Pirfenidone and Nintedanib

1. Pirfenidone and Nintedanib
DR. MD. SHAFIQUL ISLAM DEWAN
RESIDENT (PULMONOLOGY)
RESPIRATORY MEDICINE DEPARTMENT
DHAKA MEDICAL COLLEGE HOSPITAL
4/27/2023

2. 4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH
Pirfenidone

3. Mechanism of Action
Precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been
established.
Inhibits transforming growth factor (TGF)-beta, a chemical mediator that controls many cell
functions including proliferation and differentiation.
Also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in
inflammation.
Metabolized by Liver and Excreted by Kidney.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

4. Initial dose titration
Take with food
Doses should be taken at the same time each day.
Days 1-7: 267 mg PO TID (801 mg/day)
Days 8-14: 534 mg PO TID (1602 mg/day)
Day 15 and thereafter (maintenance): 801 mg PO TID; not to exceed 2403
mg/day.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

5. Treatment interruption
Following treatment interruption of ≥14 days: Titrate dosage upward using the
initial 2-week dosage titration regimen.
Following treatment interruption of <14 days: Therapy can be resumed at
dosage received prior to treatment interruption.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

6. Dosage Modifications
If patients experience significant adverse reactions (ie, gastrointestinal,
photosensitivity reaction, rash);
Consider temporary dosage reductions or therapy interruptions of pirfenidone
to allow for resolution of symptoms;
Discontinue if symptoms persist despite these interventions.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

7. CYP1A2 inhibitors
Strong inhibitors (eg, fluvoxamine, enoxacin): Reduce maintenance
dose to 267 mg (1 capsule) TID
Moderate inhibitors (eg, ciprofloxacin): Reduce maintenance dose
to 534 mg (2 capsules) TID (with ciprofloxacin 750 mg BID)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

8. Hepatic impairment
Mild-to-moderate (Child Pugh A or B): Use caution; monitor and consider
dosage modification or discontinuation as needed
Severe (Child Pugh C): Not recommended (not studied)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

9. Renal impairment
Mild, moderate, or severe: Use caution; monitor and consider dosage
modification or discontinuation as needed.
ESRD requiring dialysis: No recommended (not studied)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

10. Adverse Effects >10%
Nausea (36%)
Rash (30%)
Upper respiratory tract infection (27%)
Diarrhea (26%)
Fatigue (26%)
Abdominal pain (24%)
Headache (22%)
Decreased appetite (21%)
Dyspepsia (19%)
Dizziness (18%)
Vomiting (13%)
Gastroesophageal reflux disease (GERD) (11%)
Sinusitis (11%)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

11. 1-10%
Insomnia (10%)
Weight decreased (10%)
Arthralgia (10%)
Photosensitivity (9%)
Decreased appetite (8%)
Pruritus (8%)
Asthenia (6%)
Dysgeusia (6%)
Non-cardiac chest pain (5%)
AST/ALT ≥3 x ULN (3.7%
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

12. Post marketing Reports
Blood and lymphatic system disorders: Agranulocytosis
Immune system disorders: Angioedema
Hepatobiliary disorders: Drug-induced liver injury
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

13. Recommended liver monitoring
Perform liver function tests (ALT, AST, and bilirubin) before initiating treatment
with pirfenidone.
Monthly intervals for the first 6 months.
Then every 3 months thereafter.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

14. Dose adjustments due to liver enzyme abnormalities
3–5-times ULN without bilirubin elevation
◦ Exclude other causes
◦ Monitor the patient closely
◦ Consider discontinuing other medicines associated with liver toxicity
◦ Consider possible drug interactions if the patient is taking inhibitors of CYP isoenzymes
involved in the metabolism of pirfenidone.
◦ Reduce or interrupt the dose of pirfenidone if clinically appropriate
◦ Re-escalate pirfenidone to the recommended daily dose if tolerated once liver function
tests are within normal limits.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

15. Dose adjustments due to liver enzyme abnormalities
3–5-times ULN accompanied by hyperbilirubinaemia or clinical signs or symptoms indicative
of liver injury
◦ Permanently discontinue pirfenidone therapy; do not reinitiate
treatment
Higher than 5-times ULN
◦ Permanently discontinue pirfenidone therapy; do not reinitiate
treatment
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

16. Pregnancy & Lactation
Pregnancy: Data in pregnant women are insufficient to inform on drug
associated risks for major birth defects and miscarriage.
Lactation: No information is available on presence of pirfenidone in human
milk, effects of drug on breastfed infant, or effects of drug on milk production.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

17. 4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH
Nintedanib

18. Indication
Idiopathic pulmonary fibrosis
Chronic fibrosing interstitial lung disease with A progressive phenotype
Systemic sclerosis-associated interstitial lung disease
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

19. Mechanism of Action
Tyrosine kinase inhibitor; targets growth factors, which have been shown to be
potentially involved in pulmonary fibrosis (eg, vascular endothelial growth
factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-
derived growth factor receptor [PDGF])
Binds competitively to the adenosine triphosphate (ATP)-binding pocket of
these receptors and blocks the intracellular signaling, which is crucial for the
proliferation, migration, and transformation of fibroblasts, representing
essential mechanisms of the IPF pathology.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

20. Metabolism and Elimination
Metabolized by Liver
Excretion: 93.4% feces/biliary; 0.65% urine
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

21. Doses
Administer 150mg tab orally twice daily (approximately 12 hours apart) with
food.
Swallow capsules whole with liquid; do not chew or crush.
If a dose is missed, take the next dose at the regularly scheduled time. Do not
double the dose or take extra doses.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

22. Dosage Modification for Toxicity
Hepatic Toxicity
◦ ALT or AST elevations >3 times but <5 times the ULN without signs or
symptoms of severe liver damage: Temporarily interrupt therapy or reduce
dosage to 100 mg twice daily. When liver function tests return to baseline
values, may resume nintedanib at 100 mg twice daily and may subsequently
increase dosage to 150 mg twice daily.
◦ ALT or AST elevations >5 times the ULN, or >3 times the ULN with signs or
symptoms of severe liver damage: Discontinue therapy.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

23. Dosage Modification for Toxicity
Other Adverse Effects
◦ If adverse reactions occur and are intolerable, despite symptomatic
treatment, temporarily interrupt therapy or reduce dosage to 100 mg
twice daily until the adverse reaction improves or resolves.
◦ May resume nintedanib 150 mg twice daily; alternatively, initially
reduce dosage to 100 mg twice daily and may subsequently increase
dosage to 150 mg twice daily.
◦ Discontinue therapy if intolerable adverse reactions occur or persist at
a dosage of 100 mg twice daily.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

24. Hepatic Impairment
No initial dosage adjustment required in patients with mild hepatic impairment
(Child-Pugh class A); monitor closely and reduce dosage or temporarily interrupt
therapy if not tolerated.
Not studied in patients with moderate or severe hepatic impairment (Child-
Pugh class B or C).
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

25. Renal Impairment
No initial dosage adjustment required in patients with mild to moderate renal
impairment (Clcr 30–90 mL/minute).
Not studied in patients with severe renal impairment (Clcr <30 mL/minute) or
end-stage renal disease.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

26. Adverse Effects >10%
Idiopathic pulmonary fibrosis
◦ Diarrhea (62%)
◦ Nausea (24%)
◦ Abdominal pain (15%)
◦ Elevated liver enzymes (14%)
◦ Vomiting (12%)
◦ Decreased appetite (11%)
SSc-ILD
◦ Diarrhea (76%)
◦ Nausea (32%)
◦ Vomiting (25%)
◦ Skin ulcer (18%)
◦ Abdominal pain (18%)
◦ Liver enzyme elevation (13%)
◦ Decreased weight (12%)
◦ Fatigue (11%)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

27. Adverse Effects 1-10%
Idiopathic pulmonary fibrosis
◦ Decreased weight (10%)
◦ Bleeding events (10%)
◦ Headache (8%)
◦ Hypertension (5%)
◦ Arterial thromboembolic events (2.5%)
◦ Myocardial infarction (1.5%)
◦ Bronchitis (1.5%)
◦ Hypothyroidism (1.1%)
SSc-ILD
◦ Decreased appetite (9%)
◦ Headache (9%)
◦ Pyrexia (6%)
◦ Back pain (6%)
◦ Dizziness (6%)
◦ Hypertension (5%)
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

28. Post marketing Reports
Pancreatitis
Thrombocytopenia
Drug-induced liver injury
Rash
Pruritus
Alopecia
Nephrotic range proteinuria
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

29. Monitoring
Monitor liver function tests prior to initiation,
Monthly for the first 3 months,
Then every 3 months, and as clinically indicated.
4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH

30. 4/27/2023 DR. MD. SHAFIQUL ISLAM DEWAN, RESIDENT (PULMONOLOGY), DMCH
Thank You