Pirfenidone

Registered South African indications:

• Reduction of progression of mild to moderately severe idiopathic pulmonary fibrosis (IPF) in non-smoking and former-smoking adults

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• History of angioedema with pirfenidone
• Severe renal impairment (CrCl<30ml/min) or end stage renal disease requiring dialysis
• Severe hepatic impairment or end stage liver disease
• Coadministration with fluvoxamine
• Coadministration with strong cytochrome P450 CYP1A2 inducers, including cigarette smoking

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Moderate renal impairment
• Mild to moderate hepatic impairment

Hepatic function

• Medicine-induced liver injury 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
• Liver function tests (ALT, AST and bilirubin) should be performed prior to initiation of treatment with pirfenidone, and subsequently at monthly intervals for the first 6 months and then 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. For patients with confirmed elevation in ALT, AST or bilirubin during treatment, dose adjustments may be necessary

Photosensitivity reaction and rash

• Exposure to direct sunlight (including sunlamps) should be avoided or minimised 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 medicines known to cause photosensitivity
• Patients should be instructed to report symptoms of photosensitivity reaction or rash to their doctor. Dose adjustments or temporary treatment discontinuation may be necessary for photosensitivity reaction or rash. Caution is advised if pirfenidone is used concomitantly with medicines that can cause photosensitivity

Severe skin reactions

• Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening or fatal, have been reported post-marketing in associated with pirfenidone treatment. If signs and symptoms suggestive of these reactions appear, pirfenidone should be withdrawn immediately
• If the patient has developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of pirfenidone, treatment with pirfenidone must not be restarted and should be permanently discontinued

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 must not be used in patients with a history of angioedema or hypersensitivity due to pirfenidone

Dizziness

• Dizziness has been reported in patients taking pirfenidone. Therefore, patients should know how they react to pirfenidone before they engage in activities requiring mental alertness or coordination
• Data from clinical studies indicate that 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 pirofenidone before they engage in activities requiring mental alertness or coordination

Weight loss

• Weight loss has been reported in patients being treated with pirfenidone. Doctors should monitor a patient’s 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. 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

Sodium

• This medicine contains less than 1 mmol sodium (23mg) per film-coated tablet, that is to say essentially ‘sodium free’

Effects on ability to drive and use machines

• Pirfenidone may cause dizziness and fatigue, which could have a moderate influence on the ability to drive or use machines, therefore patients should exercise caution when driving or operating machinery if they experience these symptoms

Forms avail. in SA and covered in this monograph: cap, fct

South African registered indications and dosages

Reduction of progression of mild to moderately severe idiopathic pulmonary fibrosis (IPF) in non-smoking and former-smoking adults

Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403mg/day over a 14-day period as follows:

• Oral (cap, fct): Day 1-7: 267mg, 3 times a day (801mg/day); Day 8-14: 534mg, 3 times a day (1602mg/day); Day 15 onwards: 801mg, 3 times a day (2403mg/day); Max: 2403mg/24hrs

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Doses above 2403mg/day are not recommended for any patient

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Patients who miss 14 consecutive days or more of pirfenidone 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

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Method of administration:
Pirfenidone is to be swallowed whole with water and taken with food to reduce the possibility of nausea and dizziness

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For dose adjustments and other considerations, see Additional Prescribing Points

Not established for use in children

Pregnancy

South African recommendations

• Caution; not recommended
• Pirfenidone should not be taken during pregnancy

Breastfeeding

South African recommendations

• Caution; not recommended
• Pirfenidone must not be used during breastfeeding as safety and/or efficacy has not been established

Fertility

South African recommendations

• Data from preclinical studies demonstrate no adverse effects on fertility

South African recommendations

• Mild (CrCl>50ml/min): No dose adjustment recommended
• Moderate (CrCl 30-50ml/min): Caution; no dose adjustment recommended
• Severe (CrCl<30ml/min) or End-stage renal disease: Contraindicated
  Pirfenidone has not been studied and is not recommended in patients with end-stage renal disease requiring dialysis

South African recommendations

• Mild to moderate (Child-Pugh Class A and B): Caution; no dose adjustment recommended
  Since plasma levels of pirfenidone may be increased in some individuals with mild to moderate hepatic impairment, caution should be used with pirfenidone treatment in this population. Patients should be monitored closely for signs of toxicity especially if concomitantly taking a known CYP1A2 inhibitor
  It is recommended to monitor liver function during treatment, and dose adjustments may be necessary in the event of elevations
• Severe or End-stage liver disease: Contraindicated
  Pirfenidone has not been studied and is not recommended in patients with severe hepatic impairment or end stage liver disease

South African recommendations

• No dose adjustment recommended
  No dose adjustment is necessary in patients 65 years and older

Infections and Infestations

Frequent

• Upper respiratory tract infection
• Urinary tract infection

Blood and Lymphatic System Disorders

Less frequent

• Agranulocytosis (post-marketing) 

Immune System Disorders

Less frequent

• Angioedema (post-marketing)

Frequency unknown

• Anaphylaxis (post-marketing) 

Metabolism and Nutrition Disorders

Frequent

• Decreased weight
• Decreased appetite

Less frequent

• Hyponatraemia (post-marketing) 

Psychiatric Disorders

Frequent

• Insomnia

Nervous System Disorders

Frequent

• Headache
• Dizziness
• Somnolence
• Dysgeusia
• Lethargy

Vascular Disorders

Frequent

• Hot flush

Respiratory, Thoracic and Mediastinal Disorders

Frequent

• Dyspnoea
• Cough
• Productive cough

Gastrointestinal Disorders

Frequent

• Dyspepsia
• Nausea
• Diarrhoea
• Gastroesophageal reflux disease
• Vomiting
• Constipation
• Abdominal distension
• Abdominal discomfort
• Abdominal pain
• Upper stomach discomfort
• Gastritis
• Flatulence

Hepatobiliary Disorders

Frequent

• Alanine aminotransferase (ALT) increased
• Aspartate aminotransferase (AST) increased
• Gamma glutamyl transferase increased

Less frequent

• Total serum bilirubin increased in combination with increases of ALT and AST (post-marketing) 
• Medicine-induced liver injury (cases of severe medicine-induced liver injury, including reports with fatal outcome have been identified through post-marketing surveillance)

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash
• Photosensitivity reaction
• Pruritus
• Erythema
• Dry skin
• Rash erythematous
• Rash macular
• Rash pruritic

Frequency unknown

• Stevens-Johnson syndrome (post-marketing)
• Toxic epidermal necrolysis (post-marketing)

Musculoskeletal and Connective Tissue Disorders

Frequent

• Arthralgia
• Myalgia

General Disorders and Administration Site Conditions

Frequent

• Fatigue
• Asthenia
• Non-cardiac chest pain

Injury, Poisoning and Procedural Complications

Frequent

• Sunburn

• Fluvoxamine (strong CYP1A2 inhibitor)
• Strong CYP1A2 inducers, including cigarette smoking
• Inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6)
• Strong and selective inhibitors of CYP1A2 (e.g. enoxacin)
• Ciprofloxacin (moderate and selective inhibitor of CYP1A2)
• Amiodarone
• Propafenone
• Fluconazole
• Chloramphenicol
• Fluoxetine
• Paroxetine
• Omeprazole
• Rifampicin

Other interactions

• Grapefruit juice

• Hepatic function
  - Transaminases
  - Bilirubin
• Weight loss
• Laboratory parameters
  - Sodium levels

Additional observations

• Signs and symptoms such as nausea, headache or dizziness (indicative of hyponatraemia)
• Emergence of adverse reactions associated with pirfenidone therapy

Dose adjustments and other considerations

Gastrointestinal events

• Patients who experience intolerance to therapy due to gastrointestinal side effects should be reminded to take pirfenidone with food
• If symptoms persist the dose of pirfenidone may be reduced to 267mg to 534mg two to three times a day with food with re-escalation to the recommended daily dose as tolerated
• 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 to use a sunblock daily and to avoid exposure to the sun
• The dose of pirfenidone may be reduced to 801mg each day (267mg, three times daily). If the rash persists after 7 days, pirfenidone should be discontinued for 15 days, with reescalation 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. Once the rash has resolved, pirfenidone may be reintroduced and re-escalated up to the recommended daily dose at the discretion of the doctor

Hepatic function

• If a patient exhibits an aminotransferase elevation >3 to ˂5 x ULN without bilirubin elevation after starting pirfenidone 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 should be reduced or interrupted. Once liver functions tests are within normal limits, pirfenidone may be re-escalated to the recommended daily dose if tolerated
• If a patient exhibits aminotransferase elevation >3 to ˂5 x ULN accompanied by hyperbilirubinemia or clinical signs or symptoms indicative of liver injury, pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to ≥5 x ULN, pirfenidone should be discontinued and the patient should not be re-challenged

The mechanism of action of pirfenidone has not been established. However, existing data indicate that pirfenidone exerts both anti-fibrotic and anti-inflammatory properties in a variety of in vitro systems and animal models of pulmonary fibrosis (bleomycin- and transplant induced fibrosis). Idiopathic pulmonary fibrosis 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) and pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli. Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as transforming growth factor-beta (TGF- β) and platelet-derived growth factor (PDGF).

Capsule 267mg

• Esbriet (Roche) originator