Parmodia

Pemafibrate.

Each tablet contains 0.1 mg of pemafibrate.
Excipients/Inactive Ingredients: Tablet core: Lactose hydrate, Croscarmellose sodium, Microcrystalline cellulose, Hydroxypropylcellulose, Magnesium stearate.
Film coating: Hypromellose, Triethyl citrate, Light anhydrous silicic acid, Titanium oxide, Carnauba wax.

Pharmacotherapeutic group: Not yet assigned. ATC Code: Not yet assigned.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Pemafibrate activates PPARα by binding to this receptor and regulates the target gene expression, leading to decreased plasma triglyceride (TG) concentration, decreased triglyceride-rich lipoprotein, decreased apolipoprotein (Apo) C-3, and increased HDL-cholesterol.
(1) The activation of PPARα by pemafibrate was more potent than the activation of PPARγ or PPARδ, indicating the selectivity of pemafibrate to PPARα (in vitro).
(2) Pemafibrate inhibited TG synthesis in the liver (rats).
(3) Pemafibrate significantly reduced TG secretory rate (rats).
(4) Pemafibrate increased LPL activity (rats).
(5) Pemafibrate significantly reduced plasma concentrations of ApoC-3 and Angiopoietin-like Protein 3, which negatively regulate LPL activity; moreover, pemafibrate inhibited the gene expression (Apoc3, Angptl3) in the liver. In addition, pemafibrate upregulated the expression of genes (Aco, Cpt1a) involved in β-oxidation of free fatty acids that inhibits LPL activity (rats).
(6) Pemafibrate facilitated plasma TG clearance (rats).
(7) Pemafibrate increased plasma concentration of fibroblast growth factor 21 (FGF21), a protein that reduces TG concentration and increases HDL-cholesterol concentration (rats).
Pharmacodynamic effects: Pharmacological action: (1) Effect of reducing plasma lipid: When pemafibrate was orally administered to rats with high fructose-induced hypertriglyceridemia, plasma TG concentration was decreased in a dose-dependent manner.
(2) Effect of increasing HDL-cholesterol: When pemafibrate was orally administered to human ApoA-1 transgenic mice, plasma concentration of HDL-cholesterol and concentration of human ApoA-1 were increased.
(3) Anti-arteriosclerotic effect: When pemafibrate was orally administered to LDL-receptor deficient mice under high fat/high cholesterol diet, the area of lipid deposition area in the aortic sinus was decreased.
Clinical efficacy: Phase 2/3 Comparative Confirmatory Study with Fenofibrate: In patients with dyslipidemia who had high TG and low HDL-cholesterol levels, placebo, 0.2 mg/day or 0.4 mg/day of PARMODIA (twice daily after breakfast and dinner), or micronized fenofibrate capsules of 100 mg/day or 200 mg/day (once daily after breakfast) was administered for 12 weeks. The percent change in fasting serum TG was as presented in the following table, which shows the superiority of PARMODIA groups over the placebo group, and non-inferiority of PARMODIA 0.2 mg/day and 0.4 mg/day groups over the micronized fenofibrate capsule 200 mg/day group. (See Tables 1 and 2.)

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The change over time in LDL-cholesterol was as presented in the following table. (See Table 3.)

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Phase 3 Comparative Confirmatory Study with Fenofibrate: In patients with dyslipidemia who had high TG and low HDL-cholesterol levels, placebo, 0.2 mg/day or 0.4 mg/day of PARMODIA (twice daily after breakfast and dinner), or fenofibrate tablets of 106.6 mg/day (once daily after breakfast) was administered for 24 weeks. The fenofibrate tablets (solid dispersion) of 106.6 mg are equivalent to micronized fenofibrate capsules of 134 mg. The percent change in fasting serum TG was as presented in the following table, which shows the non-inferiority of all PARMODIA groups over the fenofibrate tablet 106.6 mg/day group. (See Table 4.)

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The change over time in the LDL-cholesterol was as presented in the following table. (See Table 5.)

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Phase 3 Long-term Administration Study in Dyslipidemia Patients with High TG Levels: In patients with dyslipidemia who had high TG levels, PARMODIA 0.2 mg/day (a dose increase to PARMODIA 0.4 mg/day was allowed as necessary in subjects with inadequate response to PARMODIA 0.2 mg/day at Week 12 and after) was administered twice daily before or after breakfast and dinner for 52 weeks. The percent change from the baseline fasting serum TG of 249.7±77.5 mg/dL (2.82±0.88 mmol/L) (Mean ± SD [the same applies hereinafter], n=189) at Week 24 and Week 52 were -48.77±20.47% and -45.93±21.84%, respectively (Last observation carried forward [LOCF] method was used). LDL-cholesterol value was 119.3±31.7 mg/dL (3.09±0.82 mmol/L) at baseline, and 116.6±29.1 mg/dL (3.02±0.75 mmol/L) at Week 52 (n=189).
Phase 3 Long-term Administration Study in Patients with Dyslipidemia and Type 2 Diabetes Mellitus: In patients with dyslipidemia and type 2 diabetes mellitus, placebo/PARMODIA 0.2 mg/day (starting from Week 24, the treatment was switched from placebo to PARMODIA 0.2 mg/day), PARMODIA 0.2 mg/day, or PARMODIA 0.4 mg/day was administered twice daily before or after breakfast and dinner for 52 weeks. The percent change in fasting serum TG at Week 24 and Week 52 (LOCF) was as presented in the following table. (See Table 6.)

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Pharmacokinetics: Plasma pemafibrate concentration: (1) Single dose administration: When a single dose of PARMODIA 0.1 mg was orally administered under fasted conditions to healthy Japanese adult males (16 subjects), the plasma concentration versus time and pharmacokinetic parameters are as presented in the following figure. (See figure and Table 7.)

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(2) Repeated dose administration: When PARMODIA 0.2 mg/day or 0.4 mg/day was orally administered twice daily after breakfast and dinner for 7 days to healthy Japanese adult males (8 subjects), the pharmacokinetic parameters on Day 1 and Day 7 are as presented in the following table. The plasma concentration reached a steady state on Day 2. The accumulation ratio based on AUC_0-τ (repeated dosing/initial dosing, Mean ± SD) were 1.0997±0.0688 and 1.1169±0.1814, respectively. (See Table 8.)

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(3) Food effect: When a single dose of PARMODIA 0.1 mg was orally administered to healthy Japanese adult males (16 subjects), the ratio [90% CI] of geometric means of fasted state to fed state for C_max and AUC_0-t were 0.873 [0.803, 0.950] and 0.911 [0.863, 0.961].
Absorption: The absolute bioavailability of pemafibrate was 61.5% (Data for non-Japanese subjects).
Plasma protein binding ratio: The human plasma protein binding ratio of pemafibrate was ≥99%.
Metabolism: (1) When a single dose of ¹⁴C-pemafibrate was orally administered to healthy adult subjects, the main metabolites in plasma were an oxidized form at the benzyl position, and a mixture of glucuronide conjugate of dicarboxylated form and N-dealkylated form (Data for non-Japanese subjects).
(2) Pemafibrate is a substrate of CYP2C8, CYP2C9, CYP3A4, CYP3A7, UGT1A1, UGT1A3, and UGT1A8 (in vitro).
Excretion: (1) When a single dose of ¹⁴C-pemafibrate was administered to healthy adult subjects, excretion of radioactivity in urine and feces up to 216 hours after administration was 14.53% and 73.29%, respectively (Data for non-Japanese subjects). Pemafibrate is excreted mainly in the feces.
(2) Pemafibrate is a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, OCT2, and NTCP (in vitro).
Drug interactions: (1) Co-administration with cyclosporin, rifampicin, clopidogrel, clarithromycin, fluconazole, digoxin, or warfarin: When PARMODIA was co-administered with each drug in healthy adult subjects (non-Japanese), the effect on the pharmacokinetic parameters was as presented in the following table. (See Table 9.)

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(2) Co-administration with HMG-CoA reductase inhibitors: When PARMODIA and HMG-CoA reductase inhibitors were co-administered to healthy adult males (Japanese and non-Japanese), the effect of co-administration on the pharmacokinetic parameters was as presented in the following table. (See Table 10.)

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Special populations: Pharmacokinetics in Patients with Fatty Liver and Patients with Hepatic Cirrhosis: When a single dose of PARMODIA 0.2 mg was orally administered to Japanese patients with fatty liver and patients with hepatic cirrhosis, the ratios of pharmacokinetic parameters (patients with fatty liver or with hepatic cirrhosis to subjects with normal hepatic function) were as presented in the following table. Compared with subjects with normal hepatic function, the exposure was higher in patients with fatty liver and patients with hepatic cirrhosis. (See Table 11.)

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Pharmacokinetics in Patients with Renal Impairment: When a single dose of PARMODIA 0.2 mg was orally administered to Japanese patients with renal impairment (mild, moderate, severe, or end-stage renal failure), the ratios of pharmacokinetic parameters (patients with renal impairment to subjects with normal renal function) were as presented in the following table. Compared with subjects with normal renal function, the exposure was higher in patients with renal impairment; however, the exposure did not increase as the renal function reduced. (See Table 12.)

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PARMODIA was orally administered at a dose of 0.1 mg twice daily in morning and evening for 12 weeks to patients with dyslipidemia accompanied by high TG value and renal impairment (severe renal impairment with eGFR <30 mL/min/1.73 m² or on dialysis and mild-to-moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m²). The ratio and 90% CI of geometric means of AUC_0-τ in patients with severe renal impairment compared to those with mild-to-moderate renal impairment (control group) at Week 12 were as presented in the following table. The level of exposure did not increase in patients with severe renal impairment. (See Table 13.)

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Pharmacokinetic parameters were presented in the following table. (See Table 14.)

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Toxicology: Preclinical safety data: In a carcinogenicity study in mice (≥0.075 mg/kg/day), an increase in the incidence of hepatocellular carcinomas and hepatocellular adenomas was observed. In a carcinogenicity study in rats (≥0.3 mg/kg/day in male rats and ≥1 mg/kg/day in female rats), an increase in the incidence of hepatocellular carcinomas, hepatocellular adenomas, pancreatic acinar cell carcinomas, pancreatic acinar cell adenomas, testicular Leydig cell adenomas, and thyroidal follicular epithelial cell adenomas was observed. All of these findings are considered to be specific to rodents.

PARMODIA is indicated as adjunctive therapy to diet to reduce TG in patients with dyslipidemia, including familial hyperlipidemia.

Patients should be on a lipid-lowering diet before the initiation of PARMODIA, and should continue dietary control during treatment. Serum lipid levels should be monitored periodically. If an adequate response has not been achieved, complementary or different therapeutic measures should be considered.
Posology: Adult: The usual adult dose is 0.1 mg twice daily. The dose may be individualized according to the patient's age and symptoms. The maximum dose is 0.2 mg twice daily.
Elderly: Since elderly patients often have reduced physiological function, PARMODIA should be carefully administered with close monitoring for signs of adverse reactions and clinical status of the patient.
Pediatric population: The safety of PARMODIA in low birth weight infants, newborns, infants, and children has not been established. No data are available.
Patients with renal impairment: PARMODIA should be used with caution in patients with renal impairment defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m². A lower starting dose or prolonged dosing intervals should be considered. The maximum dose is 0.2 mg daily (see PHARMACOLOGY: Pharmacokinetics under Actions).
Patients with hepatic impairment: PARMODIA should be used with caution in patients with hepatic disorder (Child-Pugh grade A cirrhosis, etc.) or a history of hepatic disorder. Dose reduction should be considered as necessary (see PHARMACOLOGY: Pharmacokinetics under Actions).
PARMODIA is contraindicated in patients with severe hepatic disorder, Child-Pugh grade B or C cirrhosis, or biliary obstruction (see Contraindications and PHARMACOLOGY: Pharmacokinetics under Actions).
Method of administration: PARMODIA should be taken orally twice daily in the morning and evening. PARMODIA can be taken without regard to meals.
The tablet can be divided into equal halves.

There is no specific treatment in the event of overdose. The patient should be treated symptomatically and supportive measures instituted as required. Since pemafibrate is highly bound to plasma proteins, hemodialysis is unlikely to be of benefit.

PARMODIA is contraindicated: In patients with known hypersensitivity to pemafibrate or to any of the excipients; In patients with severe hepatic disorder, Child-Pugh grade B or C cirrhosis, or biliary obstruction; In patients with cholelithiasis; In pregnant or possibly pregnant women; In patients receiving concomitant cyclosporine or rifampicin.

Muscle effects: Muscle toxicity, including very rare cases of rhabdomyolysis (with and without acute renal failure), has been reported with other lipid-lowering agents.
Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscle cramps and weakness and/or marked increases in CK (>5 times the upper limit of normal range [ULN]). In such cases, treatment with PARMODIA should be stopped.
An increased risk of rhabdomyolysis has been reported with other fibrates when co-administered with an HMG-CoA reductase inhibitor (statin), especially in cases of pre-existing muscular disease. PARMODIA should be used with caution in patients receiving statins.
Liver effects: In common with other lipid-lowering agents, PARMODIA should be used with caution in patients with hepatic disorder or those with a history of hepatic disorder. Abnormal liver function tests may occur. The plasma concentration of PARMODIA may increase in patients with hepatic disorder (Child-Pugh grade A cirrhosis, etc.) (see PHARMACOLOGY: Pharmacokinetics under Actions). Liver function should be monitored periodically during treatment.
Renal effects: In patients with renal impairment, renal function should be monitored periodically during treatment with PARMODIA. If eGFR is ≤30 mL/min/1.73 m², dose reduction or prolonged dosing intervals should be considered. The maximum daily dose is 0.2 mg daily.
Cholelithiasis: Since cholelithiasis has been reported, PARMODIA should be used with caution in patients with a history of cholelithiasis.
LDL-cholesterol: Since increases in LDL-cholesterol levels may occur, LDL-cholesterol levels should be monitored periodically during treatment.
Effects on ability to drive and use machines: No studies of the effects of PARMODIA on a patient's ability to drive, or to measure a reduced capacity to safely use machines have been performed.
Use in Children: The safety of PARMODIA in low birth weight infants, newborns, infants, and children has not been established. No data are available.

Pregnancy: PARMODIA is contraindicated in pregnant or possibly pregnant women (see Contraindications). The safety of PARMODIA has not been established for use during pregnancy.
Breast-feeding: The use of PARMODIA should be avoided in breast-feeding women. If the administration of PARMODIA is unavoidable, breast-feeding should be discontinued. An animal study (rat) has shown that PARMODIA is excreted in rat milk.
Fertility: No current data.

Summary of the safety profile: In clinical studies conducted by the time of approval in Japan, adverse reactions were observed in 206 of 1,418 patients (14.5%). The most commonly reported adverse reactions included cholelithiasis observed in 20 patients (1.4%), diabetes mellitus in 20 patients (1.4%), and blood creatine phosphokinase increased in 12 patients (0.8%).
Summary of adverse reactions: Adverse reactions and frequencies observed in clinical studies conducted by the time of approval in Japan are listed as follows. If any of the following adverse reactions or similar is observed, the patients should be treated appropriately according to the symptoms. (See Table 15.)

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PARMODIA is metabolized mainly by cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A. PARMODIA is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.
Contraindications for co-administration (Do not co-administer with the following drugs): See Table 16.

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Precautions for co-administration (PARMODIA should be administered with caution when co-administered with the following drugs): See Table 17.

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Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.
After the tablet is divided, store away from humidity, and use within 4 months.
Shelf-life: 3 years.

Dyslipidaemic Agents

C10AB12 - pemafibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.

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