated.

Pirfenidone Dr.Reddy's can cause weight loss.

Your doctor will monitor your weight while you are taking this medicine.

If you have not told your doctor about any of the above, tell him/ her before you start taking Pirfenidone Dr.Reddy's

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Pirfenidone Dr.Reddy's may interfere with each other. These include:

  • fluvoxamine a medicine used to treat depression and OCD.
  • tetracyclines (such as doxycycline) medicines used to treat infections and which may make you more sensitive to sunlight
  • ciprofloxacin and enoxacin, medicines used to treat infections
  • omeprazole, a medicine used in the treatment of indigestion, and stomach ulcers.
  • rifampicin a type of antibiotic
  • amiodarone, a medicine used to treat some types of heart disease
  • propafenone, a medicine used to treat some types of heart disease.

These medicines may be affected by Pirfenidone Dr.Reddy's or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

4. How do I use Pirfenidone Dr.Reddy's?

How much to take / use

  • The recommended dose of Pirfenidone Dr.Reddy's is:
    - Days 1 to 7: one tablets, three times a day with food.
    - Days 8 to 14: two tablets, three times a day with food
    - Day 15 onward: three tablets, three times a day with food

How to take it

  • Swallow the tablets whole with a full glass of water.
  • Take Pirfenidone Dr.Reddy's with or immediately after food.

Follow the instructions provided and use Pirfenidone Dr.Reddy's until your doctor tells you to stop.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help

When to take / use Pirfenidone Dr.Reddy's

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take Pirfenidone Dr.Reddy's with or immediately after food.

It is important to take Pirfenidone Dr.Reddy's with or immediately after food. This will reduce the risks of side effects such as nausea (feeling sick) and dizziness.

Do not drink grapefruit juice while taking Pirfenidone Dr.Reddy's.

Grapefruit may prevent Pirfenidone Dr.Reddy's from working properly.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to use Pirfenidone Dr.Reddy's

If you forget to take a dose take it as soon as you remember, but separate each dose by 3 hours.

Do not take more than 3 doses a day.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much Pirfenidone Dr.Reddy's

If you think that you have used too much Pirfenidone Dr.Reddy's, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Pirfenidone Dr.Reddy's?

Things you should do

Call your doctor straight away if you:

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Pirfenidone Dr.Reddy's.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to prevent unwanted side effects.

Remind any doctor, dentist or pharmacist you visit that you are using Pirfenidone Dr.Reddy's.

Things you should not do

Do not take Pirfenidone Dr.Reddy's to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen

If for any reason you have to stop taking Pirfenidone Dr.Reddy's for more than 14 consecutive days, your doctor will restart your treatment with 1 tablets 3 times a day, gradually increasing this to 3 tablets 3 times a day.

Things to be careful of Be careful driving or operating machinery until you know how Pirfenidone Dr.Reddy's affects you.

This medicine may cause dizziness, and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Pirfenidone Dr.Reddy's can cause low sodium level in the blood.

Tell your doctor if you experience nausea, headache or dizziness.

Your doctor may monitor your sodium levels while you are taking Pirfenidone Dr.Reddy's.

Looking after your medicine

  • Keep your tablets in the bottle until it is time to take them.
  • If you take the tablets out of the bottle they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.
  • Do not store Pirfenidone Dr.Reddy's or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.
  • Heat and dampness can destroy some medicines.
  • Keep it where children cannot reach it.
  • A locked cupboard at least one-and -half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Skin reactions after going out in the sun or using sunlamps or tanning beds
  • rash or itching
  • feeling sick (nausea)
  • tiredness
  • diarrhoea
  • indigestion or stomach upset
  • loss of appetite
  • headache
  • muscle aches or pain
  • dizziness
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • infection of the throat or of the airways going into the lungs or/or sinusitis
  • stomach problems such as acid reflux, vomiting, feeling bloated, abdominal pain and discomfort, heart burn, feeling constipated and passing wind
  • yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal.
  • changes in taste
  • weight loss
  • difficulty in sleeping
  • dizziness
  • feeling sleepy
  • swelling of face, lips and/or tongue, difficulty in breathing or wheezing.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Pirfenidone Dr.Reddy's contains

Active ingredient
(main ingredient)		pirfenidone
Other ingredients
(inactive ingredients)		Lactose monohydrate
Croscarmellose sodium
Colloidal silicon dioxide
Povidone
Purified water
Magnesium stearate
Polyvinyl alcohol
Macrogol
Titanium dioxide
Purified talc
Iron oxide black
Iron oxide red
Iron oxide yellow.
Potential allergenslactose

Do not take this medicine if you are allergic to any of these ingredients.

What Pirfenidone Dr.Reddy's looks like

Pirfenidone Dr.Reddy's 267 mg film coated tablets are yellow, oval, film coated tablets, debossed with “S 35” on one side and plain on another side (Aust R 407541).

Pirfenidone Dr.Reddy's 801 mg film coated tablets are purple, oval, film coated tablets, debossed with “S 36” on one side and plain on another side (Aust R 407540).

Who distributes Pirfenidone Dr.Reddy's

Dr Reddy's Laboratories (Australia) Pty Ltd
Suite 3.03, Level 3, 390 St Kilda Road
Melbourne, VIC, 3004
Phone: 1800 733 397

This leaflet was prepared in April 2023

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Pirfenidone Dr. Reddy's

Active ingredient

Pirfenidone

Schedule

S4

 

1 Name of Medicine

Pirfenidone.

2 Qualitative and Quantitative Composition

Pirfenidone Dr. Reddy's 267 mg film coated tablets contain 267 mg pirfenidone.
Pirfenidone Dr. Reddy's 801 mg film coated tablets contain 801 mg pirfenidone.

List of excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pirfenidone Dr. Reddy's 267 mg tablets are yellow, oval, film coated tablet, debossed with "S 35" on one side and plain on the other side.
Pirfenidone Dr. Reddy's 801 mg tablets are purple, oval, film coated tablet, debossed with "S 36" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Pirfenidone Dr. Reddy's is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

4.2 Dose and Method of Administration

Dose.

Treatment with Pirfenidone Dr. Reddy's should be initiated by physicians experienced in the diagnosis and treatment of IPF.

Adults.

The recommended daily dose of Pirfenidone Dr. Reddy's for patients with IPF is 801 mg three times a day with food, for a total of 2403 mg/day. It is recommended that dose titration occur with the 267 mg capsule or tablets.
Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/ day over a 14 day period as follows:
Days 1 to 7: a dose of 267 mg administered three times a day (801 mg/day).
Days 8 to 14: a dose of 534 mg administered three times a day (1602 mg/day).
Day 15 onward: a dose of 801 mg administered three times a day (2403 mg/day).
Doses above 2403 mg/day are not recommended for any patient (see Section 4.9 Overdose).

Missed doses.

Patients who miss 14 consecutive days or more of Pirfenidone Dr. Reddy's treatment should re-initiate therapy by undergoing the initial 2 week titration regimen up to the recommended daily dose.
For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

Dose adjustments and other considerations.

Gastrointestinal events.

In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist the dose of Pirfenidone Dr. Reddy's may be reduced to 267 mg-534 mg taken two to three times a day with food with re-escalation to the recommended daily dose as tolerated. Consider changing from the 801 mg dose form to a 267 mg dose form. If symptoms continue, patients may be instructed to interrupt treatment for one to two weeks to allow symptoms to resolve.

Photosensitivity reaction or rash.

Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid exposure to the sun (see Section 4.4 Special Warnings and Precautions for Use). The dose of Pirfenidone Dr. Reddy's may be reduced to 801 mg each day (267 mg three times daily). If the rash persists after 7 days, Pirfenidone Dr. Reddy's should be discontinued for 15 days, with re escalation to the recommended daily dose in the same manner as the dose escalation period.
Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice (see Section 4.4 Special Warnings and Precautions for Use).
Once the rash has resolved, Pirfenidone Dr. Reddy's may be reintroduced and re-escalated up to the recommended daily dose at the discretion of the physician.

Hepatic function.

If a patient exhibits an aminotransferase elevation > 3 to ≤ 5 x ULN without bilirubin elevation after starting Pirfenidone Dr. Reddy's therapy, other causes should be excluded and the patient monitored closely. Discontinuation of other medicines associated with liver toxicity should be considered. If clinically appropriate, the dose of Pirfenidone Dr. Reddy's should be reduced or interrupted. Once liver function tests are within normal limits, Pirfenidone Dr. Reddy's may be re-escalated to the recommended daily dose if tolerated.
If a patient exhibits an aminotransferase elevation > 3 to ≤ 5 x ULN accompanied by hyperbilirubinemia or clinical signs or symptoms indicative of liver injury, Pirfenidone Dr. Reddy's should be discontinued, and the patient should not be rechallenged.
If a patient exhibits an aminotransferase elevation to ≥ 5 x ULN, Pirfenidone Dr. Reddy's should be discontinued, and the patient should not be rechallenged.

Special populations.

Elderly.

No dose adjustment is necessary in patients 65 years and older (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No dose adjustment is necessary in patients with mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B). However, since plasma levels of pirfenidone may be increased in some individuals with mild to moderate hepatic impairment, caution should be used with Pirfenidone Dr. Reddy's treatment in this population. Patients should be monitored closely for signs of toxicity especially if concomitantly taking a known CYP1A2 inhibitor (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Pirfenidone Dr. Reddy's has not been studied and is not recommended in patients with severe hepatic impairment or end-stage liver disease, and it should not be used in patients with these conditions (see Section 4.4 Special Warnings and Precautions for Use). It is recommended to monitor liver function during treatment, and dose adjustments may be necessary in the event of elevations (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No dose adjustment is necessary in patients with mild renal impairment. Pirfenidone Dr. Reddy's should be used with caution in patients with moderate (CrCl 30-50 mL/min) due to lack of information relating to the metabolite (see Section 5.2 Pharmacokinetic Properties). Pirfenidone Dr. Reddy's has not been studied and is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease requiring dialysis (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of fluvoxamine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
History of angioedema with pirfenidone (see Section 4.4 Special Warnings and Precautions for Use).
Severe hepatic impairment or end-stage liver disease (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease requiring dialysis (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.4 Special Warnings and Precautions for Use

Hepatic function.

Drug-Induced Liver Injury (DILI) in the form of transient and clinically silent elevations in transaminases, has been commonly reported in patients treated with pirfenidone. Uncommonly, these elevations were associated with concomitant bilirubin increases, and serious clinical consequences including isolated cases with fatal outcome have been reported post-marketing.
Patients treated with pirfenidone 2403 mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥ 3 x ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥ 10 x ULN in ALT or AST occurred in 0.3% of patients in the pirfenidone 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥ 3 x ULN were reversible with dose modification or treatment discontinuation. No cases of liver transplant or death due to liver failure that were related to pirfenidone have been reported in phase 3 trials. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that could lead to death or the need for liver transplants in some patients. Perform liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with pirfenidone in all patients, then monthly for the first 6 months and every 3 months thereafter. In addition, liver function tests should be promptly measured in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. In the event of significant elevation of liver aminotransferases or clinical signs and symptoms of liver injury, the dose of pirfenidone should be adjusted or treatment discontinued (see Section 4.2 Dose and Method of Administration). For patients with confirmed elevations in ALT, AST or bilirubin during treatment, dose adjustments may be necessary (see Section 4.2 Dose and Method of Administration).

Photosensitivity reaction and rash.

Exposure to direct sunlight (including sunlamps) should be avoided or minimized during treatment with pirfenidone. Patients should be instructed to use an effective sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Dose adjustments or temporary treatment discontinuation may be necessary for photosensitivity reaction or rash (see Section 4.2 Dose and Method of Administration).

Cigarette smoking and inducers of CYP1A2.

A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase clearance and decrease exposure to pirfenidone. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone.

Use in renal impairment.

Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 mL/min) renal impairment due to lack of information relating to the metabolite (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease requiring dialysis.
Use of pirfenidone is contraindicated in patients with severe renal impairment or end-stage renal diseases requiring dialysis.

Use in hepatic impairment.

Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with severe hepatic impairment or end-stage liver disease. pirfenidone is contraindicated in patients with severe hepatic impairment or end-stage liver disease.

Angioedema/ anaphylaxis.

Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of pirfenidone in the post-marketing setting. Reports of anaphylactic reactions have also been received. Therefore, patients who develop signs or symptoms of angioedema or severe allergic reactions following administration of pirfenidone should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. pirfenidone should not be used in patients with a history of angioedema or hypersensitivity due to pirfenidone (see Section 4.3 Contraindications).

Dizziness.

Dizziness has been reported in patients taking pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see Section 4.7 Effects on Ability to Drive and Use Machines). In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of pirfenidone may be warranted.

Fatigue.

Fatigue has been reported in patients taking pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see Section 4.7 Effects on Ability to Drive and Use Machines).

Weight loss.

Weight loss has been reported in patients treated with pirfenidone (see Section 4.8 Adverse Effects (Undesirable Effects)). Physicians should monitor patients' weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance.

Hyponatraemia.

Hyponatraemia has been reported in patients treated with pirfenidone (see Section 4.8). As the symptoms of hyponatraemia may be subtle and masked by the presence of concomitant morbidities, regular monitoring of the relevant laboratory parameters is recommended, especially in the presence of evocative signs and symptoms such as nausea, headache or dizziness.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with the use of pirfenidone in the post-marketing setting. If signs or symptoms of SCAR occur, interrupt pirfenidone treatment until the aetiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue pirfenidone.

Paediatric use.

The safety and efficacy of pirfenidone in paediatric patients has not been established.

Use in the elderly.

No overall differences in safety or effectiveness were observed between older and younger patients. No dosage adjustment is required based upon age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pirfenidone is metabolized primarily via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.

Fluvoxamine and inhibitors of CYP1A2.

In a Phase 1 study, the co-administration of pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers.
Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine (see Section 4.3 Contraindications). Fluvoxamine should be discontinued prior to the initiation of pirfenidone therapy and avoided during pirfenidone therapy due to the reduced clearance of pirfenidone.
In vitro-in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone should be reduced to 801 mg daily (267 mg three times a day). Patients should be closely monitored for emergence of adverse reactions associated with pirfenidone therapy. Discontinue pirfenidone if necessary (see Section 4.2 Dose and Method of Administration).
Co-administration of pirfenidone and 750 mg of ciprofloxacin (a moderate and selective inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of pirfenidone should be reduced to 1602 mg daily (534 mg three times a day). pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily.
Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2.
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 avoided during pirfenidone treatment.

Inducers of CYP1A2.

In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels.
Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.

Effects of pirfenidone on transporters.

Pirfenidone is not a substrate for P-glycoprotein. In vitro, pirfenidone inhibited P-glycoprotein-mediated transport by approximately 30% at 1 mM, the highest concentration tested. The predicted intestinal concentration of pirfenidone at the MRHD is 1.7 mM. Therefore, pirfenidone may inhibit intestinal P-glycoprotein during clinical use. The effects of pirfenidone on other transport proteins have not been investigated.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility indices were unaffected in male and female rats treated with pirfenidone at oral doses up to 1000 mg/kg/day. However, prolongation of the oestrous cycle and a high incidence of irregular cycles was observed in rats at doses ≥ 450 mg/kg/day (1.7-times the maximum recommended human dose based on body surface area).
(Category B3)
There are no data from the use of pirfenidone in pregnant women.
In animals, placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. Pirfenidone was not teratogenic in rats or rabbits at oral doses up to 1000 mg/kg/day and 300 mg/kg/day in the respective species (approximately 4 and 2 times the maximum recommended human dose on a body surface area basis). In rats, treatment at ≥ 450 mg/kg/day was associated with delayed fetal ossification, and at 1000 mg/kg/day, prolongation of gestation and reduction in fetal viability were observed (the doses being approximately 2 to 4 times the MRHD). As a precautionary measure, it is preferable to avoid the use of pirfenidone during pregnancy.
 It is unknown whether pirfenidone or its metabolites are excreted in human milk. Studies in lactating rats have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. Postnatal body weight gain was reduced in the offspring of rats that received oral doses of pirfenidone at ≥ 300 mg/kg/day (approximately equal to the MRHD on a body surface area basis) during gestation and lactation. A risk to the breastfeeding child cannot be excluded.
A decision must be made whether to discontinue breast feeding or to discontinue from pirfenidone therapy, taking into account the benefit of breast feeding for the child and the benefit of pirfenidone therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of the ability to drive and use machines have been performed. pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The safety of pirfenidone has been evaluated in clinical studies including 1650 volunteers and patients.
More than 170 patients have been investigated in open studies for more than five years and some for up to 10 years.
The most commonly reported adverse reactions during clinical study experience with pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.4% versus 12.2%), rash (26.2% versus 7.7%), diarrhoea (18.8% versus 14.4%), fatigue (18.5% versus 10.4%), dyspepsia (16.1% versus 5.0%), anorexia (11.4% versus 3.5%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%).Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of pirfenidone and placebo in clinical studies.
The most common adverse reactions with an incidence of ≥ 10% and more frequent in the pirfenidone than placebo treatment group are listed in Table 1.
In the bioequivalence and safety study, GP29830, where one 801 mg pirfenidone tablet was compared to three 267 mg pirfenidone capsules, a greater proportion of subjects experienced adverse effects in the tablet, fed treatment group (n = 7 [15.9%]) compared with the capsule, fed treatment group (n = 1 [2.3%]. All AEs were non-serious, mild in severity, and consistent with the known safety profile of pirfenidone. The slight increase in Cmax of the tablet relative to capsules in the fed state is not expected to have a clinically meaningful effect.

Post marketing experience.

In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post approval use of pirfenidone. 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.

Immune system disorders.

Angioedema, anaphylaxis.

Hepatobiliary disorders.

Bilirubin increased in combination with increases of ALT and AST.
Clinically relevant drug-induced liver injury including isolated reports with fatal outcome.

Metabolism and nutrition disorders.

Uncommon: hyponatraemia.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and drug reaction with eosinophilia and systemic symptoms (DRESS).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is limited clinical experience with overdose. Multiple dosages of pirfenidone up to a total dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient and consistent with most frequently reported adverse reactions for pirfenidone.
In the event of a suspected overdose, supportive medical care should be provided including monitoring of vital signs and close observation of the clinical status of the patient.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: immunosuppressants, other immunosuppressants, ATC code: L04AX05.

Mechanism of action.

The mechanism of action of pirfenidone has not been fully established. Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β). Existing data indicate that pirfenidone exerts both anti-fibrotic and anti-inflammatory properties in animal models of inflammation and pulmonary fibrosis.

Pharmacodynamic effect.

Pirfenidone attenuated the release of pro-inflammatory and pro-fibrotic cytokines in response to inflammatory stimuli in mice at clinically relevant doses. In addition, pirfenidone was able to prevent the development of lung fibrosis when given prophylactically, and arrest further fibrosis development, in the bleomycin-induced model of lung fibrosis. Pirfenidone did not reverse established lung fibrosis in rats at clinically relevant doses.

Clinical trials.

The clinical efficacy of pirfenidone has been studied in three multinational, Phase 3, multicenter, randomized, double-blind, placebo-controlled studies in patients with idiopathic pulmonary fibrosis (IPF): PIPF 004, PIPF 006 (CAPACITY) and PIPF-016 (ASCEND).
PIPF 004 and PIPF 006 compared treatment with pirfenidone 2403 mg/day to placebo. The studies were nearly identical in design, with few exceptions including an intermediate dose group (1197 mg/day) in PIPF 004. In both studies, treatment was administered three times daily for a minimum of 72 weeks. The primary endpoint in both studies was the change from baseline to Week 72 in percent predicted Forced Vital Capacity (FVC).
In study PIPF 004, the decline in percent predicted FVC from baseline at Week 72 of treatment was significantly reduced in patients receiving pirfenidone (N = 174) compared with patients receiving placebo (N = 174; p = 0.001, rank ANCOVA). Treatment with pirfenidone also significantly reduced the decline in percent predicted FVC from baseline at Weeks 24 (p = 0.014), 36 (p < 0.001), 48 (p < 0.001), and 60 (p < 0.001). At Week 72, a decline from baseline in percent predicted FVC of ≥ 10% (a threshold indicative of the risk of mortality in IPF) was seen in 20% of patients receiving pirfenidone compared to 35% receiving placebo (Table 2).
Although there was no difference between patients receiving pirfenidone compared to placebo in change from baseline to Week 72 of distance walked during a six-minute walk test (6MWT) by the pre-specified rank ANCOVA, in an ad hoc analysis, 37% of patients receiving pirfenidone showed a decline of ≥ 50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-004.
In study PIPF 006, treatment with pirfenidone (N = 171) did not reduce the decline in percent predicted FVC from baseline at Week 72 compared with placebo (N = 173; p = 0.501). However, treatment with pirfenidone reduced the decline in percent predicted FVC from baseline at Weeks 24 (p < 0.001), 36 (p = 0.011), and 48 (p = 0.005). At Week 72, a decline in FVC of ≥ 10% was seen in 23% of patients receiving pirfenidone and 27% receiving placebo (Table 3).
The decline in 6MWT distance from baseline to Week 72 was significantly reduced compared with placebo (p < 0.001, rank ANCOVA). Additionally, in an ad hoc analysis, 33% of patients receiving pirfenidone showed a decline of ≥ 50 m in 6MWT distance, compared to 47% of patients receiving placebo.
In a pooled analysis of survival in PIPF 004 and PIPF 006 the mortality rate with pirfenidone 2403 mg/day group was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47 - 1.28]).
PIPF-016 compared treatment with pirfenidone 2,403 mg/day to placebo. Treatment was administered three times daily for 52 weeks. The primary endpoint was the change from baseline to Week 52 in percent predicted FVC. In a total of 555 patients, the median baseline percent predicted FVC and %DLCO were 68% (range: 48 - 91%) and 42% (range: 27 - 170%), respectively. Two percent of patients had percent predicted FVC below 50% and 21% of patients had a percent predicted DLCO below 35% at baseline.
In study PIPF-016, the decline in percent predicted FVC from baseline at Week 52 of treatment was significantly reduced in patients receiving pirfenidone (N = 278) compared with patients receiving placebo (N = 277; p < 0.000001, rank ANCOVA). Treatment with pirfenidone also significantly reduced the decline in percent predicted FVC from baseline at Weeks 13 (p < 0.000001), 26 (p < 0.000001), and 39 (p = 0.000002). At Week 52, a decline from baseline in percent predicted FVC of ≥ 10% or death was seen in 17% of patients receiving pirfenidone compared to 32% receiving placebo (Table 4).
The decline in distance walked during a 6MWT from baseline to Week 52 was significantly reduced in patients receiving pirfenidone compared with patients receiving placebo in PIPF016 (p = 0.036, rank ANCOVA); 26% of patients receiving pirfenidone showed a decline of ≥ 50 m in 6MWT distance compared to 36% of patients receiving placebo.
In a pre-specified pooled analysis of studies PIPF-016, PIPF-004, and PIPF-006 at Month 12, all-cause mortality was significantly lower in pirfenidone 2403 mg/day group (3.5%, 22 of 623 patients) compared with placebo (6.7%, 42 of 624 patients), resulting in a 48% reduction in the risk of all-cause mortality within the first 12 months (HR 0.52 [95% CI, 0.31 - 0.87], p = 0.0107, log-rank test).

5.2 Pharmacokinetic Properties

Absorption.

Administration of pirfenidone tablets with food results in a large reduction in Cmax (by 40%) and a smaller effect on AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to healthy older adult volunteers (20-54 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80-85% of the AUC observed in the fasted state.
A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when compared to the fasted group. Therefore, it is recommended that pirfenidone be administered with food to reduce the incidence of nausea and dizziness.
Bioequivalence between the tablets and capsules was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. In the fed state, the 801 mg tablet met bioequivalence criteria based on the AUC measurements compared to the capsules, while the 90% confidence intervals for Cmax (108.26% - 125.60%) slightly exceeded the upper bound of standard bioequivalence limit.
The absolute bioavailability of pirfenidone has not been determined in humans.

Distribution.

Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean binding ranged from 50% to 62% in studies conducted in vitro (1 to 100 microgram/mL) and ex vivo. Mean apparent oral steady-state volume of distribution is approximately 70 L, indicating that pirfenidone distribution to tissues is modest.

Metabolism.

In vitro metabolism studies with hepatic microsomes indicate that pirfenidone is metabolized primarily via CYP1A2 with lesser contribution from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The major metabolite, 5-carboxy-pirfenidone, displays no or only very weak pharmacological activity.

Excretion.

The oral clearance of pirfenidone appears modestly saturable. In a multiple dose, dose ranging study in healthy older adults administered doses ranging from 267 mg to 1335 mg three times a day, the mean clearance decreased by approximately 25% above a dose of 801 mg three times a day. Following single dose administration of pirfenidone in healthy older adults, the mean apparent terminal elimination half-life was approximately 2.4 hours.
Approximately 80% of an orally administered dose of pirfenidone is cleared in the urine within 24 hours of dosing. The majority of pirfenidone is excreted as the 5-carboxy-pirfenidone metabolite (> 95% of that recovered), with less than 1% of pirfenidone excreted unchanged in urine.

Pharmacokinetics in special populations.

Hepatic impairment.

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were compared in subjects with moderate hepatic impairment (Child Pugh Class B) and in subjects with normal hepatic function. Results showed that there was a mean increase of 60% in pirfenidone exposure after a single dose of 801 mg pirfenidone (3 x 267 mg capsule) in patients with moderate hepatic impairment. Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment and patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). Pirfenidone is contraindicated in severe hepatic impairment and end-stage liver disease (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjects with mild to severe renal impairment compared with subjects with normal renal function. The parent substance is predominantly metabolised to 5-carboxy-pirfenidone, for which pharmacodynamic and safety margins were not established. The AUC0-∞ of 5-carboxy-pirfenidone was significantly higher in the moderate (p=0.009) and severe (P < 0.0001) renal impairment groups than in the group with normal renal function. The predicted amount of metabolite accumulation at steady state is not pharmacodynamically important because the terminal elimination half-life is only 1-2 hours in these subjects and there is no or minimal pharmacologic activity on the metabolite measured by TNF inhibitory effects.
Population pharmacokinetic analyses from 4 studies in healthy subjects or subjects with renal impairment and one study in patients with IPF showed no clinically relevant effect of age, gender or body size on the pharmacokinetics of pirfenidone.

5.3 Preclinical Safety Data

Genotoxicity.

Pirfenidone showed no indication of genotoxic activity in assays for bacterial mutagenicity, for chromosomal aberrations in vitro in mammalian cells, for clastogenicity in vivo in mice, and for DNA damage in rats. No significant mutagenic activity was observed with pirfenidone in bacteria when tested under UV exposure.

Carcinogenicity.

An increased incidence of liver tumours (hepatocellular adenomas and carcinomas, and hepatoblastomas) was observed in 2-year carcinogenicity studies conducted by the oral route in rats and mice. This occurred at doses ≥ 750 mg/kg/day and ≥ 800 mg/kg/day in the respective species, associated with systemic exposure (plasma AUC) less than that of patients at the maximum recommended human dose. These hepatic findings are consistent with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients receiving pirfenidone. These findings are considered unlikely to be relevant to humans, but this cannot be excluded.
A statistically significant increase in uterine tumours (adenocarcinoma) was observed in female rats administered 1500 mg/kg/day, yielding systemic exposure (plasma AUC) similar to that in patients at the maximum recommended human dose of 2403 mg/day. The relevance of this finding to humans is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Croscarmellose sodium, lactose monohydrate, colloidal anhydrous silica, povidone, magnesium stearate.

Film coating.

Polyvinyl alcohol, macrogol 4000, purified talc, titanium dioxide, iron oxide black (801 mg), iron oxide red (801 mg), iron oxide yellow (267 mg).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Pirfenidone Dr. Reddy's 267 mg, and 801 mg film-coated tablets are available in high-density polyethylene (HDPE) with a child resistant cap for bottles of 90 tablets.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

53179-13-8.
The chemical name of pirfenidone is 5-methyl-1-phenyl-2-1(H)-pyridone. It has a molecular formula of C12H11NO and a molecular weight of 185.23.
Pirfenidone is a white to pale yellow, non-hygroscopic powder. It is freely soluble in methanol, ethyl alcohol, acetone and chloroform. Sparingly soluble in 1.0 N HCl, water and 0.1 N sodium hydroxide. The melting point is approximately 109°C.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes