Pirfenidone
200 mg film-coated Tablet
Category:
Immunosuppressants
(Medicines.org.uk)
Chemistry:
Pirfenidone has a molecular formula of C12H11NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or 5-methyl-1-phenyl-2-(1H)-pyridone.
(Rxlist)
Pharmacokinetics:
Absorption: Maximum plasma concentration (Cmax) is observed between 30 minutes and 4 hours after single dose. Food decreases the rate and extent of absorption, with median time to maximal concentration (Tmax) increased from 0.5 hours to 3 hours, maximum plasma concentration (Cmax) decreased by 49%, and AUC decreased by 16%.
Distribution: Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean binding ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 μg/ml). Mean apparent oral steady-state volume of distribution is approximately 70 l, indicating that pirfenidone distribution to tissues is modest.
Metabolism: Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro data indicate some pharmacologically relevant activity of the major metabolite (5-carboxy-pirfenidone) at concentrations in excess of peak plasma concentrations in IPF patients.
Elimination: The oral clearance of pirfenidone appears modestly saturable. Following single dose administration 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% excreted unchanged in urine.
(Medicines.org.uk, PDR.net)
Indications:
pirfenidone is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF).
(Medicines.org.uk)
Contraindications:
Hypersensitivity to the active substance or to any of the excipients.
• History of angioedema with pirfenidone.
• Concomitant use of fluvoxamine.
• Severe hepatic impairment or end stage liver disease.
• Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
(Medicines.org.uk)
Warnings & Precautions:
- Liver function tests (ALT, AST and bilirubin) should be performed prior to the initiation of treatment, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter.
- In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
- Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e., Child-Pugh Class A and B). Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor.
- Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with pirfenidone. Patients should be instructed to use a 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 in mild to severe cases of photosensitivity reaction or rash.
- If signs and symptoms suggestive of Severe skin reactions appear, pirfenidone should be withdrawn immediately. If the patient has developed SJS or TEN with the use of pirfenidone, treatment must not be restarted and should be permanently discontinued.
- patients who develop signs or symptoms of angioedema or severe allergic reactions following administration of pirfenidone should immediately discontinue treatment. pirfenidone must not be used in patients with a history of angioedema or hypersensitivity due to pirfenidone.
- 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. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of pirfenidone may be warranted.
- 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.
- Weight loss has been reported in patients treated with pirfenidone. Physicians should monitor patient's weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance.
(Medicines.org.uk)
Pregnancy and Breast – feeding:
Pregnancy
There are no data from the use of pirfenidone in pregnant women.
As a precautionary measure, it is preferable to avoid the use of pirfenidone during pregnancy.
Breast-feeding
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.
(Medicines.org.uk, BNF)
Drug Interactions:
grapefruit juice, enoxacin, inhibitors of CYP1A2, ciprofloxacin, amiodarone, propafenone, fluconazole, chloramphenicol, fluoxetine, paroxetine, CYP1A2 inducers, Smoking, omeprazole, rifampicin.
(Medicines.org.uk)
Adverse Reactions:
nausea, rash, diarrhoea, fatigue, dyspepsia, decreased appetite, headache, photosensitivity reaction, Upper respiratory tract infection, Urinary tract infection, Weight decreased, Insomnia, dizziness, Somnolence, dysgeusia, lethargy, Hot flush, Dyspnoea, cough, gastroesophageal reflux disease, vomiting, constipation, Abdominal distension, abdominal discomfort, abdominal pain, gastritis, flatulence, ALT increased; AST increased; gamma glutamyl transferase increased, pruritus, erythema, dry skin, Arthralgia, Myalgia, Asthenia, non-cardiac chest pain, Sunburn, Agranulocytosis, Angioedema, Anaphylaxis, Hyponatraemia, Total serum bilirubin increased, Drug-induced liver injury, Stevens-Johnson syndrome, toxic epidermal necrolysis
(Medicines.org.uk, BNF)
OVERDOSE:
Symptoms
Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
Treatment:
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.
(Medicines.org.uk)
DOSAGE AND ADMINISTRATION:
Treatment with pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF.
(Medicines.org.uk, BNF)
Storage:
Store below 30˚ C and keep away from humidity & light.
How supplied:
Pirfenidone 200 mg tablets contain 200 mg pirfenidone and are available as round white film-coated tablets, in transparent colorless blister of 10 at boxes of 30 tablets with leaflet, manufactured at Tehran darou pharmaceutical Co.
References:
1) medicines.org.uk 2022
2) RXlist 2022
3) BNF 83
4) PDR.net 2022