Perfekt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PIRFECT (PIRFECT)

Composition:

Active substance: pirfenidone;

One film-coated tablet contains 200 mg of pirfenidone;

Excipients: lactose monohydrate, sodium croscarmellose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium stearyl fumarate, coating "Opadry KB Low viscosity White 310A180023"*, coating "Opadry KB Low viscosity Yellow 310A120019"**.

* Composition of coating "Opadry KB Low viscosity White 310A180023": polyethylene glycol, titanium dioxide (E 171), kaolin, copovidone, sodium lauryl sulfate.

**Composition of coating "Opadry KB Low viscosity Yellow 310A120019": polyethylene glycol, kaolin, yellow iron oxide (E 172), copovidone, titanium dioxide (E 171), sodium lauryl sulfate.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: yellow, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Immunosuppressants. Other immunosuppressants. ATC code L04AX05.

Pharmacological Properties

Pharmacodynamics

The mechanism of action of pirfenidone is not fully understood. However, available data indicate that pirfenidone has antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of lung fibrosis (bleomycin-induced fibrosis and transplant-induced fibrosis).

Idiopathic pulmonary fibrosis is a chronic fibrotic and inflammatory lung disease dependent on the synthesis and release of pro-inflammatory cytokines, including tumor necrosis factor alpha and interleukin-1 beta. Pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli.

Pirfenidone reduces fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and increases biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as transforming growth factor beta and platelet-derived growth factor.

Pharmacokinetics

Absorption. Administration of pirfenidone capsules with food resulted in a significant reduction in maximum concentration Cmax (by 50%) and a smaller effect on the area under the plasma concentration-time curve (AUC), compared to administration under fasting conditions. After single oral dose of 801 mg in healthy volunteers aged 50–66 years following a meal, the absorption rate of pirfenidone decreased, while AUC after administration with food was 80–85% of AUC after administration under fasting conditions. Bioequivalence of the 801 mg tablet and three 267 mg capsules was demonstrated when administered under fasting conditions. When administered after food intake, the 801 mg tablet met the bioequivalence criterion for AUC compared to capsules, whereas the 90% confidence interval for Cmax (108.26–125.60%) slightly exceeded the upper limit of the standard bioequivalence range (90% CI: 80.00–125.00%). The effect of food on AUC after oral administration of pirfenidone was similar for both tablet and capsule formulations. Compared to fasting, administration of either formulation with food led to reduced Cmax of pirfenidone, with the reduction in Cmax being less pronounced with pirfenidone tablets (by 40%) than with pirfenidone capsules (by 50%). A lower incidence of adverse events (nausea and somnolence) was observed in fed patients compared to the fasting group. Therefore, it is recommended to administer pirfenidone with food to reduce the frequency of nausea and somnolence. Absolute bioavailability of pirfenidone in humans has not been determined.

Distribution. Pirfenidone binds to human plasma proteins, primarily to serum albumin. Overall mean binding ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 µg/mL). The apparent volume of distribution at steady state after oral administration is approximately 70 L, indicating limited tissue distribution of pirfenidone.

Metabolism. Approximately 70–80% of pirfenidone is metabolized by CYP1A2, with minor involvement of other CYP isoenzymes, including CYP2C9, 2C19, 2D6, and 2E1. In vitro study data suggest some pharmacologically relevant activity of the major metabolite (5-carboxy-pirfenidone) at concentrations exceeding peak plasma levels in patients with idiopathic pulmonary fibrosis. This may be clinically relevant for patients with moderate renal impairment, in whom exposure to 5-carboxy-pirfenidone in plasma is increased.

Elimination. Oral clearance of pirfenidone is moderately saturated. In a multiple-dose study to determine optimal dosing in elderly healthy volunteers, the drug was administered at doses ranging from 267 mg to 1335 mg three times daily, and mean clearance decreased by approximately 25% at doses above 801 mg three times daily. After a single dose of pirfenidone in elderly healthy volunteers, the mean apparent terminal half-life was approximately 2.4 hours. Approximately 80% of the orally administered dose of pirfenidone is excreted in urine within 24 hours after administration. The majority of pirfenidone is excreted as the metabolite 5-carboxy-pirfenidone (>95% of recovered amount), and less than 1% of pirfenidone is excreted unchanged in urine.

Pharmacokinetics in special populations

Hepatic impairment. The pharmacokinetics of pirfenidone and its metabolite 5-carboxy-pirfenidone were comparable in individuals with moderate hepatic impairment (Child-Pugh class B) and those with normal hepatic function. In patients with moderate hepatic impairment, a mean increase of 60% in pirfenidone exposure was observed after a single 801 mg dose (3 capsules of 267 mg). Pirfenidone should be used with caution in patients with mild or moderate hepatic impairment, and patients should be closely monitored for signs of toxicity, especially when co-administered with a CYP1A2 inhibitor (see sections "Dosage and administration" and "Special precautions"). The drug is contraindicated in severe hepatic impairment and end-stage liver disease (see sections "Dosage and administration" and "Contraindications").

Renal impairment. No clinically significant differences in pirfenidone pharmacokinetics were observed in individuals with mild to severe renal impairment compared to those with normal renal function. The parent compound is primarily metabolized to 5-carboxy-pirfenidone. The mean (standard deviation [SD]) AUC_0–∞ of 5-carboxy-pirfenidone was significantly higher in groups with moderate (p = 0.009) and severe (p < 0.0001) renal impairment compared to those with normal renal function: 100 (26.3) mg·h/L and 168 (67.4) mg·h/L, respectively, versus 28.7 (4.99) mg·h/L.

AUC0–∞ = area under the concentration–time curve from zero to infinity.

a p-value compared to the normal value = 1.00 (paired comparison with Bonferroni adjustment).

b p-value compared to the normal value = 0.009 (paired comparison with Bonferroni adjustment).

c p-value compared to the normal value = 0.0001 (paired comparison with Bonferroni adjustment).

Exposure to 5-carboxy-pirfenidone increases by 3.5 times or more in patients with moderate renal impairment. Clinically relevant pharmacodynamic activity of this metabolite in patients with moderate renal impairment cannot be excluded.

Dose adjustment of pirfenidone is not required in patients with mild renal impairment. Pirfenidone should be used with caution in patients with moderate renal impairment. Pirfenidone treatment is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with end-stage renal disease requiring hemodialysis (see sections "Dosage and administration", "Contraindications").

Results of a population pharmacokinetic analysis of 4 studies involving healthy subjects or subjects with renal impairment and one study involving patients with idiopathic pulmonary fibrosis showed no clinically significant effect of age, gender, or body weight on the pharmacokinetics of pirfenidone.

Clinical characteristics.

Indications.

Pirfenidone is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients (see section "Composition"). Angioedema due to pirfenidone in medical history (see section "Special warnings and precautions for use").

Concomitant use of fluvoxamine (see section "Interaction with other medicinal products and other forms of interaction").

Severe hepatic impairment or end-stage liver disease (see sections "Dosage and administration", "Special warnings and precautions for use").

Severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease requiring dialysis (see sections "Dosage and administration", "Special warnings and precautions for use").

Interaction with other medicinal products and other forms of interaction.

Approximately 70–80% of pirfenidone is metabolized via CYP1A2, with minor involvement of other CYP isoenzymes, including CYP2C9, 2C19, 2D6, and 2E1.

Consumption of grapefruit juice is associated with inhibition of CYP1A2, and therefore should be avoided during treatment with pirfenidone.

Inhibitors of CYP1A2. During treatment with pirfenidone, concomitant use of medicinal products that are inhibitors of CYP1A2 and one or more other CYP isoenzymes involved in pirfenidone metabolism (e.g., CYP2C9, 2C19, and 2D6) should be avoided.

In vitro and in vivo extrapolations indicate that strong and selective CYP1A2 inhibitors (e.g., enoxacin) have the potential to increase pirfenidone exposure by approximately 2–4 fold.

If concomitant use of pirfenidone and a strong and selective CYP1A2 inhibitor cannot be avoided, the dose of pirfenidone should be reduced to 800 mg per day (200 mg four times daily). Patients should be closely monitored for adverse reactions related to PIRFEKT therapy. If necessary, treatment with pirfenidone should be discontinued (see sections "Dosage and administration", "Special warnings and precautions for use"). Concomitant administration of pirfenidone and 750 mg ciprofloxacin (a moderate CYP1A2 inhibitor) resulted in an 81% increase in pirfenidone exposure. If co-administration of ciprofloxacin 750 mg twice daily cannot be avoided, the dose of pirfenidone should be reduced to 1600 mg per day (400 mg four times daily). PIRFEKT should be used with caution when ciprofloxacin is administered at a dose of 250 mg or 500 mg once or twice daily. PIRFEKT should be used with caution in patients receiving other moderate CYP1A2 inhibitors (e.g., amiodarone, propafenone). Particular caution is also required when CYP1A2 inhibitors are used concomitantly with strong inhibitors of one or more CYP isoenzymes involved in pirfenidone metabolism, such as CYP2C9 (e.g., amiodarone, fluconazole), 2C19 (e.g., chloramphenicol), and 2D6 (e.g., fluoxetine, paroxetine).

Inducers of CYP1A2. Concomitant use of moderate CYP1A2 inducers (e.g., omeprazole) may theoretically reduce plasma levels of pirfenidone. Concomitant administration of medicinal products that act as potential inducers of CYP1A2 and other isoenzymes involved in pirfenidone metabolism (e.g., rifampicin) may lead to a significant reduction in plasma concentrations of pirfenidone. Concomitant use of these medicinal products should be avoided whenever possible.

Special precautions for use.

Hepatic impairment. Elevated transaminase levels have been frequently observed in patients receiving pirfenidone. Liver function tests (determination of alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin levels) should be performed prior to initiating pirfenidone treatment, then monthly for the first 6 months of treatment, and thereafter every 3 months (see section "Special precautions for use").

If, after initiation of pirfenidone therapy, a patient develops an increase in aminotransferase levels > 3 to < 5 times the upper limit of normal (ULN) without elevated bilirubin levels and without symptoms or signs of drug-induced liver injury, other causes should be ruled out and the patient should be closely monitored. Consideration should be given to discontinuing other medications associated with hepatotoxicity. Depending on clinical judgment, the dose of pirfenidone should be reduced or treatment discontinued. When liver function tests return to normal, the dose of pirfenidone may be increased to the recommended daily dose, provided it is well tolerated.

Drug-induced liver injury. Increases in AST and ALT levels were occasionally associated with concomitant increases in bilirubin. In the post-marketing period, cases of severe liver injury due to the use of the drug have been reported, including isolated cases with fatal outcomes (see section "Adverse reactions").

In addition to the recommended regular monitoring of liver function parameters, patients who develop symptoms suggestive of liver injury, including fatigue, anorexia, discomfort in the right upper quadrant of the abdomen, dark urine, or jaundice, should undergo prompt clinical evaluation and liver function testing.

If a patient develops an increase in aminotransferase levels > 3 to < 5 times ULN accompanied by hyperbilirubinemia or clinical signs or symptoms indicating liver injury, treatment with pirfenidone should be permanently discontinued and must not be reinitiated.

If a patient develops an increase in aminotransferase levels ≥ 5 times ULN, pirfenidone treatment should be permanently discontinued and must not be restarted. In subjects with moderate hepatic impairment (e.g., Child-Pugh class B), exposure to pirfenidone was increased by 60%. Pirfenidone should be used with caution in patients with mild or moderate hepatic impairment (i.e., Child-Pugh class A or B), considering the potential for increased pirfenidone exposure. Patients should be carefully monitored for signs of toxicity, particularly if they are also taking a CYP1A2 inhibitor (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics"). The use of pirfenidone has not been studied in patients with severe hepatic impairment, and pirfenidone must not be used in patients with severe hepatic impairment (see section "Contraindications").

Photosensitivity reactions and skin rashes. During treatment with pirfenidone, exposure to direct sunlight (including sun exposure) should be avoided or minimized. Patients should be instructed to apply sunscreen daily, wear sun-protective clothing, and avoid taking medications that cause photosensitivity. Patients should inform their physician if symptoms of photosensitivity or rash occur. Severe photosensitivity reactions are uncommon. Dose adjustment or temporary discontinuation of treatment may be necessary if a photosensitivity reaction or rash of mild to severe intensity occurs (see section "Dosage and administration").

Severe skin reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported in association with pirfenidone treatment, which may be life-threatening or fatal. If signs or symptoms suggestive of these reactions occur, pirfenidone should be immediately discontinued. If a patient develops Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during treatment, therapy should be permanently discontinued and never restarted.

Angioedema / anaphylaxis. Angioedema (in some cases severe) has occurred during the post-marketing period in patients receiving pirfenidone, manifesting as swelling of the face, lips and/or tongue, and possibly accompanied by difficulty breathing or wheezing. Allergic reactions have also been reported. Therefore, treatment should be immediately discontinued in patients who develop signs and symptoms of angioedema or severe allergic reactions after taking pirfenidone. Patients with angioedema or severe allergic reactions should be managed according to standard medical practice. Pirfenidone must not be prescribed to patients with a history of angioedema or hypersensitivity reactions to pirfenidone (see section "Contraindications").

Drowsiness/dizziness. Drowsiness has been reported in patients receiving pirfenidone. Therefore, patients should be aware of how they react to pirfenidone before engaging in activities requiring mental alertness or coordination (see section "Ability to affect reaction speed when driving or operating machinery"). In clinical trials, most patients experienced episodes of drowsiness, which resolved on average after 22 days. If drowsiness does not improve or worsens, dose adjustment or even discontinuation of pirfenidone treatment may be warranted.

Fatigue. Fatigue has been observed in patients receiving pirfenidone treatment. Therefore, patients should be aware of how they react to the medicinal product before engaging in activities requiring mental alertness or coordination (see section "Ability to affect reaction speed when driving or operating machinery").

Weight loss. Weight loss has been observed in patients receiving pirfenidone treatment (see section "Adverse reactions"). Physicians should monitor patients' body weight and, if necessary, encourage patients to increase caloric intake if weight loss becomes clinically significant.

Hypotension. Hyponatremia has been reported in patients receiving pirfenidone (see section "Special precautions for use"). Since symptoms of hyponatremia may be subtle and masked by concomitant conditions, regular monitoring of relevant laboratory parameters is recommended, especially in the presence of symptoms such as nausea, headache, or dizziness.

Important information on excipients. The medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains 12 mg of sodium per tablet. Caution is advised when prescribing to patients on a sodium-restricted diet.

Disposal of unused or expired medicinal product: Environmental contamination should be minimized. The medicinal product should not be disposed of in wastewater or household waste. Disposal should be carried out via a designated "waste collection system" if available.

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of pirfenidone in pregnant women.

As a precautionary measure, it is advisable to avoid using the medicinal product during pregnancy.

Breastfeeding. It is unknown whether pirfenidone or its metabolites are excreted in human milk. The risk to the breastfed infant cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue therapy with the medicinal product should be made taking into account the benefit of breastfeeding to the infant and the benefit of therapy to the mother.

Fertility. No adverse effects on fertility were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product may cause drowsiness and rapid fatigue, which may moderately affect the ability to drive or operate machinery. Therefore, patients experiencing these symptoms should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Treatment with pirfenidone should be initiated and supervised by physicians experienced in the diagnosis and management of idiopathic pulmonary fibrosis.

Route of Administration

The medicinal product is intended for oral use. The tablets should be swallowed whole with water and taken with food to reduce the likelihood of nausea and drowsiness (see sections "Side Effects", "Pharmacokinetics").

Adults.

At the beginning of treatment, the dose should be titrated to the recommended daily dose of 2400 mg/day over 14 days as follows:

• Days 1–7: 200 mg dose (one 200 mg tablet) administered four times daily (800 mg/day).
• Days 8–14: 400 mg dose (two 200 mg tablets) administered four times daily (1600 mg/day).
• From day 15 onwards: 600 mg dose (three 200 mg tablets) administered four times daily (2400 mg/day). The recommended maintenance daily dose is 600 mg four times daily with food, totaling 2400 mg/day.

Doses exceeding 2400 mg/day are not recommended for any patient (see section "Overdose"). Patients who have missed treatment for 14 consecutive days or more should restart therapy with the initial 2-week titration regimen until the recommended daily dose is reached.

Dose Adjustment and Other Factors to Consider for Safe Use of the Drug Gastrointestinal Disorders.

For patients who experience intolerance to treatment due to gastrointestinal side effects, it should be emphasized that the drug must be taken with food. If symptoms persist, the dose of pirfenidone may be reduced to 1–2 tablets (200–400 mg) four times daily with food, with subsequent dose escalation to the recommended daily dose based on tolerability. If symptoms continue, patients should be instructed to discontinue treatment for one to two weeks to allow symptoms to resolve.

Photosensitivity Reaction or Rash.

Patients who develop photosensitivity reactions or rash of mild to severe intensity should be reminded to use sunscreen daily and to avoid sun exposure (see section "Special Warnings and Precautions for Use"). The dose of pirfenidone may be reduced to 800 mg per day (200 mg four times daily). If the rash persists after 7 days, pirfenidone should be discontinued for 15 days, followed by re-escalation to the recommended daily dose in the same manner as during the dose escalation period. Patients experiencing severe photosensitivity reactions or rash should be instructed to discontinue treatment and seek immediate medical attention (see section "Special Warnings and Precautions for Use"). After the rash resolves, treatment with pirfenidone may be restarted and the dose gradually increased to the recommended daily dose at the physician’s discretion.

Liver Function.

In case of significant elevation of alanine and/or aspartate aminotransferase (ALT/AST), with or without increased bilirubin levels, the dose of pirfenidone should be adjusted or treatment discontinued according to the recommendations provided in the section "Special Warnings and Precautions for Use".

Special Patient Populations.

Elderly Patients. No dose adjustment is required for patients aged 65 years and older (see section "Pharmacokinetics").

Hepatic Impairment. No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). However, since some patients with mild to moderate hepatic impairment may exhibit increased plasma levels of pirfenidone, the drug should be used with caution in this patient population. Pirfenidone therapy is not recommended in patients with severe hepatic impairment or end-stage liver disease (see sections "Contraindications", "Special Warnings and Precautions for Use", "Pharmacokinetics").

Renal Impairment. No dose adjustment is required in patients with mild renal impairment. Pirfenidone should be used with caution in patients with moderate renal impairment (creatinine clearance 30–50 mL/min). Pirfenidone therapy is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with end-stage renal disease requiring dialysis (see sections "Contraindications", "Pharmacokinetics").

Children. There is no experience with the use of pirfenidone in children for the treatment of idiopathic pulmonary fibrosis.

Overdose.

Clinical experience with overdose is limited. Multiple daily doses of pirfenidone up to 4806 mg (6 capsules of 267 mg three times daily) have been administered to healthy volunteers over a 12-day dose-escalation period. Adverse reactions were mild, transient, and comparable to those most frequently reported. In case of suspected overdose, supportive medical care should be provided, including monitoring of vital signs and careful observation of the patient's clinical status.

Adverse Reactions

Summary of safety profile.

The most commonly observed adverse reactions during clinical trials with pirfenidone at a dose of 2403 mg/day compared to placebo were: nausea (32.4% vs. 12.2%), rash (26.2% vs. 7.7%), diarrhea (18.8% vs. 14.4%), fatigue (18.5% vs. 10.4%), dyspepsia (16.1% vs. 5.0%), anorexia (11.4% vs. 3.5%), headache (10.1% vs. 7.7%), and photosensitivity reaction (9.3% vs. 1.1%).

Summary table of adverse reactions.

The safety of pirfenidone has been evaluated in clinical trials involving 1650 healthy volunteers and patients. More than 170 patients participated in open-label studies lasting longer than 5 years, including up to 10 years.

Table 1 lists adverse reactions observed at a frequency of ≥ 2% in 623 patients who received pirfenidone at the recommended dose of 2403 mg/day in three pivotal Phase 3 clinical trials. Adverse reactions observed during post-marketing experience are also listed in the table below. Adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), and frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in decreasing order of severity.

Table 1. Adverse reactions by system organ class and frequency according to MedDRA [Medical Dictionary for Regulatory Activities]

1 Identified during post-marketing surveillance (see section "Special precautions for use").

2 Severe liver injury, including fatal cases, have been reported during post-marketing surveillance associated with the use of medicinal products (see sections "Contraindications" and "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

28 tablets per blister pack, 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Nobel Ilac Sanai ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Avenue No: 299, 81100 Duzce, Turkey.