Date of approval.
Date of revision.
Pirfenidone tablets instructions please read carefully and use under the guidance of a physician
Drug Name]
Generic name: Pirfenidone Tablets
English name: Pirfenidone Tablets
Hanyu Pinyin: BifeinitongPian
Ingredients
The main ingredient of this product is: Pirfenidone
Chemical name: 5-methyl-1-phenyl-2(1H)-pyridone
Chemical structure formula
Molecular formula: C12H11NO
Molecular weight: 185.22
【Properties】.
This product is light yellow to light yellow-brown film-coated tablets, after removing the coating appears off-white.
Indications
It is used for mild to moderate idiopathic interstitial lung fibrosis.
Specification
200mg
Dosage]
The dosage of this product is gradually increased according to the principle of dosage escalation, because when taking this product on an empty stomach, the concentration of pirfenidone in the blood will be significantly increased, and it is likely to have adverse reactions, so it is appropriate to take it after meals.
The initial dosage of this product is 200mg 3 times a day, and it is hoped that the dosage can be maintained at 600mg per dose (1800mg per day) over a period of two weeks by increasing the dosage by 200mg per dose; patients should be closely monitored for tolerance of the drug, and if there are significant gastrointestinal symptoms, skin reactions to sunlight or ultraviolet light, significant changes in enzymatic parameters of liver function and weight loss In case of obvious gastrointestinal symptoms, skin reaction to sunlight or ultraviolet light, significant changes in enzymatic index of liver function and weight loss, the dosage can be reduced or stopped according to the clinical symptoms, and after the symptoms are reduced, the dosage can be increased gradually, and the maintenance dosage should be adjusted to 400mg (1200mg daily) or more.
Adverse reactions
According to the overseas data of pirfenidone, among 265 subjects who participated in safety evaluation trials, 233 cases (87.9%) were confirmed to have adverse reactions. The main ones were photosensitivity in 137 cases (51.7%), loss of appetite in 61 cases (23.0%), gastric discomfort in 37 cases (14%), and nausea in 32 cases (12.1%). There were 120 subjects with abnormal blood biochemical indexes, and the main abnormality was elevated γ-glutamyl transpeptidase (γ-GTP) in 53 subjects (20.0%).
1. Serious adverse reactions
(1) Liver function impairment and jaundice (0.1%-1%): liver function impairment and even liver failure may occur with the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), so regular examination should be carefully conducted. When abnormalities are confirmed to have occurred, medication should be stopped and appropriate treatment should be carried out.
(2) Severe allergic reactions (hypersensitivity reactions), such as facial swelling, laryngeal edema, dyspnea, and wheezing.
(3) Severe photosensitivity reactions are rare. Sunlight or UV light exposure can cause severe skin photosensitivity reactions such as blistering and/or significant exfoliation. Avoid exposure to sunlight or UV lamps while taking the drug. Sunscreen and sun-protective clothing should be worn when going out to avoid direct exposure of the extremities and head and face to sunlight.
(4) Granulocytopenia, leukopenia, neutropenia (frequency unknown): It may cause granulocytopenia, leukopenia, neutropenia, therefore, regular hematological examination should be performed and measures such as stopping the administration of the drug should be taken when abnormalities are detected.
2. Other adverse reactions
When the following adverse reactions occur, treatment such as dose reduction or discontinuation of drug administration should be taken.
Type Incidence 5% or more 1~5% 1% or less Frequency unknown Skin photosensitivity (51.7%), itchy rash, erythema, eczema, lichen planus, skin flushing or red skin, dry skin, sun spots Digestive system Loss of appetite (23.0%), stomach upset (14.0%), nausea (12.1%), diarrhea, burning sensation in chest, indigestion bloating, vomiting, constipation, gastric Esophageal reflux, inflammation in the mouth, abdominal pain, labyrinthitis, acid reflux lip erosion Circulatory system Tachycardia Psychoneurological drowsiness, dizziness, feeling of unsteadiness walking headache, heavy head, sleep difficulties Depression, anxiety, insomnia Liver elevated γ-GTP (20.0%), elevated AST, elevated ALT, elevated alkaline phosphatase (ALP), elevated lactate dehydrogenase (LDH) Elevated bilirubin Blood Leukocytosis, eosinophilia, leukopenia thrombocytopenia Other lethargy weight loss, fever, abnormal taste, musculoskeletal pain, facial redness, general malaise, pharyngitis, sinusitis, lung infection, cystitis, cough, chest pain [Contraindication
Contraindicated in patients with hypersensitivity to any of the ingredients of this product.
Contraindicated in patients with severe liver disease.
Contraindicated in patients who are pregnant and lactating.
Contraindicated in patients with severe renal disease or requiring dialysis treatment.
For those who need to take fluvoxamine (a drug for depression or obsessive-compulsive psychosis).
[Precautions].
1, in clinical trials of pirfenidone only found that pirfenidone can improve the lung function index of patients with mild to moderate idiopathic interstitial pulmonary fibrosis, it has not been found that pirfenidone can reverse pulmonary fibrosis, so patients with severe idiopathic interstitial pulmonary fibrosis may not benefit from the application of pirfenidone.
2. Use with caution (use with caution in the following patients)
(1) In patients with impaired liver function, application of pirfenidone may further impair or worsen liver function; use with caution in patients with mild or moderate hepatic insufficiency; contraindicated in patients with severe liver disease; patients with liver disease should have their liver function checked regularly before and during the use of pirfenidone.
(2) There is a lack of data on the use of pirfenidone in patients with impaired renal function; it is contraindicated in patients with severe renal disease or those requiring dialysis treatment.
(3) Please refer to “Use in Elderly Patients” for details in elderly patients.
3. Important basic precautions
(1) Pirfenidone can cause severe photosensitivity reactions, and prolonged exposure to light may lead to skin cancer. Detailed instructions should be given to patients in advance when using it, including.
(1) Wear long-sleeved clothes, hats, sunshades, and sunscreen with good sun protection when going out to avoid direct exposure to UV rays.
②Contact your doctor immediately if a rash or itching occurs.
(3) Avoid combining other medications, such as tetracycline antibiotics (doxycycline), as much as possible, because they can increase the chance of photosensitivity reactions.
(2) Drowsiness, dizziness, and other conditions associated with the application of pirfenidone can occur, so patients using pirfenidone should not drive or engage in dangerous machine operations. Special attention should be paid to the effects if the patient has to participate in certain sports that depend on reflexes and motor coordination to complete while taking the drug.
(3) Since liver function impairment can cause elevation of AST, ALT, etc. and jaundice, regular liver function tests should be performed during use and patients’ symptoms and signs should be carefully observed.
(4) Animal experiments have shown that pirfenidone can cross the blood-brain barrier, so it is recommended that patients with episodic brain disease (focal excitation or episodic sleep) should closely observe the pathological changes of EEG and use with caution after consulting a doctor.
5.Smoking can reduce the efficacy of pirfenidone, so it is necessary to quit smoking before and during the medication.
6.Pirfenidone can cause weight loss, so close observation of weight change is needed during the medication period.
7. Do not drink grapefruit juice during medication, as grapefruit juice may interfere with the efficacy of pirfenidone.
Pregnant women and nursing mothers
1. Pirfenidone is not recommended for pregnant women or women who may become pregnant because the risk of pirfenidone to the unborn child is not known. In experiments in rats, it was confirmed that it prolonged the pregnancy cycle or caused a low birth rate, and there was a transfer to the fetus. In addition, in rabbit experiments, it was confirmed to cause abortion or preterm delivery. In short, teratogenic phenomena have occurred in many animal experiments.
2. Lactating women should avoid breastfeeding during the use of pirfenidone. In rat experiments, drug secretion could be detected in breast milk. Use during lactation can inhibit weight gain in newborns.
[Pediatric Use].
The safety and efficacy of the drug in pediatric and adolescent patients under 18 years of age have not been established.
Geriatric Use]
The physiological function of the elderly is generally reduced, and there are no large-scale clinical trials conducted specifically in the elderly, so caution is advised for use in patients of advanced age.
Drug Interactions
1. Please note that the following drugs can affect the therapeutic effect of pirfenidone.
(1) Drugs that increase the adverse effects of pirfenidone: ciprofloxacin, amiodarone, and propafenone.
(2) Drugs that reduce the efficacy of pirfenidone: omeprazole, rifampin.
Please take doctor’s advice before taking the above drugs.
2.Other drug interactions
(1) The pharmacokinetic characteristics of pirfenidone and antacid Mylanta II (mainly containing magnesium hydroxide and aluminum hydroxide) are not affected when used together.
(2) The combination of pirfenidone and fluvoxamine, a strong inhibitor of CYP1A2, can lead to significant drug interactions and the clearance rate can be significantly reduced. Combined use of fluvoxamine for 10 days can increase the AUC0-∞ of pirfenidone by approximately 6-fold. Therefore, pirfenidone should not be used in combination with intermediate or potent inhibitors of CYP1A2.
(3) Pirfenidone can be metabolized by a variety of CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1), so when combined with other drugs, it is more likely to be affected by the inhibition or induction of CYP enzyme activity triggered by other drugs.
Drug overdose
No clinical cases of pirfenidone overdose have been reported. If a large overdose occurs, in addition to the usual gavage and emetic, depending on the condition, the doctor will decide what effective detoxification measures to use.
Pharmacology and Toxicology
Pharmacological effects
Idiopathic pulmonary fibrosis is associated with chronic fibrosis and inflammation caused by the synthesis and release of tumor necrosis factor TNF-fiber and interleukin 1 (IL-1β) inflammatory cytokines. The mechanism of action of pirfenidone is not fully understood. The results show that pirfenidone reduces the accumulation of inflammatory cells in response to a variety of stimuli and attenuates cell proliferation, fibrosis-associated protein and cytokine production, and extracellular matrix synthesis and accumulation in fibroblasts stimulated by cell growth factors such as transforming growth factor beta (TGF-V) and platelet-derived growth factor (PDGF). Results of tests in animal lung fibrosis models (bleomycin and transplant-induced fibrosis) showed that pirfenidone has anti-fibrotic and anti-inflammatory effects.
Toxicological studies
Genotoxicity: Pirfenidone showed negative results in Ames test, chromosomal aberration test in CHL cells, UDS test in rat hepatocytes, and micronucleus test in mice. pirfenidone showed positive results in the presence of UV light in CHL cell photomutagenesis test.
Reproductive toxicity: No adverse effects on fertility or fetal development were observed in male and female rats given pirfenidone 50, 150, 450 and 1000 mg/kg orally; no teratogenic effects were observed in rats at 1000 mg/kg and rabbits at 300 mg/kg. No teratogenic effects were observed in rats at doses ≥ ≥. Prolonged estrous cycle and irregular cycle were seen in rats at large, prolonged estrous cycle and prolonged gestation and retarded fetal development were seen at ≥. Pirfenidone and/or its metabolites are excreted in the milk of lactating rats, and there is a potential accumulation of pirfenidone and/or its metabolites in milk.
Carcinogenicity: In a 104-week carcinogenicity test in B6C3F1 mice and F344 rats, the incidence of hepatocellular tumors was increased in mice given pirfenidone at 800, 2000, and 5000 mg/kg or 375, 750, and 1500 mg/kg, respectively, by adulteration. In rats, an increase in the incidence of hepatocellular tumors and an increase in the incidence of uterine cancer were observed. The results of the mechanism of action study suggest that the development of uterine cancer may be due to a long-term dopamine-mediated imbalance of sex hormones, a hormonal mechanism unique to rats. The increased incidence of hepatocellular carcinoma in mice and rats may be related to the induction of hepatic microsomal enzymes, which was not associated in humans.
Phototoxicity and irritation were seen in guinea pigs exposed to UVA/UVB light after oral administration of pirfenidone.
Pharmacokinetics
1. Blood concentration
(1) Fasting blood concentration
The plasma drug concentrations and pharmacokinetic parameters for single oral doses of pirfenidone 200 mg, 400 mg, and 600 mg (6 cases each) in adult healthy males on a fasting basis were reported in the literature as shown in the table below.Cmax and AUC increased almost proportionally to the administered dose.
Pharmacokinetic parameters at a single oral dose on an empty stomach (healthy adults)
Dose (mg) nCmax
(μg/mL) Tmax
(hr) AUC0-48hr
(μg-hr/mL) T1/2
(hr) 20063.88±0.820.75±0.2713.97±2.712.10±0.4540069.24±1.740.58±0.2029.10±11.771.96±0.55600610.57±1.780.83±0.2637.03±11.971.76±0.40 (Detection method: HPLC) (mean±S.D.)
(2) Repeated dosing
The pharmacokinetic parameters of the 12 healthy adult males were shown in the table below.
The plasma drug concentrations of each dose showed almost identical changes on the 1st and 6th day of administration, with Cmax and AUC increasing proportionally with increasing dose on the 1st day of administration.
Pharmacokinetic parameters during repeated oral administration of pirfenidone after meals (healthy adults)
Single
dose
(mg)nDose day of administration
(total) Cmax0-4hra)
(μg/mL)Tmax0-4hra)
(hr)Cmax4-24hrb)
(μg/mL)Tmax4-24hrb)
(hr)AUC0-24hrc)
(μg-hr /mL)T1/2
(hr)2001212.71±0.911.08±0.472.83±1.126.04 ±1.0519.17±6.462.17±0.3063.06±1.281.08±0.822.70±0.516.29 ±0.9622.03±5.472.25±0.294001 (7) 4.94±1.291.79±0.896.22±1.595.79±1.3646.13±10.012.42±0.486 (12) 6.19±1.891.17±0.545.91±2.096.38 ±1.1548.69±11.212.36±0.386001
(13) 8.20 ± 1.291.25 ± 0.459.21 ± 1.976.33 ± 1.1577.22 ± 15.442.53 ± 0.426 (18) 8.19 ± 1.541.71 ± 0.5410.00 ± 1.706.13 ± 1.0082.31 ± 16.502.55 ± 0.45a): at morning dosing value of
(b): value at noon dosing
c): The value at the time of 2 doses in 1 day
(Detection method: HPLC) (mean±S.D.)
2. Effect of eating
The plasma drug concentrations and pharmacokinetic parameters of six healthy adult males at single oral doses of pirfenidone 400 mg after meals and on an empty stomach are shown in the table below. Due to the effect of eating, Cmax and AUC were significantly lower and Tmax was significantly delayed. (Cross-tabulation ANOVA)
Pharmacokinetic parameters at single oral dose after meals and on an empty stomach (healthy adults)
Dose (mg) nCmax
(μg/mL) Tmax
(hr) AUC0-48hr
(μg-hr/mL) T1/2
(hr) 400 postprandial 64.88±1.721.83±0.7522.13±10.631.77±0.55 fasting 9.24±1.740.58±0.2029.10±11.771.96±0.55p value 0.0024＊＊0.0179＊0.0307＊0.1373＊: p < 0.05 **: p < 0.01 (cross-tabulation ANOVA) (Assay method: HPLC) (mean±S.D.)
3. Based on information from animal and human pharmacokinetic studies, the tissue distribution, metabolism and excretion of pirfenidone were as follows
Tissue distribution
1. Tissue distribution: In rats given a single oral dose of pirfenidone (14C) 100 mg/kg, the organ tissues with higher drug concentrations than plasma were, in order, liver, kidney and spleen. The highest drug concentration in most organ tissues was reached 5-30 minutes after administration, with an elimination half-life of 4-7 hours.
Pirfenidone also has a high distribution in the brain, and prodrugs and metabolites can be measured in brain tissue, indicating that the drug can cross the blood-brain barrier.
2. Plasma protein binding rate: The plasma of healthy adults was measured by ultrafiltration method after a single oral dose of 600mg under fasting. The results showed that the serum protein binding rate was 54%-62% after 1 hour and 3 hours of administration. The results of this study, conducted on blank plasma from healthy Chinese volunteers, showed that the human plasma protein binding rate of pirfenidone was 66 % to 78 %.
Human metabolism
1. Pirfenidone is rapidly transformed into metabolites in the body, the main metabolites are: 5-carboxy-pirfenidone, 5-hydroxymethyl-pirfenidone and glucuronide conjugate of 5-carboxy-pirfenidone. After absorption into the blood, the plasma drug concentration decreases rapidly, and the metabolite concentration peaks in about 10 minutes. 48 hours to eliminate, the urinary excretion rate of the prototype drug is less than 1%, mainly through the carboxylic acid metabolite form, and this metabolite 5-carboxy-pyrazinone is inactive.
2. In vitro studies on human liver microsomes have shown that pirfenidone can be metabolized by a variety of cytochrome P450 isoenzymes CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1), mainly by CYP1A2 (nearly 48%), with a relatively low rate of metabolism by other CYP enzymes (each <13%). Because metabolism is associated with multiple CYP enzymes, it is thought to be more susceptible to inhibition or induction of CYP activity due to other drugs.
3. Patients who smoke have higher CYP1A2 enzyme activity compared to non-smoking populations, and clearance of pirfenidone is significantly increased in the smoking population. Therefore, smoking reduces the AUC0-∞ of pirfenidone and 5-carboxy-pirfenidone by about 43% and 30%.
Drug excretion
Healthy adult males, 6 cases in each group. Urinary excretion of the prototype drug in the urine was less than 1% in each group over 48 hours when 200 mg, 400 mg and 600 mg of this product were administered orally in a single dose on an empty stomach, respectively. Pirfenidone-5-carboxylic acid (the main metabolite) is about 90%.
Storage】Sealed and stored.
【Packaging】Packaging in aluminum blister: 3 tablets/plate, 7 plates/box; 6 tablets/plate, 7 plates/box; 9 tablets/plate, 1 plate/box; 9 tablets/plate, 2 plates/box; 9 tablets/plate, 3 plates/box; 9 tablets/plate, 7 plates/box; 9 tablets/plate, 10 plates/box; 10 tablets/plate, 10 plates/box; 10 tablets/plate, 20 plates/box; 12 tablets/plate, 7 plates/box; 12 tablets/plate, 10 plates/box. 20 tablets/plate, 10 plates/box; 20 tablets/plate, 5 plates/box.
【Validity】36 months
【Execution standard
【Approval number】
【Manufacturer】
Company Name: Beijing Kain Technology Co.
Address: Building 201 and 203, No. 7, Rongchang East Street, Beijing Economic and Technological Development Zone, Beijing, China
Postal Code: 100176
Telephone number: (010) 87120888
Fax number: (010) 67872896
Medical Consultation Hotline：4006-610-910
Website: www.kawin.com.cn