Consumer medicine information

Pirfenidone Sandoz

Pirfenidone

BRAND INFORMATION

Brand name

Pirfenidone Sandoz

Active ingredient

Pirfenidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pirfenidone Sandoz.

SUMMARY CMI

PIRFENIDONE SANDOZ®

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 SANDOZ?

PIRFENIDONE SANDOZ contains the active ingredient pirfenidone. PIRFENIDONE SANDOZ is used to treat Idiopathic Pulmonary Fibrosis (IPF).

For more information, see Section 1. Why am I using PIRFENIDONE SANDOZ? in the full CMI.

2. What should I know before I use PIRFENIDONE SANDOZ?

Do not use PIRFENIDONE SANDOZ 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 SANDOZ? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PIRFENIDONE SANDOZ 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 SANDOZ?

  • The recommended dose of PIRFENIDONE SANDOZ is:
    Days 1 to 7: one 267 mg tablet, three times a day with food
    Days 8 to 14: two 267 mg tablets or one 534 mg tablet, three times a day with food
    Day 15 onward: three 267 mg tablets or one 801 mg tablet, three times a day with food

More instructions can be found in Section 4. How do I use PIRFENIDONE SANDOZ? in the full CMI.

5. What should I know while using PIRFENIDONE SANDOZ?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using PIRFENIDONE SANDOZ.
  • PIRFENIDONE SANDOZ can cause low sodium levels 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 SANDOZ.
Things you should not do
  • Do not stop using this medicine or lower the dosage without checking with your doctor.
Driving or using machines
  • PIRFENIDONE SANDOZ 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.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Store below 30°C.

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

6. Are there any side effects?

Common side effects: rash or itching, diarrhoea, feeling sick (nausea), indigestion or stomach upset, loss of appetite, headache

Serious side effects: yellowing of your skin or the white part of your eyes (jaundice), dark or brown urine, infection of the throat or of the airways going into the lungs or sinusitis

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 SANDOZ®

Active ingredient(s): pirfenidone

Consumer Medicine Information (CMI)

This leaflet provides important information about using PIRFENIDONE SANDOZ. 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 SANDOZ.

Where to find information in this leaflet:

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

1. Why am I using PIRFENIDONE SANDOZ?

PIRFENIDONE SANDOZ contains the active ingredient pirfenidone.

PIRFENIDONE SANDOZ is used to treat Idiopathic Pulmonary Fibrosis (IPF). PIRFENIDONE SANDOZ 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.

2. What should I know before I use PIRFENIDONE SANDOZ?

Warnings

Do not use PIRFENIDONE SANDOZ 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 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
  • you are taking a medicine called fluvoxamine (used to treat depression and obsessive compulsive disorder (OCD)).
  • you have or have had any of the following:
    - severe liver problems
    - severe kidney problems including dialysis
  • it is after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions
    - kidney problems
    - liver problems
  • are a smoker
  • take any medicines for any other condition

Serious skin reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms and toxic epidermal necrolysis have been reported in association with pirfenidone treatment. Stop using PIRFENIDONE SANDOZ and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in Section 6. Are there any side effects?

Avoid the sun, including sunlamps or tanning beds, whilst taking PIRFENIDONE SANDOZ.

You may become more sensitive to sunlight while taking PIRFENIDONE SANDOZ. 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 SANDOZ. Cigarette smoking can reduce the effect of PIRFENIDONE SANDOZ.

PIRFENIDONE SANDOZ may cause dizziness and tiredness. Be careful if you have to take part in activities where you have to be alert and coordinated.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

Use in Children

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.

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 may interfere with PIRFENIDONE SANDOZ and affect how it works. 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 Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect PIRFENIDONE SANDOZ.

4. How do I use PIRFENIDONE SANDOZ?

How much to take

  • The recommended dose of PIRFENIDONE SANDOZ is:
    Days 1 to 7: one 267 mg tablet, three times a day with food
    Days 8 to 14: two 267 mg tablets or one 534 mg tablet, three times a day with food
    Day 15 onward: three 267 mg tablets or one 801 mg tablet, three times a day with food

When to take PIRFENIDONE SANDOZ

  • PIRFENIDONE SANDOZ should be used 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.

How to take PIRFENIDONE SANDOZ

  • Swallow the tablets whole with a full glass of water.
    If you are having trouble swallowing the tablets, talk to your pharmacist.
  • Take PIRFENIDONE SANDOZ with or immediately after food.
    It is important to take PIRFENIDONE SANDOZ 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 SANDOZ.
    Grapefruit may prevent PIRFENIDONE SANDOZ from working properly.

How to long to take PIRFENIDONE SANDOZ

  • Continue taking your medicine for as long as your doctor tells you to.
    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 SANDOZ

PIRFENIDONE SANDOZ should be used regularly at the same time each day.

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 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 SANDOZ

If you think that you have used too much PIRFENIDONE SANDOZ, 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 SANDOZ?

Things you should do

Call your doctor straight away if you:

  • Experience nausea, headache or dizziness. Your doctor may monitor your sodium levels while you are taking PIRFENIDONE SANDOZ. PIRFENIDONE SANDOZ can cause low sodium levels in the blood.
  • Become pregnant while taking this medicine.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PIRFENIDONE SANDOZ.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • Keep all 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 SANDOZ.

Things you should not do

  • Do not stop using this medicine or lower the dosage without checking with your doctor.
    If you stop suddenly, your condition may worsen.
    If for any reason you have to stop taking PIRFENIDONE SANDOZ for more than 14 consecutive days, your doctor will restart your treatment with one 267 mg tablet three times a day, gradually increasing this to three 267 mg tablets or one 801 mg tablet three times a day.
  • Do not take PIRFENIDONE SANDOZ 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PIRFENIDONE SANDOZ affects you.

PIRFENIDONE SANDOZ 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place below 30°C away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-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 related
  • skin reactions after going out in the sun or using sunlamps or tanning beds
  • rash or itching
Gut related
  • diarrhoea
  • feeling sick (nausea)
  • indigestion or stomach upset
  • loss of appetite
  • stomach problems such as acid reflux, vomiting, feeling bloated, abdominal pain and discomfort, heart burn, feeling constipated and passing wind.
Others
  • muscle aches or pain
  • dizziness
  • tiredness
  • headache
Speak to your doctor if you have any of these less serious side effects and they worry you.
They are generally mild and do not cause patients to stop taking PIRFENIDONE SANDOZ.

Serious side effects

Serious side effectsWhat to do
Mental states related
  • difficulty in sleeping
  • feeling sleepy
Liver related:
  • 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.
Allergy related
  • swelling of face, lips and/or tongue
  • difficulty in breathing or wheezing
Infection related
  • infection of the throat or of the airways going into the lungs or sinusitis
Skin related
  • reddish non-elevated, or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes.
    These serious skin rashes can be preceded by fever and flu-like symptoms. These signs and symptoms may indicate Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms or toxic epidermal necrolysis.
Others
  • change in taste
  • weight loss
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 SANDOZ contains

Active ingredient
(main ingredient)		pirfenidone
Other ingredients
(inactive ingredients)
  • pregelatinised starch
  • croscarmellose sodium
  • hyprolose
  • silicon dioxide
  • magnesium stearate
  • OPADRY II Complete Film Coating System Yellow (267 mg)
  • OPADRY II Complete Film Coating System Pink (801 mg)

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

What PIRFENIDONE SANDOZ looks like

PIRFENIDONE SANDOZ 267 mg - yellow, oval, biconvex, film-coated tablets, debossed SD267 on one side.
(Aust R 356830)

PIRFENIDONE SANDOZ 801 mg - dark pink, oval, biconvex, film-coated tablets, debossed SD801 on one side.
(Aust R 356831)

Who distributes PIRFENIDONE SANDOZ

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was prepared in November 2023.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Pirfenidone Sandoz

Active ingredient

Pirfenidone

Schedule

S4

 

1 Name of Medicine

Pirfenidone.

2 Qualitative and Quantitative Composition

Pirfenidone Sandoz 267 mg film coated tablets contain 267 mg pirfenidone.
Pirfenidone Sandoz 801 mg film coated tablets contain 801 mg pirfenidone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pirfenidone Sandoz 267 mg tablets are yellow, oval, biconvex, film-coated tablets, debossed SD267 on one side.
Pirfenidone Sandoz 801 mg tablets are dark pink, oval, biconvex, film-coated tablets, debossed SD801 on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Pirfenidone Sandoz is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

4.2 Dose and Method of Administration

Dosage.

Treatment with Pirfenidone Sandoz should be initiated by physicians experienced in the diagnosis and treatment of IPF.

Adults.

The recommended daily dose of Pirfenidone Sandoz 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 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 Sandoz 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 Sandoz 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 Sandoz may be reduced to 801 mg each day (267 mg three times daily). If the rash persists after 7 days, Pirfenidone Sandoz 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 Sandoz 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 Sandoz 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 Sandoz should be reduced or interrupted. Once liver function tests are within normal limits, Pirfenidone Sandoz 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 Sandoz should be discontinued and the patient should not be rechallenged.
If a patient exhibits an aminotransferase elevation to ≥ 5 x ULN, Pirfenidone Sandoz 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 Sandoz 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 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 Sandoz 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 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 Sandoz 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 Sandoz 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 Sandoz. 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 Sandoz 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 Sandoz is contraindicated in patients with severe renal impairment or end-stage renal diseases requiring dialysis.

Use in hepatic impairment.

Pirfenidone Sandoz 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 Sandoz 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 Sandoz should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Pirfenidone Sandoz 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 Sandoz 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 Adverse Effects (Undesirable Effects)). 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 Sandoz treatment until the aetiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue Pirfenidone Sandoz.

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.

Paediatric use.

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

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 Sandoz is contraindicated in patients with concomitant use of fluvoxamine (see Section 4.3 Contraindications). Fluvoxamine should be discontinued prior to the initiation of Pirfenidone Sandoz therapy and avoided during Pirfenidone Sandoz 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 Sandoz therapy. Discontinue Pirfenidone Sandoz 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 Sandoz should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily.
Pirfenidone Sandoz 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 Sandoz 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 Sandoz 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 Sandoz therapy, taking into account the benefit of breast feeding for the child and the benefit of Pirfenidone Sandoz 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 Sandoz 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.

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 suspected adverse effects.

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 (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

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 Poisons Information Centre on 131126 (Australia) and 0800 POISON or 0800 764766 (New Zealand).

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 antifibrotic 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 PIPF-016 (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.
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 Sandoz 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

Pregelatinised starch, croscarmellose sodium, hyprolose, silicon dioxide, magnesium stearate, Opadry II Complete Film Coating System Yellow (267 mg), Opadry II Complete Film Coating System Pink (801 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 Sandoz 267 mg.

Pack size of 90 and 270 tablets in high-density polyethylene (HDPE) bottles. However, not all pack sizes are being distributed in Australia.

Pirfenidone Sandoz 801 mg.

Pack size of 90 tablets in high-density polyethylene (HDPE) bottles.
*Pirfenidone Sandoz is only available as a film-coated tablet.

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)

S4 - Prescription Only Medicine.

Summary Table of Changes